[Federal Register: January 3, 1997 (Volume 62, Number 2)]
[Proposed Rules]               
[Page 551-583]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]


[[Page 551]]
Part IV

Department of Health and Human Services
Food and Drug Administration

21 CFR Part 589

Substances Prohibited From Use in Animal Food or Feed; Animal Proteins 
Prohibited in Ruminant Feed; Proposed Rule


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 589

[Docket No. 96N-0135]
RIN 0910-AA91

 
Substances Prohibited From Use in Animal Food or Feed; Animal 
Proteins Prohibited in Ruminant Feed

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend 
the regulations to provide that animal protein derived from ruminant 
and mink tissues is not generally recognized as safe (GRAS) for use in 
ruminant feed, and is a food additive subject to certain provisions of 
the Federal Food, Drug, and Cosmetic Act (the act). The proposed 
regulations would establish a flexible system of controls, designed to 
ensure that ruminant feed does not contain animal protein derived from 
ruminant and mink tissues in a manner that encourages innovation. FDA 
is also considering alternatives to this proposed ruminant-to-ruminant 
prohibition, and is requesting comment on the relative merits and 
disadvantages of the alternatives. FDA is proposing this action because 
the feeding to ruminants of protein derived from potentially 
transmissible spongiform encephalopathy (TSE)-infective tissues may 
cause TSE in animals. TSE's are progressively degenerative central 
nervous system (CNS) diseases of man and animal that are fatal. 
Epidemiologic evidence gathered in the United Kingdom (U.K.) suggests 
an association between an outbreak of a ruminant TSE, specifically 
bovine spongiform encephalopathy (BSE) and the feeding to cattle of 
protein derived from sheep infected with scrapie, another TSE. Also, 
scientists have postulated that there is an epidemiologic association 
between BSE and a form of human TSE, new variant Creutzfeldt-Jakob 
disease (nv-CJD) reported recently in England. BSE has not been 
diagnosed in the United States. However, this proposed rule is intended 
to prevent the establishment and amplification of BSE in cattle in the 
United States, and thereby minimize any risk which might be faced by 
animals and humans.

DATES: Written comments by February 18, 1997. FDA proposes that any 
final rule that may issue based on this proposal become effective 60 
days after the date of its publication in the Federal Register.
    Submit written comments on the collection of information 
requirements by February 18, 1997.

ADDRESSES: Submit written comments to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23, 
Rockville, MD 20857. Submit written comments on the information 
collection requirements to the Office of Information and Regulatory 
Affairs, Office of Management and Budget (OMB), New Executive Office 
Bldg., 725 17th St. NW., rm. 10235, Washington, DC 20503, ATTN: Desk 
Officer for FDA.

FOR FURTHER INFORMATION CONTACT:

Regarding Scientific and Industry Issues:
    George A. (Bert) Mitchell, Center for Veterinary Medicine (HFV-1), 
Food and Drug Administration, 7500 Standish Pl., Rockville, MD 20855, 
301-594-1761.
Regarding Procedural and Regulatory Issues:
    Richard E. Geyer, Center for Veterinary Medicine (HFV-201), Food 
and Drug Administration, 7500 Standish Pl., Rockville, MD 20855, 301-
594-1761.

SUPPLEMENTARY INFORMATION

Table of Contents

I. Summary
    A. Introduction
    B. GRAS Status of Ruminant and Mink Tissues
    C. The ``No Action'' Alternative
    D. The Basis for the Agency's Proposed Action
    1. General Discussion
    2. Analysis of Risk Factors
    a. The risk of BSE occurring in the United States
    b. The risk of amplification in the cattle population
    c. The risk of transmission to humans
    E. Enforcement Provisions
    F. Alternatives
II. Background
    A. TSE's
    1. Scrapie
    2. BSE
    3. Other Animal TSE's
    4. TSE's of Humans
    a. CJD
    b. nv-CJD
    c. Gertsmann-Strausller-Scheinker (GSS) syndrome
    d. Kuru
    e. Fatal familial insomnia (FFI)
    5. Etiology
    6. Pathogenesis
    7. Transmission
    8. Genetics
    9. Diagnostics
    10. Inactivation
    B. The Association Between Scrapie and BSE
    C. The Association Between Animal TSE's and Human TSE's
    D. Infectivity of Specific Tissues
    E. Potential Risk of TSE's to the United States
    1. Overview
    2. Comparison with the U.K. Conditions
    F. Historical Efforts to Control TSE's
    1. U.S. Actions
    a. FDA
    b. USDA
    c. Public Health Service
    i. CDC
    ii. National Institutes of Health (NIH)
    iii. Other actions
    2. International Actions
    a. United Kingdom
    b. WHO
    c. OIE
    d. European Community (EC)
    3. Voluntary Measures by the U.S. Animal Industries
    a. Voluntary ban on rendering adult sheep
    b. Voluntary ban on feeding ruminant proteins to ruminants
    G. Processing Animal Tissues for Feed Ingredients
    1. Current Rendering Practices
    2. Assay Methodologies for Proteins
III. Statutory Provisions Regarding Food Additives
    A. GRAS Determination
    B. Prior Sanction
    C. Food Additive Status of Ruminant Tissues
IV. Comments
V. Analysis of Alternatives
    A. Overview
    B. Ruminant-to-Ruminant Prohibition
    C. Partial Ruminant-to-Ruminant Prohibition
    D. Mammal-to-Ruminant Prohibition
    E. Prohibition of Materials from U.S. Species diagnosed with 
TSE's (sheep, goats, mink, deer, and elk)
    F. Sheep-Specified Offal Prohibition
    G. No Action
VI. Description of the Proposed Rule
    A. Introduction
    1. Regulatory Alternatives
    2. The Regulated Industry
    3. Enforcement Consideration
    B. Outline of the Proposed Regulation
VII. Specific Protein Sources
    A. Milk Proteins
    B. Gelatin Proteins
    C. Blood Meal Proteins
    D. Canine and Feline Derived Proteins
VIII. Environmental Impact
IX. Analysis of Impacts
    A. The Need for Regulation
    B. Benefits
    1. Methodology
    2. Reduced Risk to Public Health
    3. Reduced Risk of Direct Livestock Losses
    4. Costs of Future Regulation
    5. Reduced Risk of Losses in Domestic Sales and Exports
    6. Total Losses Averted
    7. Comparison of Alternatives
    C. Industry Impacts
    1. The Proposed Rule
    2. Partial Ruminant-to-Ruminant Prohibition
    3. Mammalian-to-Ruminant Prohibition
    4. Other Regulatory Alternatives

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    D. Small Business Impacts
    E. Unfunded Mandates Analysis
X. The Paperwork Reduction Act of 1995
XI. Federalism
XII. References
XIII. Request for Comments

I. Summary

A. Introduction

    In the Federal Register of May 14, 1996 (61 FR 24253), FDA 
published an advance notice of proposed rulemaking (ANPRM) that 
solicited information and public comment on the issue of using protein 
derived from ruminants (cattle, sheep, goats, deer, and elk) in 
ruminant feed. The agency requested information and comment on a number 
of issues because it was assessing whether to prohibit the use of 
ruminant protein in ruminant feed. BSE has not been identified in the 
United States. The agency issued an ANPRM because of its concern about 
the possible adverse effect on animal and human health if TSE's were to 
be spread through animal feed. After reviewing the ANPRM comments and 
other sources of information, the agency is proposing to prohibit the 
use of ruminant and mink animal tissue in the feed of ruminants. 
Because TSE has been found in U.S. mink, the agency is also including 
mink tissue in the proposed prohibition. The agency is also considering 
alternatives to the proposed ruminant-to-ruminant prohibition, 
including the alternative of taking no action.

B. GRAS Status of Ruminant and Mink Tissues

    The agency is proposing to declare that protein derived from tissue 
from ruminant animals and mink is not GRAS, by qualified experts, for 
use in ruminant feed and is therefore a ``food additive'' under the 
law. As a result, because neither a food additive regulation nor an 
exemption is in effect for ruminant and mink tissues intended for 
feeding to ruminants, such tissues would be deemed adulterated. Milk 
and gelatin proteins derived from ruminants, and blood from cattle are 
exempt from the proposed prohibition. The proposed rule does not apply 
to any nonprotein animal tissues such as tallow or other fats.
    Expert opinion that the tissues are GRAS would need to be supported 
by scientific literature, and other sources of data and information, 
establishing that there is a reasonable certainty that the material is 
not harmful under the intended conditions of use. Expert opinion would 
need to address topics such as whether it is reasonably certain that 
BSE does not, or will not, occur in the United States; whether it is 
reasonably certain that the BSE agent will not be transmitted through 
animal feed, i.e., that the processed tissues are not infected by the 
agent, are deactivated by the rendering process or are not transmitted 
orally; and whether it is reasonably certain that the agent will not be 
transmitted to humans through consumption of ruminant products. 
``General recognition'' cannot be based on an absence of studies that 
demonstrate that a substance is unsafe; there must be studies to 
establish that the substance is safe. Also, the burden of establishing 
that substance is GRAS is on the proponent of the substance. See U.S. 
v. An Article of Food * * * Co Co Rico, 752 F.2d 11 (1st Cir. 1985).
    Although the ANPRM did not specifically ask for opinion on the GRAS 
issue, a number of comments from scientific organizations and 
individual scientists strongly suggest that the comments would support 
the view that ruminant and mink tissue is not GRAS when fed to 
ruminants. Some of these comments submitted data and information that 
would support such opinions. Only a few comments included statements by 
scientists, or scientific organizations, to the contrary. Similarly, 
the opinions stated by scientists who spoke during a 1996 symposium on 
TSE's would, in general, support the ``nonGRAS'' position. The 
symposium, ``Tissue Distribution, Inactivation and Transmission of 
Transmissible Spongiform Encephalopathies,'' was cosponsored by FDA and 
USDA, and was held in Riverdale, MD, on May 13 and 14, 1996.
    FDA has searched for but has not found sufficient literature or 
other sources of data and information that would, on balance, support 
expert opinion that ruminant and mink protein is GRAS as a ruminant 
feed additive. Previous comments on the agency's proposal to prohibit 
the feeding of specified sheep and goat offal (59 FR 44584, August 29, 
1994) did not include either written GRAS opinions from qualified 
experts, or data and information that would support such opinions. The 
relevant data and information, and lack thereof, are discussed more 
fully in this section, and in section II. of this document. See Section 
III.A., of this document, for a further explanation of ``GRAS'' and 
``food additive.''

C. The ``No Action'' Alternative

    Even when, as in this case, FDA has taken steps leading to a 
tentative determination that a substance added to food is not GRAS, the 
agency is not required to issue a proposal declaring that the substance 
is not GRAS and is a food additive subject to section 409 of the act. 
Section 570.38 provides that the agency may take such an action. The 
agency considered the possibility of not issuing a proposal with regard 
to the feeding of ruminant and mink tissues to ruminants.
    The fact that the data and information do not document an immediate 
threat to the U.S. public health supports this ``no action'' 
alternative. Moreover, certain of the available data and information 
can be used to support the view that the threat, if any, is minimal.
    The evidence suggesting that there is no immediate threat is 
summarized as follows. First, BSE has not been detected in cattle in 
the United States despite an extensive surveillance effort that has 
been in place for several years. Restrictions on the importation of 
cattle, cattle products and feed ingredients from BSE-affected 
countries are in place to minimize the possibility of BSE entering into 
the United States. Surveillance, training of veterinary practitioners 
and diagnosticians, and other efforts are in place to detect any 
occurrence of BSE quickly, and to minimize its spread among the cattle 
population. No empirical scientific evidence is available to establish 
that BSE will occur from any of the possible sources, such as 
transmission from another U.S. species in which TSE's have been 
diagnosed; spontaneous occurrence in cattle; or importation of live 
animals or animal feed products carrying the BSE agent. For example, 
transmission between any two species is difficult to predict, based on 
available data, because of variability in species barriers (Ref. 1).
    Second, even if BSE did develop in the United States there is no 
conclusive scientific evidence that the disease would be spread through 
animal feed, the product that provides FDA's jurisdictional nexis. 
Although there is strong epidemiological evidence that the feeding of 
processed tissue from sheep containing scrapie to cattle caused the 
widespread BSE infections in the United Kingdom, many experts believe 
that the chances that the United States will have a BSE outbreak, 
similar to the epidemic that took place in the United Kingdom, are low. 
For example, most of the industry practices and other conditions 
believed to have been associated with the BSE epidemic in the United 
Kingdom do not exist in the United States. Further, the U.K. 
epidemiological evidence of transfer from sheep to cattle has not been 
confirmed by direct scientific data. This has caused some to question 
the assumption that the BSE originated from scrapie (Ref. 1). Further, 
some

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experimental information suggests that the TSE's in general are not 
readily transferred by the oral route. Experimentally, the oral route 
has been suggested to be the least efficient means of transmission for 
TSE's (Ref. 1).
    Third, the postulated connection between BSE and CJD has not been 
definitively established. Scientists have theorized an association 
between BSE and the recent appearance of nv-CJD in the United Kingdom. 
While the epidemiological association, both in time and geography, of 
these two diseases in the United Kingdom provides suggestive evidence 
of an association between the two, the available evidence does not 
establish causation. Although the BSE agent has been transmitted to 
laboratory animals, the species barrier between cattle and humans may 
be higher than between cattle and mice (Ref. 1). Epidemiological 
evidence linking BSE with classical CJD is even less supportive. 
Although CJD occurs in the United States, nv-CJD has not been reported 
in this country.
    The FDA's conclusion that there is no immediate threat to the 
public health in the United States is supported by a statement from the 
World Health Organization (WHO) that the ``risk, if any, of exposure to 
the BSE agent in countries other than the U.K. is considered lower than 
in the U.K.'' (Ref. 2). A number of comments to the ANPRM made a 
similar assertion, urging that FDA's regulatory decision be made on the 
basis of scientific information and contending that the available 
information did not support the contemplated action.

D. The Basis for the Agency's Proposed Action

1. General Discussion
    Even though there is no immediate threat to the U.S. public health 
and some information that indicates that a threat, if any, is minimal, 
after careful consideration the agency has tentatively concluded that 
regulatory action is necessary to protect animal and human health. The 
agency has reached that tentative conclusion because there is a growing 
body of data and information that affirmatively raises public health 
concerns.
    The data and information raise concern that BSE could occur in 
cattle in the United States; and that if BSE does appear in this 
country, the causative agent could be transmitted and amplified through 
the feeding of processed ruminant protein to cattle, and could result 
in an epidemic. The agency believes that the high cost, in animal and 
human lives and economics, that could result if this scenario should 
occur, justifies the preventive measure reflected by the proposed 
regulation. Although the agency expects some continued voluntary 
reduction in the feeding of ruminant and mink tissues to ruminants, the 
reduction is not expected to be extensive enough to obviate the need 
for mandatory preventive measures.
    Statements from several prominent public and animal health 
organizations support this proposal to regulate the feeding of ruminant 
tissues to ruminant animals. For example, the Centers for Disease 
Control and Prevention (CDC) has urged the agency to adopt a ruminant-
to-ruminant feed prohibition (Ref. 3), and USDA has recommended the 
same action. Although WHO considers the risk in countries such as the 
United States to be minimal, that organization has nevertheless called 
on all countries to prohibit the use of ruminant tissues in ruminant 
feed (Ref. 2).
    A number of comments to the ANPRM, including comments by several 
consumer groups, supported regulatory action by FDA. The Pharmaceutical 
Research and Manufacturers of America urged FDA to take all necessary 
steps to prevent an outbreak of BSE, and to prevent the potential 
spread of BSE should a case occur in the United States. One 
pharmaceutical firm emphasized the importance of acknowledging public 
perception, stating that a ruminant-to-ruminant prohibition would 
``significantly decrease the concern regarding this perceived risk.'' 
Another pharmaceutical firm characterized the risk as ``small but 
real.'' A group of livestock producers, veterinary associations and 
scientific organizations cited the WHO recommendations to support their 
call for a voluntary ruminant-to-ruminant prohibition. The group stated 
that such a prohibition would ``eliminate any risk, no matter how 
remote [and would] totally prevent BSE from ever occurring in the 
United States.''
    The agency is concerned about the public health issues raised but 
not resolved by the available scientific information. The fact that the 
causative agent or agents for TSE's have not been clearly identified, 
and their transmissibility has not been fully characterized, adds to 
the concern. However, certain information that is well documented 
supports the agency's decision as well. TSE's are 100-percent fatal 
diseases that have been diagnosed in humans and a number of animal 
species. The diseases are progressively degenerative CNS diseases that 
are characterized by a relatively short clinical course of neurological 
signs. TSE's have a prolonged incubation period, i.e., 2 to 8 years in 
animals, and scientific evidence supports the view that TSE's can be 
transmitted in the preclinical stage. There is no practical method to 
detect the presence of TSE's during the preclinical stage.
2. Analysis of Risk Factors
    This section describes the evidence that supports the agency's 
tentative conclusion. The evidence relates to the risks that BSE could 
occur in cattle in the United States; that the BSE agent or other TSE 
agents could be amplified in the cattle population by the feeding of 
ruminant and mink tissues to cattle; and that the agent could 
potentially be transmitted to humans.
    a. The risk of BSE occurring in the United States. BSE has not been 
diagnosed in the United States. FDA does not have evidence to support 
the theory that BSE already exists, undiagnosed, in this country. 
However, the agency does find plausible the arguments of the theory 
that BSE could develop in the United States from three possible 
sources: Transmission of TSE's from other susceptible species, 
spontaneous occurrence, and importation in live animals or animal 
products.
    The evidence concerning transmission from other species is 
summarized as follows. TSE's other than BSE have been diagnosed in 
animals in the United States. These include scrapie in sheep and goats, 
transmissible mink encephalopathy (TME), and chronic wasting disease 
(CWD) in deer and elk. Feline spongiform encephalopathy (FSE) has been 
diagnosed in cats in other countries. In general, the TSE's have been 
shown to be naturally transmissible within species and are believed by 
some scientists to be naturally transmissible (as distinguished from 
experimentally transmissible), at least to a limited extent, between 
species. Consumption of meat and bone meal (the predominant animal 
tissue-containing product fed to animals) which was produced under 
conditions similar to the meat and bone meal which was implicated in 
the U.K. BSE epidemic, as well as the feeding of raw bovine tissue, 
also appeared to cause TSE in exotic cats and various zoo animals. This 
implies that the species barrier for BSE may be uncharacteristically 
low. (See e.g., Refs. 3 and 4). In addition to the epidemiological 
evidence relating to TSE transmission from sheep to cattle in the 
United Kingdom, there is limited experimental evidence of transmission

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of the BSE agent from cattle to sheep. Many laboratory animal species 
have also been experimentally infected following the administration of 
tissues from animals with TSE disease.
    There is some evidence to support the theory that BSE can occur 
spontaneously in cattle. The leading theory as to the causative agent, 
e.g., infectious protein or prion, inherently suggests that the BSE 
could occur spontaneously. Additional support arises from the fact that 
85 percent of CJD cases are sporadic, and have no familial or 
identifiable link as to their cause. Recent surveillance information 
from Northern Ireland and Switzerland also supports the spontaneous 
theory. In these countries, BSE has occurred in cases in which no 
exposure to rendered protein can be found, and there is no evidence of 
BSE in the parental stock or herd mates of affected animals (Ref. 5).
    As described more fully in section II.F.1.b. of this document, 
USDA-APHIS has implemented import restrictions on live animals and 
animal products from BSE-affected countries. As a result of the 
restrictions, the potential risk of BSE occurring in this country as a 
result of exposure from imported cattle and imported animal protein 
products appears to be small (Ref. 6). However, the risk from foreign 
sources of BSE introduction into the United States cannot be dismissed 
entirely because the USDA import restrictions are unlikely to be 100 
percent effective even though no cases of BSE have been diagnosed to 
date in the United States. The USDA regulations are intended to reduce 
or control risk, not completely eliminate it. See e.g., 56 FR 63866, 
December 6, 1991.
    b. The risk of amplification in the cattle population. Research has 
shown that various animal tissues can transmit BSE infectivity. There 
is also evidence supporting the view that the agent could be 
transmitted orally (e.g., through animal feed). Although some 
experimental evidence suggests that the TSE's in general are more 
readily transmitted by means other that the oral route, research also 
suggests that the BSE agent is more susceptible to oral transmission. 
In most cases (e.g., the U.K. epidemic) the natural route of exposure 
to TSE's including BSE is suspected to be oral. This belief is 
supported by the dramatic decline in BSE cases in the United Kingdom 
following implementation of the ruminant-to-ruminant feeding 
prohibition. In the United Kingdom, where more than 160,000 cases of 
BSE have been diagnosed, a 1988 ban on the feeding of ruminant-derived 
protein supplements to other ruminants was associated with a steady 
decrease in the disease incidence starting in 1993. The 5-year period 
between the initiation of the ruminant-to-ruminant ban and the decline 
in the incidence of BSE is consistent with the known incubation period 
in cattle of 2 to 8 years. Further, preliminary experimental data show 
that the BSE agent can be transmitted orally to cattle through feeding 
of material from an infected cow (Ref. 3). Thus, there is a chance that 
BSE could be spread in animal feed if it developed in the U.S. cattle 
population, whether spontaneously, from another species or by some 
other means.
    The greatest risk factor for cattle may not be the single 
occurrence of a BSE case. Instead, the greatest risk may arise from the 
potential, given the prolonged incubation period, for unrecognized 
amplification of BSE in the cattle population, resulting in a potential 
for greater animal exposure. The possibility of risk from recycling 
ruminant tissues is enhanced by the fact that current rendering methods 
have not been shown, and are not expected, to completely deactivate the 
BSE agent, and that practical tests are not available for detecting 
either the BSE agent in rendered material or the presence of ruminant 
material in feed.
    The preliminary experimental cow-to-cow TSE transmission data 
previously described occurred with as little as a single dose (one-time 
exposure) of 1 gram of brain material from the infected cow, indicating 
a low transmitting dose. This means, among other things, that FDA 
cannot determine the level of feed ingredients from animals tissues, if 
any, that is considered safe in ruminants.
    c. The risk of transmission of humans. Finally, there exists the 
theoretical possibility of the transmission of a TSE in animals, such 
as BSE, to humans. CDC agrees that the link between BSE, and TSE's in 
humans, has not been fully demonstrated. Some of the ANPRM comments 
agreed. For example, one pharmaceutical firm stated that the evidence 
is not entirely conclusive. Nevertheless, a body of epidemiological and 
experimental evidence is developing to support the postulated 
association between BSE and nv-CJD. This and other scientific evidence 
developed more fully in section II leads the agency to propose for 
comment the prudent risk reduction regulatory action that is 
incorporated in the proposed rule.

E. Enforcement Provisions

    The agency is issuing this proposed rule within the context of 
comprehensive government-wide efforts to minimize the risks previously 
described, and within the statutory authority provided to the agency. 
The proposed rule has two major components. First, the agency proposes 
to prohibit feeding animal materials derived from ruminant and mink 
tissues to ruminants, in the absence of a food additive regulation or 
investigational exemption. Thus, the prohibition would ensure that 
tissues which could contribute to a TSE epidemic by spreading the 
causative agent rapidly would not be allowed in ruminant feed.
    The second component of the rule provides for a system of controls 
to ensure that the proposed rule would achieve its intended purpose. 
These provisions are necessary because limited controls are in place, 
or available, to prevent the spread of BSE through animal feed in the 
United States, should BSE occur. The proposed regulation places two 
general requirements on persons that manufacture, blend, process and 
distribute animal protein products, and feeds made from such products. 
The first requirement is to place cautionary labeling on the protein 
and feed products. The second is to provide FDA with access to sales 
and purchase invoices, for compliance purposes.
    Firms that handle animal protein products from both ruminant and 
nonruminant sources, and that intend to keep the two kinds of products 
separate, would have certain additional requirements. These 
requirements would relate to the need for separate facilities or 
cleanout procedures; the need for standard operating procedures 
(SOP's); and in the case of renderers, their source of nonruminant 
material. Similar requirements would be placed on firms that handle 
animal feed containing animal protein products from both ruminant and 
nonruminant sources, and intend to keep the two kinds of feed separate. 
Requirements would be greater for the firms that intend to separate the 
animal protein products and feeds, because of the greater risk these 
operations would present for the possibility that ruminant protein 
might be fed, inadvertently, to ruminants.
    However, the regulatory system would be flexible, allowing the 
regulated firms to innovate and choose the most cost-effective means of 
compliance. For example, some or all of the regulatory requirements 
previously described would not apply if any of the following 
innovations were developed and validated by FDA: Processing methods 
that deactivate the agent that causes BSE; test methods to detect the 
presence of the agent; or methods of marking or otherwise identifying 
the

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material that contains ruminant protein. Further, the agency will 
consider modifying or revoking any final rule that is published 
prohibiting the use of ruminant and mink tissues in ruminant feed, if 
scientific and technical advances permit even greater flexibility than 
that offered in the proposed regulation. Conversely, the diagnosis of 
one or more cases of BSE in the United States, or new scientific 
findings, could lead to stricter regulatory requirements.

F. Alternatives

    The agency is soliciting comments on several alternative means of 
minimizing the risk of transmitting TSE's in ruminant feed, in addition 
to the proposed ruminant-to-ruminant prohibition. These alternatives 
include:
    (1) A partial ruminant-to-ruminant prohibition which would exclude 
all ruminant and mink tissues from ruminant feed except those bovine 
tissues that have not been found to present a risk of transmitting 
spongiform encephalopathy. Possible exclusions include slaughter 
byproducts from cattle that have been inspected and passed in inspected 
slaughter facilities, except tissues that have been shown through 
experimental trials and bioassays to transmit spongiform 
encephalopathy. Examples of the latter might include the brain, eyes, 
spinal cord and distal ileum. The agency solicits comments on the scope 
of this alternative;
    (2) A prohibition on the feeding of all mammalian tissues to 
ruminants;
    (3) A prohibition on the feeding of rendered material from those 
animal species in which TSE's have been diagnosed in the United States 
(sheep, goats, mink, elk, and deer);
    (4) A prohibition on the feeding of specified offal from adult 
sheep and goats as proposed in 1994;
    (5) Other alternative approaches that meet the agency's regulatory 
objectives and that might be suggested in comments to the proposed 
rule. The agency may in any final rule issued adopt such alternative 
approaches. Such alternatives may be more or less stringent than this 
proposal or may be a combination of provisions from this proposal and 
other alternatives. For example, one such option might be a proposal to 
exclude from the scope of any regulation certain facilities that apply 
specified risk-reduction measures in addition to, or in place of, those 
included in the regulation FDA is proposing in this publication. 
Therefore, the agency specifically requests comments on other 
approaches that would achieve the agency's regulatory objectives. Any 
proposed alternative approaches should be explained in detail, and 
their justification should be well documented. To the extent possible, 
please include information on costs and benefits of the proposals; and
    (6) The ``no action'' alternative as it relates to this proposed 
rule. Again, detailed explanation and well-documented justification 
should be presented.
    The agency's views on the advantages and disadvantages of these 
options appears in section V of this document. The agency invites 
comments on the relative merits and disadvantages of all these 
alternative concepts.
    FDA has estimated that the annualized costs of the proposal, 
comprised of both the direct compliance costs and various indirect 
gains and losses, would range from $21.4 to $48.2 million. The agency 
also estimated that the annualized costs could range from $45.0 to 
$56.5 million for the mammalian-to-ruminant option; from $28.5 to $37.3 
million for the partial ruminant-to-ruminant option; and would total 
less than $10 million for each of the remaining options. On the other 
hand, if the agency chooses the ``no action'' option and a BSE epidemic 
occurs, the above costs could be expanded by a great magnitude.
    Because the body of scientific research related to TSE's is growing 
rapidly, the agency will place in the Docket copies of relevant 
scientific literature published after the agency completes work on this 
proposal, and before the agency completes work on any final regulation. 
The agency will add to the Docket, as appropriate, a brief statement of 
its assessment of the significance of the literature, and will invite 
comments. However, substantive changes from the proposed rule would be 
made in accordance with the discussions in the preceding paragraphs and 
the Administrative Procedure Act.

II. Background

A. TSE's

1. Scrapie
    Scrapie is a slowly progressive, transmissible disease of the CNS 
in sheep and goats. Scrapie is characterized by a prolonged incubation 
period averaging 2 years, followed by a clinical course of 2 to 6 
months when the animal exhibits sensory and motor malfunction, 
hyperexcitability, and death. The agent presumably moves from infected 
to susceptible animals by direct or indirect contact and enters through 
the gastrointestinal tract. Consequently, its spread appears to be both 
vertical (mother to offspring in utero) (Ref. 7) and horizontal (direct 
contact) between sheep (Ref. 8). Early signs of scrapie include subtle 
changes in behavior or temperament which may be followed by scratching 
and rubbing against fixed objects. Other signs include loss of 
coordination, weight loss despite a good appetite, biting of feet and 
limbs, tremor around head and neck, and unusual walking habits (Ref. 
9).
    The scrapie agent is found in lymphatic tissue (spleen, thymus, 
tonsil, and lymph nodes) in sheep with preclinical infections; however, 
in clinically affected sheep, the agent is identified in the 
intestines, nervous tissues (brain and spinal cord), and lymphatic 
tissues as determined by experimental infectivity studies in a 
susceptible animal model (Ref. 8). The brain has been demonstrated to 
have the highest level of infectivity of all tissues (Ref. 10).
    Scrapie is known to have existed in Britain, Ireland, France, and 
Germany for over 200 years. It has been observed in the United States 
and Canada for about 50 years. The first case of scrapie in the United 
States was diagnosed in Michigan in 1947. From 1947 through January 
1993, approximately 653 flocks have been diagnosed with scrapie (Ref. 
11). At the present time, there are 67 known scrapie-infected flocks 
(flocks with sheep diagnosed with scrapie), and there are 8 known 
scrapie-source flocks (flocks to which scrapie-infected sheep were 
traced) (Ref. 12). In the absence of an antemortem diagnostic test, it 
is not possible to establish with absolute certainty that a flock is 
free of scrapie. Moreover, lack of reporting, the long incubation 
period, and open range husbandry practices in the western United States 
make it difficult to detect classical clinical signs and completely 
monitor scrapie in the United States.
2. BSE
    BSE is a transmissible, slowly progressive, degenerative disease of 
the CNS of adult cattle. This disease has a prolonged incubation period 
in cattle following oral exposure (2 to 8 years) and is always fatal. 
BSE is characterized by abnormalities of behavior, sensation, posture, 
and gait. These signs are similar to those seen in sheep that are 
infected with scrapie. BSE is associated with spongiform lesions in the 
gray matter neuropil of the brainstem and neuronal vacuolization (Ref. 
13). The clinical signs usually begin with changes in animal behavior, 
and may include separation from the rest of the herd while at pasture, 
disorientation, or excessive licking of the nose or flanks (Ref. 14). 
The most common history given by the herdsman was nervousness

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or altered behavior or temperament, weakness associated with pelvic 
limb ataxia, paresis, and loss of body weight (Ref. 15). In some 
animals there are few gross pathological changes at necropsy associated 
with BSE other than the loss of body weight. However, postmortem 
histopathology of BSE distinguish it from other neurological disorders 
(Refs. 16 and 17). Neither vertical nor horizontal transmission has 
been documented for BSE.
    BSE was first recognized as a new cattle disease by researchers at 
the Central Veterinary Laboratory of the British Ministry of 
Agriculture, Fisheries, and Foods at Weybridge, England in November 
1986. As of November 15, 1996, BSE had been diagnosed in Great Britain 
in more than 165,000 head of cattle from more than 31,000 herds. Cases 
have been confirmed in 59.2 percent of the dairy herds and 15.3 percent 
of the beef herds (Ref. 18). The BSE epidemic curve for Great Britain 
peaked in January 1993 and is decreasing steadily, concomitantly with 
changes in rendering and feeding practices. BSE has also been reported 
in native cattle of Northern Ireland, Guernsey, Jersey, Isle of Man, 
the Republic of Ireland, Switzerland, France, and Portugal. BSE has 
been confirmed in cattle exported from Great Britain to Oman, the 
Falkland Islands, Germany, Denmark, Canada, and Italy.
    There have been no cases of BSE in cattle in the United States. 
There has been one case of BSE in a cow imported into Canada from Great 
Britain. That cow was destroyed, along with its herdmates and other 
nearby cattle considered by animal health authorities in Canada to have 
possibly been exposed to the cow with BSE (Ref. 19).
3. Other Animal TSE's
    Other animals have TSE's with typical characteristics of long 
incubation, neurological degeneration, and a 100-percent death rate. 
These animals include: Mink, elk and deer, zoo ruminants, and exotic 
and domestic cats.
    TME is a mink disease with clinical signs and brain lesions similar 
to those of sheep infected with scrapie. TME is a rare disease in the 
United States. Since the disease was first recognized in 1947, in 
Wisconsin, four additional outbreaks have occurred in the United 
States. The last outbreak occurred in 1985 and was limited to a single 
mink ranch in Wisconsin (Ref. 20).
    CWD of deer and elk is characterized by emaciation, changes in 
behavior and excessive salivation, polydipsia, and polyuria. The 
clinical course is from several weeks to 8 months, and the disease is 
invariably fatal (Ref. 20). From 1967 to 1979, CWD was observed in 53 
captive mule deer in Colorado and Wyoming. Clinical signs were seen in 
adult deer and included behavioral alterations, progressive weight loss 
and death in 2 weeks to 8 months. Consistent histopathologic change was 
limited to the CNS and characterized by widespread spongiform 
transformation of the neuropil. The disease is a specific, 
spontaneously occurring form of spongiform encephalopathy (Ref. 21). 
Topographic distribution and lesion severity were most similar to those 
of scrapie and BSE. The duration of the clinical disease did not 
significantly influence lesion distribution or severity in either 
species (Ref. 22).
    Scrapie-like encephalopathies have been described in certain zoo 
ruminants, i.e., a nyala, an Arabian oryx, and a greater kudu. Clinical 
signs included ataxia and loss of coordination with a short, 
progressive clinical course. Histopathological examination of the 
brains revealed spongiform encephalopathy characteristic of that 
observed in scrapie and BSE (Refs. 23, 24, and 25). Strain typing of 
the agent suggests that all of the cases are directly related to BSE.
    Seventy domestic cats in the United Kingdom have developed FSE, a 
spongiform encephalopathy that was never previously reported. The cats 
all had progressive, neurological disease involving locomotor 
disturbances, abnormal behavior and, in most cases, altered sensory 
responses. Histopathological examination of the central nervous system 
revealed changes pathognomonic of spongiform encephalopathy; this 
included widespread vacuolization of the gray matter neuropil and 
neuronal perikarya (Refs. 26 and 27). Infective tissue from several of 
these cases, when injected into mice, resulted in brain lesions with a 
distribution and morphology that is undistinguishable from the lesions 
produced by BSE infective tissue injected into mice.
4. TSE's of Humans
    The TSE's of humans are divided into specific clinical types, which 
may appear similar histopathologically but are either transmitted 
differently or demonstrate different patterns of distribution and 
prevalence.
    a. CJD. CJD was first described in 1920 and 1921 when it was known 
as ``spastic pseudosclerosis'' or ``subacute spongiform 
encephalopathy'' (Ref. 28). The illness exists throughout the world and 
is claimed to have a similar prevalence in each of the countries tested 
with an annual incidence of approximately one case per million of the 
population. Autopsies are sometimes not performed on persons who may 
have died of CJD and many older people dying of a dementing illness do 
not have autopsies performed. There is an increased incidence among 
Libyan Jews (26 cases per million) and spatial or temporal clusters in 
areas of Slovakia, Hungary, England, the United States, and Chile. The 
average age of a typical CJD victim is 56 years of age, and only a few 
cases involving persons between 4 and 29 years have been reported prior 
to 1993. Between 4 and 15 percent of cases have a familial connection 
with other cases. There is a slightly higher incidence of CJD in women 
compared to men. Clinical prodromal symptoms start with changes in 
sleeping and eating patterns, and often include confusion, 
inappropriate behavior, vague visual complaints and/or ataxia. Those 
symptoms progress over a few weeks to a clearly neurological syndrome. 
A rapid onset of neurological symptoms appears in 20 percent of cases, 
most commonly myoclonic jerks and dementia with loss of higher brain 
function and behavioral abnormalities. The disease progresses with 
continued deterioration in cerebral and cerebellar function, and the 
onset of seizures. Ninety percent of the cases end in death within 1 
year of onset. Diagnosis is by clinical assessment of patients and by 
examination of electroencephalogram patterns. Post mortem diagnosis is 
currently carried out by histological examination of cerebral tissue 
under the light microscope, although this is not always reliable. 
Research techniques that have been used to demonstrate CJD (and other 
TSE's) include electron microscopic examination of brain tissue 
extracts for scrapie-associated fibrils (SAF), immuno-staining of the 
tissue for prion-protein (PrP) antigens, western blotting of extracted 
PrP antigens and the intracerebral injection of tissue suspensions into 
test animals.
    In some patients, the source of CJD has been claimed to be an 
infection transferred from other patients with the condition. For 
example, in one case, cerebral electrodes that had been sterilized with 
alcohol and formalin vapor after use in a patient with CJD, were used 
in the brains of two young epileptic patients, both of whom contracted 
CJD after a short incubation. The transfer of CJD by corneal transplant 
in 1 patient, by cadaveric dura mater grafts in several patients and by 
pituitary-derived human growth hormone injections in over 80 patients 
has also been reported.

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    Only the medical procedures described previously have been 
conclusively linked to transmission. The transmission of the disease 
from animal sources has been suggested; see further discussion in 
section II.C. of this document.
    b. nv-CJD. A previously undetected new variant of CJD (nv-CJD) was 
reported by British scientists at a meeting of international experts 
convened by WHO on April 2 and 3, 1996 (Ref. 29), and published 3 days 
later (Ref. 30).
    The major evidence for the existence of nv-CJD is the recognition 
of a new neuropathologic profile and the unusually young ages of 10 
U.K. patients. Although all the cases had evidence of the pathognomonic 
spongiform changes characteristic of classic CJD, and therefore were 
appropriately classified as a form of CJD, the clinical course of the 
disease was atypical of classic CJD. The most striking and consistent 
neuropathologic feature of nv-CJD was the formation of amyloid plaques 
surrounded by halos of spongiform change. Plaques were extensively 
distributed throughout the cerebrum and cerebellum. Many of these 
plaques resembled those in kuru and were visible when examined by 
routine staining methods.
    The temporal cluster of cases of nv-CJD in young patients (three 
were teenagers, five were in their twenties, and two were in their 
thirties at onset of disease) is highly unusual. Five of the eight 
deceased patients died before 30 years of age. (The expected annual 
mortality rate for CJD in persons under 30 years of age is less than 
five per billion.) The characteristic clinical features of the nv-CJD 
cases were: (1) A psychiatric presentation, (2) onset of a progressive 
cerebellum syndrome with ataxia within weeks or months of the initial 
presentation, (3) memory impairment with dementia in the late stages, 
(4) myoclonus, and (5) the absence of electroencephalographic changes 
typical of classic CJD.
    Review of the patients' medical histories and consideration of 
various risk factors for CJD yielded no adequate clues as to the cause 
of this disease. The PrP genotype was determined for eight cases. The 
researchers noted that all genotypes were methionine homozygotes at 
codon 129 of the PrP gene. The research did not identify any of the 
known mutations associated with the inherited forms of CJD (Ref. 30).
    Although scientists have stated that exposure to the BSE agent 
prior to the U.K. bans described in section II.F. of this document is 
the most plausible explanation for these findings, no clear 
epidemiologic link to BSE was identified. (See further discussion in 
section II.C. of this document.) Another potential explanation is 
exposure to TSE agents from animals other than cattle. Because the 
United Kingdom reinstituted epidemiological surveillance for CJD in 
1990, increased surveillance is still another potential reason for the 
identification of this cluster of 10 cases of nv-CJD.
    c. Gertsmann-Strausller-Scheinker (GSS) syndrome. GSS syndrome is 
an autosomal dominant condition in about 50 percent of siblings of 
reference cases (Ref. 28). The disease is similar to CJD except that it 
has a more extended onset and duration, a tendency towards cerebellar 
ataxia as the initial predominant neurological sign, and a large number 
of amyloid plaques present among the spongiform encephalopathic changes 
of the brain. The extensive distribution of amyloid plaques in the 
patient's brain is an observation shared by GSS syndrome and v-CJD. It 
has been transmitted to monkeys and rodents by intracerebral 
inoculation.
    d. Kuru. Kuru is a condition of the Fore people of the Okapa 
district of the Eastern Highland in Papua New Guinea, in which a 
practice of ritual cannibalism of fellow tribesmen took place until 
approximately 1956 (Ref. 28). This TSE disease, which affected mainly 
adult women and children of both sexes, caused an annual disease 
specific mortality of approximately 3 percent. Most deaths of women in 
the tribe occurred through this disease. Some men who died from this 
disease were thought to have contracted it when they were young. Kuru 
may be transmitted by eating infected tissue or through open wounds. 
The brains of dead tribal members were eaten by women and children and 
the muscle tissue by men. The cohort of children born since 1957 have 
not suffered from kuru at all.
    Clinically the disease causes a progressive cerebellar ataxia, 
uncoordinated movements, neurological weakness, palsies, and decay in 
brain stem function. Most patients dying of kuru are not demented, a 
major clinical difference between kuru and CJD.
    e. Fatal familial insomnia (FFI). FFI is another inherited TSE-
linked disease (Ref. 31). FFI is characterized clinically by 
untreatable progressive insomnia, dysautonomia, and motor dysfunctions. 
The disease often starts between 35 and 60 years of age and leads to 
death within 7 to 32 months. FFI is characterized pathologically by 
atrophy, neuronal loss, and gliosis in the anterior and dorsomedial 
nuclei of the thalamus (Ref. 32). FFI has been successfully transmitted 
to mice (Ref. 33), but not to primates.
5. Etiology
    The cause of TSE's is controversial. The TSE agent: (1) Is 
presumably smaller than most viral particles and is highly resistant to 
heat, ultraviolet light, ionizing radiation, and common disinfectants 
that normally inactivate viruses or bacteria; (2) causes little 
detectable immune or inflammatory response in the host; and (3) has not 
been observed microscopically.
    Resistance of the TSE agent to physical and chemical methods that 
destroy nucleic acid have essentially ruled out conventional 
microbiological agents as the cause. Currently, the infectious protein 
or prion theory is favored. Other proposed causes are an unconventional 
virus, consisting of virus-coded protein and virus-specific nucleic 
acid with unconventional properties, and a ``virino'' consisting of a 
core of nontranslated nucleic acid associated with host cell proteins 
(Ref. 34). Proposed causes of TSE's with less supporting evidence are: 
(1) Retroviruses (Ref. 35), (2) a spiroplasma (Refs. 36 and 37), (3) 
organophosphates (Ref. 38), and (4) peptide hormones (Ref. 39).
    The prion theory suggests that the causative agent is a normal host 
protein (PrP or PrP-C) that is posttranslationally transformed into the 
causative agent or PrP-Sc. Transformation of the PrP can occur from 
rare somatic mutation of the prion gene, spontaneously or from contact 
with extraneous PrP-Sc. The spread of BSE in the United Kingdom is 
postulated to have occurred through the feeding of ruminant protein 
that contained the PrP-Sc protein and thus follows the portion of the 
theory that involves contact with extraneous PrP-Sc. This explanation 
requires that one accept that abnormal prion protein from sheep crossed 
the species barrier and resulted in BSE in cattle. An alternate 
explanation is that a spontaneous mutation or transformation or other 
nonorally induced event, occurred and resulted in undetected disease in 
a bovine. These explanations are not mutually exclusive and it is 
possible that both occurred.
    Recent surveillance information from Northern Ireland and 
Switzerland tend to support the spontaneous mutation as a method by 
which BSE can occur. Northern Ireland has had more than 10 cows produce 
offspring, after the feeding ban, that developed BSE. Thus, 10+ cases 
are theorized to be spontaneous because there is no evidence of feeding 
meat and bone meal to the offspring and the dams are alive

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and show no signs of BSE (Ref. 5). Switzerland, which has one of the 
most aggressive BSE investigational surveillance of any European Union 
(EU) country, has reported 205 cases of BSE. Some of these cases are in 
animals that were fed only grass and hay (Ref. 5). Regardless of how 
the initial cases occurred, however, the resulting unrecognized disease 
was amplified by the feeding of ruminant protein to ruminants.
    Additional support for the feasibility of the TSE spontaneous 
mutation explanation is the fact that 85 percent of all CJD cases are 
sporadic and have no familial or identifiable link as to their cause. 
It is these cases that give rise to the very stable, 1 in a million per 
year, world wide incidence of the disease. DeArmond and Prusiner (Ref. 
40), and Lansbury and Caughey (Ref. 41) have postulated that a 
noninduced somatic cell mutation or the spontaneous conversion of PrP-C 
into PrP-Sc are plausible explanations for the sporadic cases of CJD. 
DeArmond and Prusiner theorized that the 1 in a million

    * * * may represent the combined probabilities that a mutation 
occurs in the PRNP gene, the probability that the mutation leads to 
the synthesis of the PrP-cjd (the abnormal protein), and the 
probability that the resultant PrP-cjd targets other neurons for the 
synthesis of more PrP-cjd at a rate fast enough to cause clinical 
disease in the patient's lifetime.

    The etiology of human and animal TSE's are similar. Therefore the 
spontaneous mutation explanation cannot be dismissed with regard to 
BSE.
6. Pathogenesis
    Following oral exposure of goats or sheep to the scrapie agent, the 
agent first accumulates in gut-associated lymphoid organs (tonsils and 
Peyers patches of terminal ileum) and later in other lymphoid organs, 
such as spleen and thymus, and finally in the spinal cord and brain 
(Ref. 8).
    Likewise, in mice inoculated intra-peritoneally with the CJD agent, 
the agent localizes first in Peyer's patches and spleen, followed by 
the central nervous system (Ref. 42). The agent may enter the body 
through macrophages in the tonsils and domes over Peyer's patches in 
the intestine (distal ileum). The proposed routes of spread from the 
point of entry to other tissues and central nervous system are blood 
stream or nerve trunks. In experimentally inoculated animals, spread 
from the inoculation site in the eye of monkeys and peritoneum of mice 
has been shown to be by optic and splanchnic nerves respectively (Ref. 
43).
    Other investigators have demonstrated transient infectivity in the 
blood of experimentally infected laboratory animals, and naturally 
occurring infections of humans and mink, causing speculation that the 
agent is carried in the blood (Refs. 45 to 49). With one exception in 
serum (Ref. 50), all attempts to isolate TSE agents from the blood or 
milk of sheep or cattle have failed (Refs. 51 to 54). When TSE agents 
are injected intravenously into mice, the rate of clearance from the 
blood is extremely rapid (Ref. 55). In natural cases of BSE, 
infectivity has been found only in the brain, spinal cord, and eye; in 
experimental cases the agent has also been identified in the ileum 
(Ref. 56).
    The question of disease mechanism remains open. Candidate 
mechanisms are the storage or accumulation of a large amount of 
abnormal PrP in the brain (Refs. 57 to 60), or insufficient amounts of 
normal PrP.
7. Transmission
    There is little information about the natural transmission of TSE's 
of animals. In most cases the natural route of exposure to the TSE 
agent is suspected to be oral, although genetic disposition is known to 
play a role in sheep scrapie (Ref. 61). Investigators have suspected 
transmission of scrapie in sheep and goats by ingestion of placenta and 
have been successful in experimentally transmitting scrapie by feeding 
placenta to sheep (Ref. 62); however, genotyping of the PrP gene was 
not conducted.
    In 1993, a study by Foster, et al., (Ref. 63) using a line of sheep 
in which natural scrapie does not occur demonstrated that sheep can be 
experimentally infected with BSE by intracerebral or oral 
administration. The intracerebral challenge resulted in five of six 
sheep developing the disease. The oral challenge resulted in one of six 
sheep developing the disease. Brain and spleen were recovered from the 
orally infected sheep and from one of the intracerebrally injected 
sheep. Goldmann, et al. (Ref. 64), confirmed that both sheep had the 
same PrP genotype. In 1996, Foster, et al. (Ref. 65) reported the 
results of injecting homogenized tissue harvested from these infected 
animals into a panel of mice. Transmission from the brains and spleen 
of both sheep gave incubation periods and pathology in mice similar to 
those seen in direct BSE transmissions from cattle to mice. Foster's 
work supports the position that BSE can cross species barriers by the 
oral route and that, when judged by the mouse bioassay, the disease 
manifested in sheep retains the incubation time and pathology 
characteristic of BSE rather than scrapie. However, the manifestation 
of BSE in the sheep is histopathologically and clinically 
indistinguishable from natural scrapie.
    Information regarding the interaction of the TSE agents and the 
environment is limited. In 1964, Gordon reported the transmission of 
scrapie among bands of unrelated sheep on pasture. The mode of 
transmission was unknown (Ref. 66). In an effort to eradicate scrapie 
from Iceland a large area was depopulated of sheep and restocked with 
new sheep following a period of 3 years. Despite this effort, a few 
flocks of the new sheep developed scrapie; the origin was believed to 
be from scrapie that survived in the environment and not from 
reintroduction of the agent with the new sheep or through contaminated 
hay remaining on farms. However, a 1996 report suggests that six 
species of hay mites may be potential vectors associated with 
transmission of TSE's in Iceland (Ref. 67).
8. Genetics
    There is a genetic component associated with several of the human 
TSE diseases. A specific point mutation at codon 178 is associated with 
fatal familial insomnia (Ref. 68). Point mutations at codons 102, 105, 
117, 145, 198, and 217 are associated with GSS syndrome (Ref. 69). 
Point mutations at codons 178, 180, 200, 210, and 232 are associated 
with CJD (Refs. 68 and 70). Various insertions into the octapeptide 
repeat region of the PrP gene have also been associated with human 
TSE's (Ref. 71). It appears that the methionine/valine polymorphism at 
codon 129 may modify the phenotype and the transmission rate from GSS 
syndrome patients to mice (Ref. 72). No abnormalities in the sequence 
of the PrP gene in kuru patients were found.
    There is also a genetic component associated with sheep scrapie. 
Point mutations at codon 171 of the sheep PrP gene are linked to the 
disease in the Corriedale, Lacaune, Romanov, Suffolk, and Texel breeds 
(Refs. 73 to 76).
    An analysis of 370 cattle from Scotland revealed no difference 
between healthy cattle and cattle with BSE in the number of octapeptide 
repeat sequences (either five or six) and in a silent HindII 
restriction site polymorphism on the PrP gene (Ref. 77). No data were 
found that compared the sequence of the PrP gene of healthy deer, elk, 
mink, and goats with those afflicted by TSE's.
9. Diagnostics
    Because of the long incubation period, the ability to diagnose the 
presence of a BSE infection prior to the onset of the

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clinical disease would enhance the efficacy of surveillance and 
prevention programs. Because there is no fully characterized immune 
response to BSE or scrapie, diagnosis in live animals has been thought 
to be possible only when clinical signs are evident and must be 
confirmed by histopathology at post mortem (Ref. 10), or brain biopsy 
of moribund patients. Recently published research suggests antemortem 
tests for the TSE agent may be possible.
    The observation of histopathological changes in the brain, such as 
vacuolization of the brainstem in BSE are positive indicators of 
disease (Ref. 78). Other available diagnostic tests are 
immunohistochemical staining and immunoblotting of the abnormal protein 
(Ref. 10). Detection and titration of the TSE agent can also be 
accomplished by intracerebral inoculation in mice or hamsters with a 
brain homogenate from a suspected animal. After an appropriate 
incubation period, the brain of the laboratory animal is examined for 
histopathological changes characteristic of TSE (Ref. 8).
    The potential antemortem tests that have been published are 
described as follows: (1) Tests specific for PrP: (a) A capillary 
electrophoresis test (Ref. 79), and (b) a western blot test with 
increased sensitivity (Ref. 80); and (2) tests which identify 
metabolites of infected animals or humans: (a) A cyclic voltametric 
method which describes metabolites in urine (Ref. 81), and (b) an 
immunoblot test describing metabolites in cerebral spinal fluid (Ref. 
82). Antemortem tests have not yet been validated for practical use.
    Recent research has shown some promise for antemortem testing. 
Research by Shreuder et al. (Ref. 83), detected scrapie-associated 
PrPsc protein in tonsils from scrapie susceptible sheep about a year 
before the expected onset of the clinical disease. The research holds 
promise for preclinical detection in sheep, but needs further 
development. With regard to cattle, the researchers concluded that the 
technique may not work but is worth investigating. Research by Hsich et 
al. (Ref. 84), describes an experimental assay in humans and animals. 
The research found that a positive immunoassay in human dementia 
patients supports a diagnosis of CJD. The authors concluded that the 
assay may be helpful in premortem diagnosis of TSE in humans and 
animals showing clinical signs associated with TSE's. The validity of 
the test as a preclinical screen has not been established.
10. Inactivation
    The agency considered requiring procedures for the manufacture of 
animal-derived proteins that would inactivate TSE infectivity. There 
have been several studies on the inactivation of TSE agents. The only 
broad generalization that can be drawn is that agents that denature 
protein can diminish the infectivity of the TSE agents. TSE infectivity 
does not appear to be markedly diminished by radiation or UV-light.
    Recent research (Ref. 85) showed that 11 of the 15 rendering 
procedures tested produced meat and bone meal with no detectable BSE 
infectivity in a mouse bioassay. Only limited conclusions can be drawn 
about safety from these 11 procedures because the infectivity titer of 
the spiked starting material (which consisted of 10 percent brain) was 
several logs lower than that typically found in brain that is not 
minced and not stored at -20  deg.C. Also, the question of the adequacy 
of the mouse bioassay as the regulatory test which acceptably assures 
the absence of TSE infectivity to animals or man remains to be answered 
through future research investigations.
    The four procedures that failed included two protocols using 
continuous vacuum rendering of high fat material and two protocols 
using continuous atmospheric rendering of natural fat material. The 
continuous vacuum rendering processes that failed were 120  deg.C for 
20 minutes at a vacuum of 0.38 bar and 121  deg.C for 57 minutes at a 
vacuum of 0.4 bar. The continuous atmospheric rendering processes of 
natural fat material that failed were end temperatures of 112 and 122 
deg.C after 50 minutes; however, end temperatures of 123 and 139  deg.C 
after 125 minutes both inactivated the BSE agent. Unexpectedly, the BSE 
agent was inactivated by three wet rendering processes that only 
reached a maximum temperature of 119  deg.C with a cooking time of 240 
minutes, a maximum temperature of 101  deg.C with a cooking time of 120 
minutes, and a maximum temperature of 72  deg.C with a cooking time of 
240 minutes under a vacuum of 0.85 bar.
    Preliminary, unpublished results indicate that the only rendering 
process which completely inactivates the scrapie agent (which was 
spiked with higher infectivity than that in the BSE experiments 
described in this section) is batch rendering under pressure (Ref. 86). 
The agency encourages more research in this area.

B. The Association Between Scrapie and BSE

    Epidemiological studies of the outbreak of BSE in the United 
Kingdom, including a computer simulation of the BSE epidemic, have 
characterized it as an extended common-source epidemic. Each case has 
been considered a primary case resulting from exposure to a single 
common source of infection. It is believed in the United Kingdom that 
rendered feed ingredients contaminated with scrapie infected sheep, or 
cattle with a previously unidentified TSE, served as the common source 
of infection. One study demonstrated that meat and bone meal could be 
incorporated into cattle feed in sufficient quantity to transmit BSE to 
some of the animals that consumed the feed (Ref. 87). Thus far, other 
research including research by USDA has not confirmed that the feeding 
of U.S.-origin scrapie-infected feed ingredients to cattle produces 
BSE. Therefore, the theory that BSE evolved naturally in cattle has not 
been ruled out (Ref. 88). See also the discussion in II.A.5. of this 
document.
    Furthermore, the U.K. studies suggest that the spread of BSE 
appeared to have been exacerbated by the practice of feeding 
ingredients from rendered BSE-infected cattle to cattle, including 
young calves, a practice that was subsequently banned. Incomplete 
immediate compliance with the feeding ban may account for the fact that 
some cattle born after the ban continue to be infected with BSE and has 
complicated any theory of vertical transmission of the disease. The 
research findings of maternal transmission of BSE are inconclusive, but 
if it occurs, it does so at a rate insufficient to maintain the 
epidemic (Ref. 89).

C. The Association Between Animal TSE's and Human TSE's

    All the animal and human TSE's have been shown to be transmissible 
experimentally to laboratory animals. The human and animal diseases are 
pathologically similar and share some etiological similarities. TSE's 
are not officially considered zoonotic diseases, i.e., known to be 
naturally transmissible from animals to humans. The distribution of CJD 
in the world does not coincide with that of scrapie in sheep or of BSE 
in cattle. Human exposure to sheep or cattle has a low correlation with 
CJD. However, the recent report from the United Kingdom of nv-CJD, and 
its possible relationship to BSE, is causing scientists around the 
world including those at CDC to

[[Page 561]]

reevaluate whether BSE may be a zoonotic disease.
    This concern is further supported by the recent report of 
experimental BSE transmission to macaques, with the development of nv-
CJD-like plaques in these monkeys (see the following discussion in this 
section).
    The possibility of transmission of TSE's from animals to humans has 
been suggested, most recently in connection with the identification of 
nv-CJD in the United Kingdom. Scientists in the United Kingdom 
concluded that the nv-CJD cases may be unique to the United Kingdom, 
raising the possibility that they are causally linked to BSE. The 
scientists stated that ``the common neuropathological picture may 
indicate infection by a common strain of the causative agent, as in 
sheep scrapie in which strains of the disease have been identified * * 
* '' (Ref. 30). The United Kingdom Spongiform Encephalopathy Advisory 
Committee (SEAC) stated that ``although there is no direct evidence of 
a link, on current data and in absence of any credible alternative the 
most likely explanation at present is that these cases are linked to 
exposure to BSE before introduction of the SBO [specified bovine offal] 
ban in 1989'' (Ref. 90). A WHO consultation in April 1996 concluded 
that ``a link has not yet been proven between v-CJD in the U.K. and the 
effect of exposure to the BSE agent. The most likely hypothesis for v-
CJD is the exposure of the United Kingdom population to BSE'' (Ref. 2). 
However, a second WHO consultation, in May 1996 concluded that ``the 
clinical and neuropathological features of the newly recognized CJD 
variant do not provide information which could be used to prove the 
possible link between this disease and BSE in cattle'' (Ref. 91).
    The recent finding of florid amyloid plaques in the brains of 
macaques inoculated with suspensions of BSE-infected cow brains 
increases suspicion that exposure to the BSE agent may be the source of 
nv-CJD. Amyloid plaques have never before been seen in monkeys with 
TSE's, and the florid plaques resembled those in nv-CJD patients (Ref. 
92). In a recent paper by Collinge, et al. (Ref. 93), it is stated that 
``strains of transmissible encephalopathies are distinguished by 
differing physicochemical properties of PrPsc, the disease-related 
isoform of prion protein, which can be maintained on transmission to 
transgenic mice. 'New variant' CJD has a strain characteristic distinct 
from other types of CJD and which resembles those of BSE transmitted to 
mice, domestic cat and macaque, and is consistent with BSE being the 
source of this new disease. Strain characteristics revealed here 
suggest that the prion protein may itself encode disease phenotypes.''
    The possible association between BSE and nv-CJD may be further 
clarified by results from studies that are under way (e.g., 
experimental inoculation of brain tissue from the nv-CJD patients into 
mice).

D. Infectivity of Specific Tissues

    The WHO in a recent publication has summarized the infectivity of 
various tissues from sheep, goat, and cattle (Ref. 94). Scientific 
studies are currently being conducted in which calves are fed 
homogenized brain tissue from United Kingdom cattle confirmed to have 
BSE, and then various tissues are collected from the calves at 4-month 
intervals (Refs. 56 and 95). The tissues from these calves are being 
analyzed for the presence of the BSE agent. The study has been in 
progress for 18 months and only brain, spinal cord, and retina have 
been shown to be highly infectious. Distal ileum has been shown to be 
infectious, but much less than the previously mentioned tissues. No 
other tissues, most notably, muscle meat, milk, or blood have been 
shown to be infectious. The results of these current experiments 
parallel the previous research as summarized by WHO. However, the 
agency notes that infectivity of other tissues that might be fed to 
ruminants has not been definitively determined. This is, in part, 
because of the lack of desired sensitivity in the available assay 
methods.
    In summary, meat, milk, milk products, and blood have not been 
shown to transmit BSE infectivity. These products are considered safe 
for human consumption by health authorities including the WHO.

E. Potential Risk of TSE's to the United States

1. Overview
    This proposed FDA action is designed to reduce the risk of a BSE 
epidemic in the United States and thereby protect the health of animals 
and possibly of people if there is, in fact, a zoonotic relationship 
between BSE and CJD. Risk is defined as the probability of an adverse 
effect to an individual or a population. The four steps that are 
typically involved in risk analysis are hazard identification, hazard 
exposure, dose response, and risk characterization.
    While BSE has not been found in the United States, the agency 
believes it presents a potential risk to the health of animals and 
people. There are incubational and symptomatic similarities (as well as 
several differences) among the TSE's. The scientific characterization 
of these diseases is incomplete. However, interspecies cross-infections 
have been scientifically demonstrated by parenteral injection and oral 
routes of exposure.
    The typically long incubation period and the potentially 
devastating effect that a BSE outbreak would have on animal health and 
U.S. agribusiness also supports a conservative regulatory approach 
aimed at prevention. While the current level of exposure to products 
derived from animals with a TSE is extremely low or absent, the 
potential consequences of such exposure and the apparent small intake 
of the agent needed to achieve infection in some animals further 
encourage a conservative regulatory policy.
    Dose response assessments will be difficult because of the lack of 
good exposure data and the possibility of different susceptibilities, 
e.g., age or genetic factors, in different subpopulations. Although the 
TSE's are generally transmissible to laboratory animals following 
intraperitoneal (ip) or intracerebral (ic) routes of administration, 
the limited data that are available following the oral route of 
administration suggests that this route is much less efficient than ip 
or ic. Currently, it is quite difficult to make an accurate dose 
response assessment for a TSE agent following oral administration.
    A number of actions, in addition to this proposed rule, have been 
taken to manage a reduction in risk that BSE will enter the United 
States cattle population. Restrictions have been placed on the 
importation of live cattle (July 1989) and ruminant products (e.g., 
meat and bone meal, bone meal, blood meal, offal, fat, and glands) from 
countries which have BSE. Live animals imported prior to the 
restrictions on imports have been regularly monitored by Animal and 
Plant Health Inspection Service (APHIS) veterinarians, and APHIS is 
currently in the process of purchasing the remaining live cattle for 
diagnostic research purposes. Histopathological examination of brain 
tissues has been carried out on more than 5,000 specimens from cattle 
that were disabled or that demonstrated neurological signs prior to 
slaughter or on the farm, e.g., nonambulatory or rabies-negative 
cattle. Histopathological and immunohistochemical examination of the 
nonambulatory or ``downer'' cows has been carried out since 1993. There 
has been no finding of BSE in tissues from these animals. These animals 
represent the highest BSE risk in the country, however, they also 
represent an extremely small percentage of the cattle

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slaughtered in the United States. This active surveillance program is 
continuing and may be expanded. The expansion of this program was 
indirectly supported by a comment to the ANPRM that all ``downer'' cows 
should be examined for BSE.
    Voluntary actions by industry have reduced the feeding of rendered 
sheep proteins to ruminants and the rendering of adult sheep. A 
voluntary Scrapie Flock Certification Program was implemented in 1992. 
The program, a cooperative effort among industry, State animal health 
officials and APHIS, seeks to reduce the prevalence of scrapie in U.S. 
sheep. A considerable educational effort continues to increase the 
awareness of veterinarians, veterinary laboratory diagnosticians, 
livestock and related industry businesses, and producers to the early 
clinical signs of BSE. Videos of United Kingdom BSE affected animals 
have been distributed to USDA veterinarians to enhance their ability to 
clinically diagnose BSE in suspect live animals. CDC has recently 
published an update (Ref. 96) of its previous review of national CJD 
mortality and the results of active CJD surveillance in five sites in 
the United States. These reviews did not detect evidence of the 
occurrence of the newly described variant form of CJD in the United 
States. As an important complement to these other public health 
efforts, this proposed rule would declare that animal protein derived 
from ruminant and mink tissues is an unapproved food additive for use 
in ruminant feeds, and would establish enforcement procedures. These 
actions, individually and collectively, contribute to a greatly reduced 
risk of a BSE epidemic ever occurring in the United States.
2. Comparison With the U.K. Conditions
    Investigators have identified several major risk factors that 
apparently contributed to the emergence of the disease and the 
resultant epidemic in the United Kingdom. These are: (1) A large sheep 
population relative to the cattle population, (2) a large, 
uncontrolled, scrapie incidence rate, (3) the production of 
``greaves,'' an incompletely processed intermediate product in the 
rendering process, (4) changes in rendering processes, such as the 
reduced use of solvent extraction, and (5) the feeding of significant 
amounts, up to 4 percent of the diet, of meat and bone meal to young 
dairy calves.
    In addition to the risk factors described in section II.E.2. of 
this document, the practice of processing dead sheep and cattle in the 
United Kingdom likely contributed to the amplification of the TSE 
agent. In the United Kingdom, sheep which may have died of scrapie and 
cattle with BSE, were picked up by ``knackers'' for rendering into 
animal feed. This material was partially rendered into ``greaves,'' 
which might have contained large amounts of the scrapie/BSE agent, and 
was fed to dairy calves in large amounts. The spread of BSE appeared to 
be facilitated by the feeding of rendered BSE-infected cattle back to 
calves. The BSE agent is postulated to have recycled from cows to 
calves through ruminant-to-ruminant feeding until the practice ceased 
following the 1989 ban on the practice.
    In the United States, the cattle population is much larger than the 
sheep population, the incidence of scrapie is much lower and a scrapie 
control program is in place; renderers in the United States do not 
manufacture greaves; and the rendering processes used in the United 
States are thought to reduce the titre (level) of TSE agents if any. 
The lack of a practice of feeding large amounts of meat and bone meal 
to calves in the United States, and the comparatively younger average 
age of U.S. dairy cattle are also differences that are believed to be 
important in protecting the United States against a U.K.-type BSE 
epidemic. Nevertheless, scrapie does exist in the United States, sheep 
are rendered and included in ruminant feed, the rendering process does 
not totally inactivate TSE agents, and calves are fed meat and bone 
meal. Therefore the risk of a BSE epidemic in the United States, while 
much less, cannot be completely discounted.

F. Historical Efforts to Control TSE's

1. U.S. Actions
    a. FDA. FDA is the Federal agency responsible for the safety and 
effectiveness of a large number of products and commodities. Briefly, 
these include, drugs for use in people and animals, human biological 
products, medical devices, food, dietary supplements, cosmetics, and 
animal feeds. Each of these product groups provides the potential for 
the transmission of spongiform encephalopathies in man or animals. FDA 
formed a Working Group composed of the Deputy Commissioner for 
Operations and representatives from the Centers to consider TSE's in 
relation to FDA regulated products. As a result of the Working Group's 
deliberations, FDA has taken the following actions:
    <bullet> In 1992, letters were sent to manufacturers of dietary 
supplements asking those manufacturers to reformulate their products to 
be certain they do not contain materials from BSE or scrapie infected 
animals;
    <bullet> In 1993, letters were sent to manufacturers of drugs, 
biologics, and devices asking them not to use bovine-derived materials 
from countries with BSE; and
    <bullet> In 1996, letters were sent to manufacturers of drugs, 
biologics, devices, and animal feeds noting a possible relationship 
between BSE and nv-CJD and asking that they not use materials from BSE 
countries.
    In 1992, FDA conducted a survey of major sheep rendering plants to 
determine compliance with a 1989 voluntary industry ban on the use of 
adult sheep offal in ruminant feeds. The voluntary ban and results of 
the survey are described in section I.F.3. of this document. In the 
Federal Register of August 29, 1994 (59 FR 44584), FDA published a 
proposed rule proposing to declare that specified offal from adult 
sheep and goats is an unapproved feed additive in ruminant feed 
(hereinafter referred to as the August 1994 proposed rule). In the 
Federal Register of May 14, 1996, FDA published an ANPRM stating that 
FDA was considering whether to provide that the use of protein derived 
from ruminants in ruminant feed be prohibited.
    An international symposium entitled ``Tissue Distribution, 
Inactivation, and Transmission of Transmissible Spongiform 
Encephalopathies'' and cohosted by APHIS and FDA's Center for 
Veterinary Medicine (CVM) was held on May 13 and 14, 1996, in 
Riverdale, MD. The symposium participants engaged in discussion of 
findings from unpublished, recently completed, and in-progress 
scientific investigations on TSE's, and optimal approaches to managing 
any risk of TSE's to animal health.
    b. USDA. USDA policy has been both proactive and preventive. The 
Food Safety and Inspection Service (FSIS) and APHIS have been active in 
taking measures in surveillance, prevention, and education about TSE's. 
In 1990, APHIS created a BSE Issues Management Team to analyze risks of 
BSE to the United States, disseminate accurate information about the 
disease, and act as a reference source for responding to questions 
about BSE. APHIS has also collaborated in the education of veterinary 
practitioners, veterinary laboratory diagnosticians, industry and 
producers on the clinical signs and pathology of BSE.
    APHIS has increased its surveillance efforts to verify that the 
United States is free of BSE and to detect the disease should it be 
introduced into the United

[[Page 563]]

States. As part of an ongoing active surveillance program, more than 60 
veterinary diagnostic laboratories across the United States, and the 
National Veterinary Service Laboratories (NVSL) of APHIS, continue to 
examine bovine brains from the following sources: (1) APHIS 
investigations in the United States where suspected encephalitic 
conditions in cattle are reported under the foreign animal disease 
investigation program; (2) CDC and State public health laboratories 
(specimens from bovine that were found negative for rabies); and (3) 
FSIS (specimens from ``downer'' cows or those exhibiting CNS 
abnormalities). More than 5,000 bovine brains have been examined, and 
none of these specimens contained lesions with the characteristics and 
distribution typical for BSE (Refs. 12 and 97). APHIS is currently in 
the process of purchasing the 69 living cattle (from a total of 496 
cattle) imported from the United Kingdom between 1981 and 1989. In July 
1989, the importation of live ruminants and ruminant products from all 
countries known to have BSE in native animals was banned.
    USDA continues to analyze and report epidemiologic findings and 
potential risks to the United States. In 1991, USDA issued two reports 
analyzing risk factors associated with BSE in the United Kingdom based 
on the British hypothesis of the disease occurring as a result of 
feeding scrapie-contaminated meat and bone meal (Refs. 98 and 84). 
Because of some similarities in the animal industries between the two 
countries, the possibility of BSE occurring in the United States could 
not be eliminated. However, the probability of occurrence was 
determined to be very low as the amount of sheep offal was found to be 
0.6 percent of all U.S. rendered product compared to the estimate of 14 
percent of all U.K. rendered product. Furthermore, the incidence of 
scrapie in the United States is much lower than in Great Britain; a 
scrapie eradication or control program has been in effect in the United 
States and rendered products are not routinely incorporated into calf 
diets as was the practice in the United Kingdom.
    Since 1991, USDA has closely followed scientific findings and has 
updated the BSE risk factor analysis, first in 1993 (Ref. 99) and as 
recently as February 1996 (Ref. 4). Changes within each of the risk 
factors have been evaluated, and because there has either been no 
change or a decrease in the magnitude of risk factors, the overall risk 
of BSE in the United States is believed to have decreased. The 
February, 1996 report estimated the maximum potential 1-year period 
prevalence of BSE to range from 2.3 to 12 cases per 1 million adult 
cattle. In other words, under the worst case scenario between 
approximately 115 and 600 adult cattle would become infected with BSE 
each year, in a U.S. population of nearly 50 million adult cattle.
    APHIS has had a scrapie control program in effect since 1952. 
Flocks that have been enrolled in the voluntary certification program 
for sheep for 5 years, and have not had a diagnosed case of scrapie 
within 5 years or a case traced back to the flock during that period, 
may apply for APHIS certification and be officially identified as such. 
This new control effort provides a mechanism to recognize flocks as 
scrapie-free in the absence of a live animal diagnostic test.
    There is no official USDA program on TME or CWD. Although the last 
TME case detected in the United States was in 1985, monitoring for this 
disease continues. APHIS cooperates with State wildlife and diagnostic 
officials in Colorado and Wyoming in the limited areas where CWD has 
been reported.
    In December 1991, APHIS placed a ban on importation of certain 
products of ruminant origin from countries known to have BSE (56 FR 
63865, December 6, 1991). These products include: Meat and bone meal, 
bone meal, blood meal, offal, fat, and glands. In addition to 
prohibiting the materials listed previously, the regulation requires 
that imported meat for human or animal consumption from bovines be 
deboned, with visible lymphatic and nervous tissue removed; that it be 
obtained from animals which have undergone a veterinary examination 
prior to slaughter; and that it be obtained from ruminants which have 
not been in any country in which BSE has been reported during a period 
of time when that country permitted the use of ruminant protein in 
ruminant feed. APHIS may allow the importation of the banned products 
under a special permit for scientific or research purposes, or under 
special conditions to be used in cosmetics. No bovine meat from the 
United Kingdom has been allowed to be imported into the United States 
by FSIS for human consumption since before the BSE epidemic occurred in 
the United Kingdom. The network of private veterinary practitioners 
that refers unusual cases to veterinary schools or State diagnostic 
laboratories around the United States provides an extensive 
surveillance system. FSIS performs both antemortem and post mortem 
inspections at all federally-inspected slaughter establishments, and 
inspectors condemn all animals with central nervous system disorders. 
State-inspected slaughter operations follow the same procedures.
    USDA also maintains a database on these and other conditions. The 
Veterinary Diagnostic Laboratory Reporting System (VDLRS) is a database 
of selected disease conditions submitted by 29 State and university 
veterinary diagnostic laboratories throughout the United States, and 
includes the results of histologic examinations for BSE. The VDLRS is a 
cooperative effort of the American Association of Veterinary Laboratory 
Diagnosticians (AAVLD), the U.S. Animal Health Association (USAHA), 
APHIS' Veterinary Service Centers for Epidemiology and Animal Health, 
and the 29 laboratories mentioned previously.
    c. Public Health Service (PHS). i. CDC. CDC conducts surveillance 
for CJD through examination of death certificate data compiled by the 
National Center for Health Statistics, CDC, for U.S. residents for whom 
CJD was listed as one of the multiple causes of death (Ref. 100). These 
data indicate that the annual CJD mortality rates in the United States 
between 1979 and 1993 have been relatively stable, ranging between only 
0.8 case per million in both 1979 and 1990 and 1.1 cases per million in 
1987. In addition, CJD deaths in persons younger than 30 years of age 
in the United States remain extremely rare (<5 cases per billion per 
year) (Ref. 101).
    CDC is working with the Council of State and Territorial 
Epidemiologists to consider expansion of current CJD surveillance. CDC 
is also working with its four established Emerging Infections Programs 
(Minnesota, Oregon, Connecticut, and the San Francisco Bay area, 
California), the Georgia Department of Human Resources, and the Atlanta 
Metropolitan Active Surveillance Program to pilot enhanced surveillance 
efforts for CJD (Ref. 101). This effort includes an active search for 
v-CJD as described in the United Kingdom (Ref. 30). On August 9, 1996, 
the results of this enhanced CJD surveillance effort was published; no 
evidence of the occurrence of the newly described variant form of CJD 
was found in the United States. No evidence of v-CJD has been found in 
the United States.
    ii. National Institutes of Health (NIH). A project of the 
Laboratory of Central Nervous System Studies of the National Institute 
of Neurological Diseases and Stroke is conducting investigations on 
slow, latent, and temperate viral infections associated with chronic 
degenerative neurological diseases. Important areas of study are the 
pathogenesis of slow infections and mechanisms of persistence in kuru 
and

[[Page 564]]

CJD. Also intensive molecular, biological, genetic, and immunological 
studies are being conducted on amyloid formation in the brain in 
Alzheimer's disease, normal aging, Down's syndrome, and slow viral 
infections, and the elucidation of the de novo generation of infectious 
amyloid proteins from normal host precursor proteins in kuru, CJD, GSS 
syndrome, scrapie and BSE. Research on TSE's has also been conducted by 
the NIH Laboratory of Persistent Viral Disease. FDA maintains close 
contact with scientists in the laboratories and expects to use their 
expertise in the evaluation of inactivation methods and transmission 
studies.
    iii. Other actions. On April 8, 1996, an interagency meeting at CDC 
including representatives from CDC, NIH, FDA, USDA, and the U.S. 
Department of Defense was held to disseminate conclusions from the WHO 
consultation regarding v-CJD and to coordinate preventive activities 
among these agencies to address the BSE and CJD issues.
2. International Actions
    a. United Kingdom. Regulatory controls taken to manage the BSE 
epidemic in the United Kingdom and to address public health concerns 
include: (1) An action in June 1988 to make the disease reportable; (2) 
a ban in July 1988 on the feeding of ruminant-derived protein 
supplements to other ruminants; (3) an order in August 1988 for the 
compulsory slaughter and incineration of BSE suspect cattle; (4) a ban 
in November 1989 on the inclusion of specified bovine offal (brain, 
spinal cord, thymus, spleen, tonsils, and intestines) for human 
consumption; and (5) a ban in September 1990 on use of specified bovine 
offal in any animal feed.
    A CJD Surveillance Unit was established to monitor CJD numbers in 
the United Kingdom. SEAC, consisting of experts in neurology, 
epidemiology, and microbiology from outside the British government, was 
established in 1990 to oversee all aspects of TSE's and human and 
animal health. USDA has a representative on this committee.
    Major regulatory actions occurring after the SEAC report on nv-CJD 
(Ref. 90) include legislation to ban the feeding of mammalian meat and 
bone meal to any farmed animal, and legislation to ban the use of 
cattle head meat for human consumption.
    b. WHO. WHO has held meetings on the spongiform encephalopathies in 
1991, 1993, 1995, and 1996, and a meeting in collaboration with the 
Office International des Epizooties (OIE) in 1994. The general purposes 
of these meetings were to review the existing state of knowledge on 
spongiform encephalopathies including BSE, to evaluate possible means 
of transmission, and to identify risk factors for infection. A specific 
purpose was to review the possible human public health implications of 
animal spongiform encephalopathies, with special emphasis on BSE. The 
group of international experts convened in April 1996 by WHO 
recommended that all countries should ban the use of ruminant tissues 
in ruminant feed. The WHO group also declared that milk and milk 
products, including such products from the United Kingdom, are safe for 
human consumption and that gelatin in the food chain is considered safe 
because its preparation effectively destroys BSE. Finally, the group 
concluded that tallow could be safe if effective rendering procedures 
are in place (i.e., rendered as protein-free) (Ref. 2).
    c. OIE. OIE has supported the U.K. ban on the use of specified 
offals and has recommended that the same action be taken in other 
countries with a high incidence of the disease (Ref. 102). OIE has held 
meetings in 1990, 1991, 1992, 1995, and 1996, and has developed 
guidelines concerning animals and animal products to prevent movement 
to unaffected countries.
    d. European Community (EC). The EC has held a series of meetings 
related to BSE. Following issuance of the U.K. SEAC statement 
suggesting a possible link between nv-CJD and BSE, the EC imposed a ban 
on British cattle, beef and bovine derivatives (Ref. 103).
3. Voluntary Measures by the U.S. Animal Industries
    a. Voluntary ban on rendering adult sheep. In 1989, the National 
Renderers Association (NRA) and the Animal Protein Producers Industry 
(APPI) recommended to their members that they stop rendering adult 
sheep or providing sheep offal for sale as meat and bone meal for 
inclusion in cattle feed (Ref. 104). Following the recommendation of 
the voluntary ban, FDA carried out a survey of current practices in the 
United States for rendering or otherwise disposing of adult sheep 
carcasses and parts, specifically head, brain, and spinal cord. Limited 
inspections of rendering plants were conducted in 1992 to: (1) Assess 
compliance by U.S. renderers with the voluntary ban; (2) identify 
rendering plant practices concerning adult sheep; and (3) determine if 
rendered adult sheep protein byproducts were being sold or labeled for 
use as feed or feed components for cattle. Of the 19 plants surveyed, 
15 rendered carcasses or offal of adult sheep. These 15 plants 
processed more than 85 percent of the adult sheep rendered in the 
United States. Eleven of the 15 plants rendered carcasses of adult 
sheep with heads, 7 of the 15 rendered sheep carcasses separately from 
other species, 6 of the 15 maintained meat and bone meal from adult 
sheep separate from meat and bone meal from other species, and 4 of the 
15 rendered sheep that had died of causes other than slaughter. Six of 
the 11 renderers processing adult sheep with heads had sold meat and 
bone meal to manufacturers of cattle feed. Thus, the rendering 
industry's voluntary ban on the rendering of adult sheep or providing 
sheep offal for use in cattle feed was not fully implemented at the 
time of the survey (Ref. 105).
    b. Voluntary ban on feeding ruminant proteins to ruminants. On 
March 29, 1996, the National Cattlemen's Beef Association (NCBA), the 
National Milk Producers Federation, the American Sheep Association, the 
American Veterinary Medical Association, the American Association of 
Veterinary Medical Colleges, and the American Association of Bovine 
Practitioners announced the recommendation of a voluntary ban on the 
feeding of ruminant-derived proteins to ruminant animals (Ref. 106). 
USDA, PHS, the American Society of Animal Science, and other 
organizations announced support for the voluntary ban (Refs. 107 and 
108). According to the NCBA (Ref. 109), a comprehensive communication 
strategy, seeking removal of ruminant-derived proteins from the rations 
of ruminants, was implemented in May 1996 by the feed industry, 
nutritionists, veterinarians, extension specialists, and dairy and beef 
producers. NCBA has not conducted a survey to assess the impact of its 
communication strategy; however, NCBA did point out that past requests 
for voluntary action by the cattle industry have been quite successful, 
approaching 90 percent compliance. In contrast, an anonymous comment to 
the ANPRM suggested a compliance level of less than 5 percent (Ref. 
110). FDA has not conducted a survey to ascertain the level of 
compliance with the voluntary ban.

G. Processing Animal Tissues for Feed Ingredients

1. Current Rendering Practices
    The following discussion on current rendering practices comes 
directly from comments supplied to FDA in response to the ANPRM from 
representatives of

[[Page 565]]

APPI and NRA. Knowledge about the four basic types of rendering systems 
that are most commonly used in the United States today may be crucial 
in dealing with the TSE issue in this country. Data on the inactivation 
of the BSE and scrapie agents following simulation of the most commonly 
used basic types of rendering systems in the United States could be 
quite useful, especially because some of these systems do not appear to 
have been used in the only published rendering study on BSE 
inactivation (Ref. 85).
    Rendering, the process of cooking raw material to remove the 
moisture and fat from the solid protein portion of animal tissues, has 
been practiced by humans for more than 2,000 years. The United States 
rendering industry has developed over the last 160 years. Modern 
rendering systems are high-technology recycling processes that 
efficiently convert animal byproducts (shop fat and bone, beef and pork 
slaughterhouse materials, poultry offal, fish, etc.) to stable protein 
and fat supplements for feed.
    Current technology consists of four basic types of rendering 
systems--batch cooker, continuous cooker, continuous multi-stage 
evaporator, and continuous preheat/press/evaporator. All systems 
consist of three basic steps: Grinding the raw material, cooking it to 
remove moisture, and separating the melted fat from the protein solids.
    Batch cookers are multiple units, each consisting of a horizontal, 
steam-jacketed cylindrical vessel with an agitator. Batch cookers are 
operated at atmospheric pressure. The cooked material is discharged to 
the percolator drain pan, which contains a perforated screen that 
allows the free-run fat to drain and be separated from the protein 
solids known as ``tankage.''
    Because ``tankage'' contains considerable fat, it is processed 
through a screw press to complete the separation of fat from solids. 
The fat discharged from the screw press usually contains fine solid 
particles that are removed by either centrifuging or filtration. The 
protein solids discharged from the screw press are known as 
``cracklings,'' which normally are screened and ground with a hammer 
mill to produce protein meal.
    The continuous cooker rendering system normally consists of a 
single continuous cooker, operating at atmospheric pressure. The 
discharge from the continuous cooker usually passes across either a 
vibrating screen or stationary perforated screen to allow the free-run 
fat to drain. The subsequent steps in the continuous cooker rendering 
process are similar to those described before for the batch cooker.
    In the continuous multi-stage evaporator rendering system, crushing 
is used as the first stage of size reduction of the raw material. A fat 
recycle stream is then used to deliver the material as a pumpable 
slurry through the secondary grinding step to reduce further the 
particle size. Particle size and fat ratios are important components of 
this system. The slurry discharge from the final stage of evaporation 
is pumped to a centrifuge which removes most of the fat and part of it 
is recycled back to the second stage of size reduction. The solids 
discharged from the centrifuge are conveyed to screw presses which 
complete the separation of fat from the protein solids.
    The continuous preheat/press/evaporator rendering system is known 
by a variety of names including the Stord dewatering rendering system 
and the Atlas low temperature wet rendering system. In either case, raw 
material is ground in two stages and passes through the preheater to 
raise the temperature to 180 to 190  deg.EF before entry to the twin 
screw press. The press separates this material into two phases: A 
presscake of solids containing moisture and a low fat concentration, 
and a liquid containing mostly water (stickwater) with fine solids, 
soluble protein, insoluble protein and melted fat.
    The press liquid is processed either by passing through a 
multistage evaporator system to remove the water before centrifuging to 
remove the fine solids from the fat, or by passing through a centrifuge 
to separate the fat before multistage evaporation of the remaining 
water/fine solids fraction. The liquid separation system consisting of 
two stages of centrifuges completes the separation of the melted fat 
from the solids and water. In this system, the screw press normally 
used to process the ``tankage'' is no longer needed. Longer drying 
times are needed with this system as compared to previous systems 
because of the early fat removal (less fat means less effective heat 
transfer).
    The agency encourages further research into methods of deactivation 
of the BSE agent during the rendering process.
2. Assay Methodologies for Proteins
    Enforcement of the proposed regulation would be facilitated if a 
test to detect and distinguish ruminant from nonruminant materials in 
feeds or feed ingredients was available. However, practical assays that 
could be used to enforce the proposed regulation are not available at 
this time. The test procedure would need to exhibit a high degree of 
sensitivity and selectivity; that is, the test must be able to detect 
the analyte of interest to the exclusion of other components. A test 
for acceptable rendered products in animal feed must therefore be able 
to discriminate and differentiate between permitted and prohibited 
animal derived proteins. Other factors of importance are the ruggedness 
of the test method, speed, and simplicity of design.
    An enzyme-linked immunosorbant assay (ELISA) based analytic method 
that is both sensitive (detects low levels of analyte) and specific 
(detects primarily the analyte of interest) is one possibility. ELISA 
is a relatively straightforward methodology. There are numerous 
commercial sources for antisera capable of binding to bovine, ovine, 
porcine, and caprine proteins. Antisera have also been generated from 
muscle extracts and validated for use in USDA-approved ELISA methods to 
determine the identity of raw and cooked meats (Refs. 111 and 112). 
However, rendered products present a unique problem because rendering 
causes the destruction of most of the antibody binding epitopes needed 
for an ELISA test. Therefore, detection of rendered proteins by a given 
antibody cannot be automatically assumed.
    Other potential methodologies include western blot analysis, 
capillary electrophoresis, and high pressure liquid chromatography. The 
applicability of these three methods to this issue has not been 
addressed. Furthermore, they require expensive, specialized equipment 
and a high degree of technical competence.
    The agency encourages research to detect and distinguish ruminant 
from nonruminant materials in rendered products and animal feeds.

III. Statutory Provisions Regarding Food Additives

    The term ``food'' as defined in the act includes animal feed. 
Section 201(f) of the act (21 U.S.C. 321(f)) defines food as ``articles 
used for food or drink for man or other animals'' and ``articles used 
for components of any such article.'' Furthermore, any substance whose 
intended use results or may reasonably be expected to result in its 
becoming a component of food is a food additive unless, among other 
things, it is GRAS or is the subject of a prior sanction. Section 
402(a)(2)(C) of the act (21 U.S.C. 342(a)(2)(C)) deems food adulterated 
``if it is, or it bears or contains, any food additive which is unsafe 
within the meaning of section 409 * * *.'' Under section 409(a) of the 
act (21 U.S.C 348(a)), a food additive is unsafe unless

[[Page 566]]

a food additive regulation or an exemption is in effect with respect to 
its use or its intended use.
    A food additive regulation is established by the submission and 
approval of a food additive petition, as provided in 21 CFR 571.1, or 
on FDA's initiative as provided in 21 CFR 570.15. FDA on its own 
initiative or at the request of an interested party, also may propose 
to determine that a substance intended for use in animal feed is not 
GRAS and is a food additive subject to section 409 of the act as 
provided in Sec. 570.38 (21 CFR 570.38). Subsequent to the publication 
of such a proposal and after consideration of public comments, FDA may 
issue a final rule declaring the substance to be a food additive and 
require discontinuation of its use except when used in compliance with 
a food additive regulation.

A. GRAS Determination

    A determination that a substance added directly or indirectly to a 
food is GRAS, is generally based on specific information regarding the 
composition of the substance, its use, method of preparation, methods 
for detecting its presence in food, and information about its 
functionality in food (21 CFR 570.35) as determined by experts 
qualified by scientific training and experience to evaluate the safety 
of such a substance. A substance added to food becomes GRAS as the 
result of a common understanding about the substance throughout the 
scientific community familiar with safety of such substances. The basis 
of expert views may be either scientific procedures, or, in the case of 
a substance used in food prior to January 1, 1958, experience based on 
common use in food (Sec. 570.30(a)) (21 CFR 570.30(a)). General 
recognition of safety through experience based on common use in food 
prior to January 1, 1958, may be determined without the quantity or 
quality of scientific studies required for the approval of a food 
additive regulation. However, substances that are GRAS based on such 
use must be currently recognized as safe based on their pre-1958 use. 
(See United States v. Naremco, 553 F.2d 1138 (8th Cir. 1977); compare 
United States v. Western Serum, 666 F.2d 335 (9th Cir. 1982).) A 
recognition of safety through common use is ordinarily to be based on 
generally available data and information (Sec. 570.30(c)). An 
ingredient that was not in common use in food prior to January 1, 1958, 
may achieve general recognition of safety only through scientific 
procedures.
    General recognition of safety based upon scientific procedures 
requires the same quantity and quality of scientific evidence as is 
required to obtain approval of a food additive regulation for the 
ingredient (Sec. 570.30(b)). (See United States v. Naremco, 553 F.2d at 
1143.) A substance is not GRAS if there is a genuine dispute among 
experts as to its recognition (An Article of Drug * * * Furestrol 
Vaginal Suppositories, 251 F. Supp. 1307 (N.D. Ga. 1968), aff'd 415 
F.2d 390 (5th Cir. 1969).) Further, general recognition of safety 
through scientific procedures must be based upon published studies 
(United States v. Articles of Food and Drug Colitrol 80 Medicated, 372 
F. Supp. 915 (N.D. Ga. 1974), aff'd, 518 F.2d 743, 747 (5th Cir. 
1975)), so that the results are generally available to experts. It is 
not enough, in attempting to establish that a substance is GRAS, to 
establish that there is an absence of scientific studies that 
demonstrate the substance to be unsafe; there must be studies that show 
the substance to be safe (United States v. An Article of Food * * * Co 
Co Rico, supra.)
    Conversely, a substance may be ineligible for GRAS status if 
studies show that the substance is, or may be, unsafe. This is true 
whether the studies are published or unpublished (50 FR 27294 at 27296, 
July 2, 1985). If there are studies that tend to support a finding that 
a particular substance is GRAS, but also studies that tend to support a 
contrary position, the conflict in the studies, just as a conflict in 
expert opinion, may prevent the general recognition of the safe use of 
the substance.

B. Prior Sanction

    Under section 201(s) of the act, the term ``food additive'' does 
not apply to any substance used in accordance with a sanction or 
approval granted prior to enactment of section 201(s) of the act and 
granted under the act, the Poultry Products Inspection Act (21 U.S.C. 
451 et seq.), or the Federal Meat Inspection Act (21 U.S.C. 601 et 
seq.). Section 570.38(d) provides that if the Commissioner of Food and 
Drugs is aware of any prior sanction for use of a substance, he will, 
concurrently with a notice determining that a substance is not GRAS and 
is a food additive subject to section 409 of the act, propose a 
separate regulation covering such use of the substance.
    In the case of the materials subject to this proposed rule, FDA has 
determined that it is unaware of any applicable prior sanction. Any 
person who intends to assert or rely on such sanction is required to 
submit proof of the existence of the applicable prior sanction. The 
failure of any person to come forward with proof of such an applicable 
prior sanction in response to this notice will constitute a waiver of 
the right to assert or rely on such sanction at any later time.

C. Food Additive Status of Ruminant Tissues

    The agency recognizes that processed ruminant byproducts have a 
long history of use in animal feeds without known adverse effects. 
However, the evidence as discussed in sections I and II.A. through 
II.D. of this document, for the development of a new pattern of disease 
transmission, now indicates that these ingredients can no longer be 
categorically regarded as safe. The agency tentatively concludes that, 
based on this evidence, use of such products in ruminant feed is not 
GRAS. The agency is proposing this regulation in light of the findings 
and conclusions described in sections I and II in this notice. Nor is 
the agency aware of a prior sanction for any feed products that contain 
these tissues. Therefore, FDA is proposing that the addition of protein 
derived from ruminant tissues to ruminant feed would constitute the use 
of an unapproved food additive because no regulation is in effect 
providing for such use. Any ruminant feed that contains protein derived 
from ruminant and mink tissues would be adulterated. Accordingly, FDA 
is proposing to list protein derived from ruminant tissues in part 589.

IV. Comments

    FDA's May 1996 ANPRM requested public comment and information on 
all aspects of TSE's, including BSE, and the potential consequences of 
a prohibition on the feeding of ruminant protein to ruminants. The 
agency received nearly 600 comments, including many that were submitted 
long after the comment period ended. The agency has attempted to 
address the comments in this proposal. If there are any significant 
concerns that the agency has not addressed, these concerns should be 
brought to the agency's attention in timely comments on this proposal. 
Comments that were specific to the topics covered by the other sections 
of this preamble were considered in the preamble as written. Comments 
are discussed in the text of some of these sections. The following is a 
general discussion of the comments received.
    Many comments, especially from renderers, meat packers, feed 
companies and farmers, opposed the prohibition of ruminant protein 
being fed to ruminants. The main reasons offered were the lack of 
evidence of BSE in the United States, lack of scientific data to 
support the proposal in the absence of

[[Page 567]]

BSE, environmental concerns, lack of an assay or other practical means 
to support enforcement, and the economic hardship that would fall upon 
the animal producers, slaughter facilities, renderers, feed 
manufacturers, and packers. Support for such a prohibition from 
consumer groups, pharmaceutical firms, scientists and veterinarians, 
and some livestock organizations, emphasized a potential effect on 
human health, the experience and data from the United Kingdom, and 
significant economic detriment if a BSE epidemic were to occur in this 
country. Other comments described a need to ensure that exported U.S. 
bovine-derived products met international standards and guidelines, and 
to maintain consumer confidence in the beef and dairy industries even 
though those comments acknowledged that there is a minimal potential 
risk of infectivity to animals and humans.
    The agency requested scientific information regarding the 
occurrence, transmission, etiology, pathogenesis, epidemiology, and 
inactivation of TSE agents. Many comments were received that contained 
useful scientific information that was considered in the preparation of 
this proposed rule, as described in this preamble and supporting 
documents.
    Three comments suggested that the documented existence of nonBSE 
TSE's, and the presence of ``downer'' cows (cows unable to walk) in the 
United States is evidence that BSE is present in this country. Three 
comments stated that the BSE surveillance in the United States provides 
sufficient assurance that BSE does not exist in this country. A number 
of persons commented on whether specific tissues, such as milk, blood, 
and gelatin, should be excluded from any prohibition, with nearly all 
supporting such exclusion.
    The agency requested information on the economic impact of the 
described action. Numerous comments provided data on volume of product 
impacted, potential economic benefits, and cost of compliance to 
affected persons. The data were used to develop the preliminary 
economic assessment supporting this proposed rule.
    The agency requested information on the environmental impact and 
potential mitigating factors of the described action. Many comments 
stated that alternative disposal of the prohibited carcasses would be 
less environmentally safe than rendering. These and other comments were 
considered in the development of the environmental assessment.
    Numerous comments were received regarding the need to prohibit only 
tissues that have been demonstrated to be infective. Generally, the 
comments stated that tissues that have been proven to be noninfective 
should be exempted. Although the agency is proposing a rule that would 
prohibit the use of all ruminant-derived protein in ruminant feeds, the 
agency will, as explained elsewhere in this document, consider a 
partial ruminant-to-ruminant prohibition as well as a mammalian-to-
ruminant prohibition.
    Many comments supported establishment of Hazard Analysis Critical 
Control Points (HACCP) for the rendering industry, often with 
concurrent support for current good manufacturing practices (CGMP's) 
for animal-derived proteins. For example, the American Feed Industry 
Association proposed a specific set of Good Manufacturing Practices for 
the producers of animal protein products, and the National Renderers 
Association proposed a specific HACCP regulation for rendering 
operations. The agency agrees that the need for HACCP, perhaps 
supported by CGMP's, for animal-derived proteins could be considered in 
future rulemaking. Several comments were received regarding labeling 
requirements for animal-derived proteins. The majority of the comments 
supported a statement of the origin of animal-derived protein. The 
agency has included a labeling requirement in the proposed rule.

V. Analysis of Alternatives

A. Overview

    In addition to the proposed ruminant-to-ruminant rule, the agency 
is considering alternative approaches. The alternatives include: (1) 
excluding from ruminant feed all ruminant and mink materials except 
those that have not been found to present a risk of transmitting 
spongiform encephalopathy (partial ruminant-to-ruminant prohibition); 
(2) prohibiting the use in ruminant feed of all mammalian protein 
(mammalian-to-ruminant prohibition); (3) prohibiting the feeding of 
materials from species in which TSE's have been diagnosed in the United 
States (sheep, goats, mink, deer, and elk); (4) prohibiting the feeding 
of specified sheep and goat offal, as proposed by the agency in 1994; 
(5) other alternatives that might be proposed by the comments; and (6) 
no action.
    Analysis of the advantages and disadvantages of the options 
follows. Analysis of costs and benefits, including detailed economic 
analysis, also appears in section IX. of this document. Environmental 
consequences are discussed in section VIII. of this document.
    In determining the scope of the final rule, the agency will weigh 
carefully the comments received, along with material contained in the 
administrative record for this proposal and the comments submitted in 
response to the ANPRM. Comments regarding the scope of the rule, 
including those comments supporting other options other than the 
proposed option, should be addressed accordingly.

B. Ruminant-to-Ruminant Prohibition

    Advantages of this option, compared with the ``no action'' option, 
are discussed in detail in section I. of this document. The advantages 
of this option that are discussed in that section would apply if BSE 
were to occur in this country. As discussed in separate sections that 
follow, there would also be environmental and economic advantages to 
the ruminant-to-ruminant option, if BSE were to occur in this country. 
Disadvantages of the ruminant-to-ruminant option, compared to the ``no 
action'' option, would be relevant primarily if BSE did not occur in 
the United States. These disadvantages would include the time and 
expense required to comply with the provisions of the regulation, and 
the limited, short term environmental effects described in section 
VIII. of this document.
    Compared with the mammalian-to-ruminant option, the ruminant-to-
ruminant option has the advantages of being tailored more precisely to 
the identified scientific concerns, and less burdensome on the affected 
industries. Economic and environmental costs would be less. The major 
disadvantage is that the ruminant-to-ruminant option results in more 
complexity for the regulated industries, and thereby provides less 
assurance of compliance. This is explained further in the discussion of 
the mammalian-to-ruminant option, in section V.D. of this document.
    Compared to the other remaining options, which are less 
restrictive, the ruminant-to-ruminant option provides greater assurance 
of protection of the public health and, if BSE were to occur in the 
United States, lower economic and environmental costs. The 
disadvantages relate generally to the greater economic and 
environmental costs that would be incurred if BSE did not occur in the 
United States.

C. Partial Ruminant-to-Ruminant Prohibition

    As an alternative to the proposed ruminant-to-ruminant prohibition, 
the agency is considering a partial

[[Page 568]]

ruminant-to-ruminant prohibition which would exclude from ruminant feed 
all ruminant and mink materials except those that have not been found 
to present a risk of transmitting spongiform encephalopathy. The 
exclusions would be in addition to milk products, gelatin and bovine 
blood, which are excluded in the proposed rule. Possible exclusions 
include slaughter byproducts from bovine that have been inspected and 
passed in inspected slaughter facilities, except the brain, eyes, 
spinal cord, and distal ileum. The four named tissues would be 
prohibited because they have been shown through experimental trials and 
bioassays to transmit spongiform encephalopathy. The remaining tissues 
have not been demonstrated to transmit spongiform encephalopathy.
    This option has the advantage of having its prohibitions based 
primarily on scientific information related to infectivity of specific 
tissues. A number of persons who commented on the ANPRM urged the 
agency to base its regulation entirely on such scientific information. 
In addition, this option would likely involve lower lost sales revenues 
to the affected industries, and could have fewer adverse economic 
effects, than would the other options.
    However, the agency has three concerns with regard to the adequacy 
of this option in providing sufficient protection for the public 
health. First, FDA recognizes that it may be impractical in the 
slaughter and rendering processes to segregate and exclude the bovine 
tissues that have not been found to present a risk. For example, USDA 
has expressed reservations that separating the distal ileum from the 
other intestinal offal could jeopardize a slaughter plant's ability to 
meet pathogen reduction goals required under USDA's HACCP regulations. 
Furthermore, regulatory enforcement of a prohibition affecting only 
specified bovine tissues may be impractical in the absence of specific 
diagnostic methods for identifying protein derived from such tissues. 
If a partial prohibition were adopted, it would be based on a finding 
that practical methods can be implemented for segregating, processing, 
storing, and identifying feed materials derived from tissues that have 
not been found to present a risk.
    Second, this option would be inconsistent with actions taken in a 
number of other nations. For example, CDC has commented that any 
prohibition of lesser scope than a ruminant-to-ruminant prohibition 
would place the United States out of step with the international public 
health community.
    Third, limiting the prohibition of tissues to those that have been 
shown to be infective would not address the risk that may be presented 
by other tissues. Definitive assays using methods more sensitive than 
currently available methods might identify such additional tissues as 
infective. The possibility of undetected low dose exposure cannot be 
eliminated, particularly for tissues such as lymph nodes and spleens 
which would be expected to be infective (Ref. 1).
    These issues raise a substantial question as to whether the tissues 
could be GRAS. To achieve the highest level of public health 
protection, the agency believes that it may be reasonable to assume 
that, in the absence of scientific data definitively establishing that 
each tissue does not transmit spongiform encephalopathy, all ruminant 
tissues present a risk of infectivity.
    The agency nevertheless welcomes comments on this alternative to 
the proposed ruminant-to-ruminant prohibition and especially invites 
comments on possible practical means of separating the distal ileum in 
compliance with USDA and industry standards, as well as the 
practicality of the removal of brain, spinal cord, and eye and the 
segregation of these tissues from others in the slaughter plant.

D. Mammal-to-Ruminant Prohibition

    The agency received comments in support of a rule that would 
prohibit the use in ruminant feed of all mammalian-derived protein. For 
instance, the American Feed Industry Association, NRA, and APPI 
expressed concerns that segregating certain mammalian derived proteins 
from others would not be feasible because of regular commingling of 
protein products at feed mills and rendering facilities. A mammalian-
to-ruminant prohibition would provide greater assurance of industry 
compliance than either a partial or total ruminant-to-ruminant 
prohibition because practical analytical methods exist for 
distinguishing mammalian from nonmammalian proteins. Implementation of 
a mammal-to-ruminant prohibition by the regulated industries would be 
less complex, and would reduce the potential for contamination of 
cattle feeds with material intended for feeding monogastric animals. 
Contamination of cattle feeds with material intended for feeding 
nonruminants was the primary reason that the United Kingdom has 
prohibited mammalian proteins in the rations of cattle. A mammal-to-
ruminant prohibition would enable the continued use of Association of 
American Feed Control Officials definitions for the purpose of 
identifying and labeling products covered by the prohibition, and would 
not require additional or new labeling. Finally, concerns were 
expressed that allowing certain products containing meat and bone meal 
to be used in ruminant feeds while prohibiting others would lead to 
instability in financially sensitive commodity markets for animal 
protein.
    On the other hand, the agency is not aware of any scientific data 
that establish or suggest TSE infectivity in nonruminant mammals except 
in mink. Thus, excluding nonruminant tissues from ruminant feed would 
be based primarily on the view that the possibility of infection of 
nonruminant tissue through cross-contamination or commingling with 
ruminant tissue is sufficient to preclude GRAS status for the 
nonruminant tissue. However, FDA is aware that some portions of the 
affected industries would prefer to segregate ruminant from nonruminant 
tissues, and believe that such separation is practical. Accordingly, 
the agency invites comments on the relative merits and disadvantages of 
a mammal-to-ruminant prohibition compared with a total or partial 
ruminant-to-ruminant prohibition.

E. Prohibition of Materials From U.S. Species Diagnosed With TSE's 
(Sheep, Goats, Mink, Deer, and Elk)

    This option would involve requiring that ruminants not be fed any 
proteins derived from any U.S. animal species in which a TSE has been 
diagnosed. This includes sheep, goats, mink, deer, and elk. This 
approach would eliminate the scrapie agent, along with TME and CWD, 
from ruminant feed, and thereby reduce the risk of BSE in cattle caused 
by TSE transmission from other species. However, it would not prevent 
the spread of BSE among cattle if BSE occurred for some other reasons, 
e.g., by a spontaneous mutation in cattle or importation of animals 
with BSE, and the animals were processed and subsequently included in 
ruminant feed. As explained in section IX. of this document, this 
option involves lower economic costs than the three options previously 
described, in the absence of a BSE outbreak.

F. Sheep-Specified Offal Prohibition

    The option of prohibiting only protein from specified offal from 
sheep and goats for use in ruminant feed would eliminate the scrapie 
agent from bovine feed. However, it would not prevent the spread of BSE 
among cattle if BSE occurred for some other reason, e.g., by

[[Page 569]]

a spontaneous mutation in cattle or importation of animals with BSE, 
and the animals were processed and subsequently included in ruminant 
feed. The agency notes that if it were to select this option, it would 
reconsider its statement in the 1994 proposed rule that sheep less than 
12 months of age presented a minimal risk. Cases of scrapie in sheep as 
young as 7 months have been reported (Ref. 113). Although the risk 
presented by young animals may be minimal, excluding them may provide 
inadequate protection to the public health. As explained in section IX. 
of this document, this option involves lower economic costs than the 
options described previously, in the absence of a BSE outbreak.

G. No Action

    The advantages and disadvantages of this option, in relation to the 
other options, are discussed in detail in section I. of this document 
and in the preceding subsections of this section, as well as the 
environmental and economic sections. In general, this option offers 
lower economic and environmental costs if BSE does not occur in the 
United States, and higher such costs (in addition to public health 
implications) if BSE does occur.

VI. Description of the Proposed Rule

A. Introduction

1. Regulatory Alternatives
    Typically, FDA regulates products that are of public health concern 
through a combination of regulatory tools including: labeling for 
appropriate use; CGMP regulations and, recently, HACCP regulations; 
specifications for the product or its manufacture; and testing to 
determine the presence or level of the agent of concern. Use of two or 
more of these means provides for appropriate reinforcement to ensure 
that the public is protected.
    The agency's choice of readily available approaches for regulating 
animal protein products derived from ruminant and mink tissues is 
limited. For example, there are no practical tests for the presence of 
the TSE agent or of ruminant protein in animal feed. No commercial 
method of deactivating the TSE agent in animal protein products has 
been scientifically validated as effective. None of the agency's CGMP 
or HACCP regulations apply to this situation. Labeling requirements can 
be used but, by themselves, do not meet the agency's regulatory 
objectives.
2. The Regulated Industry
    Often, the industry that manufactures and distributes an FDA-
regulated product is fairly easily characterized. This facilitates 
regulation. That is not the case for animal protein products, as the 
following brief overview makes clear.
    Renderers collect animal tissues from a variety of sources, and 
process these tissues into both protein and nonprotein products. The 
renderers may be specialized (packer/renderer) or independent. The 
packer/renderer, which involves a renderer associated with a large 
slaughter operation, specializes in one species--primarily cattle, 
swine, or poultry. Thus, whether the packer/renderer handles ruminant 
materials is fairly easily determined. The independent renderer, on the 
other hand, obtains a variety of raw materials ranging from restaurant 
scraps to byproducts from multi-species slaughtering operations to dead 
animals obtained from farmers. Typically, the independent renderer does 
not have a practical method to separate incoming ruminant from 
nonruminant materials, and thus commingles both ruminant and 
nonruminant materials in the rendering process. The rendered product is 
typically designated ``meat and bone meal,'' but rendering operations 
produce a variety of other products. Renderers sell their products to 
animal protein blenders, animal feed manufacturers or pet food 
manufacturers. Virtually all rendered material at present is used 
ultimately for pet food or the feed of livestock or poultry.
    Animal protein blenders mix animal and plant protein materials to 
meet a protein guarantee stated on the label, and to make a balanced 
nutritional product. Typically, the blender does not separate ruminant 
from nonruminant animal protein in its blending operation, although it 
may keep mammalian, poultry, fish and soybean meal protein separate at 
least in the initial stages. The blender sells its products to feed or 
pet food manufacturers. Some renderers also blend animal protein 
products.
    Feed manufacturers use the protein material to make a complete feed 
(ready to be feed to animals), or a concentrated feed that needs to be 
further diluted (blended) before it can be fed to animals. The feed may 
be manufactured by an off-farm miller, or on the farm. Feed that is 
manufactured off-farm may be sold to one or more persons (for blending 
and/or further distribution) before reaching the farm.
    Farmers that feed animals typically raise one species, but may have 
more than one (including both ruminants and nonruminants). Only about 
10 percent of all animal protein products are fed to ruminants (mainly 
cattle) but approximately half of all animal protein products comes 
from ruminants.
3. Enforcement Considerations
    The industry scenario described in the preceding section presents 
unique enforcement challenges. The agency is aware, from the comments 
to the ANPRM and other sources, of concerns that the regulatory impact 
be minimized. The agency is also aware of the need to provide incentive 
for innovation, e.g., in testing methodology and manufacturing 
technology, that would reduce the need for regulation. Finally, the 
agency is aware of the need, in designing a regulatory program, to 
acknowledge the different circumstances that exist in the industries 
previously described.
    Therefore, the agency has designed a proposed regulatory scheme 
using the following principles. First, the agency has identified 
minimally necessary requirements to meet its regulatory objectives. The 
agency's goal is to apply risk management principles that minimize 
risk. Second, the proposed regulation applies greater restriction where 
the risk is greater--for example, where a firm handles both ruminant 
and nonruminant materials and intends to keep them separated. Third, 
the agency intends to rely on normal business records for much of the 
documentation it needs.
    A fourth and most important principle concerns the related 
objectives of flexibility and providing incentives to reduce 
recordkeeping and labeling requirements. The proposed regulation 
provides for the reduction or elimination of recordkeeping and labeling 
requirements, upon the development of methods for detection, 
deactivation, or verification of product identity. These provisions are 
described further in the discussion that follows.
    Industry-wide adoption of scientific advances including, or in 
addition to, those specified in the regulation, could ultimately lead 
to amendment or revocation of any final regulation. An example of an 
additional method would be the development of a practical method to 
detect the presence of ruminant protein in animal protein products or 
feed, which could be used for quality control by firms that separate 
ruminant from nonruminant protein, and by firms downstream from 
renderers.
    Similarly, research leading to identification of the TSE causative 
agent and the etiology of BSE, and the characterization of the zoonotic 
nature of animal TSE's, could also lead to amendment or revocation of 
any final regulation.

[[Page 570]]

    The agency has tentatively decided not to place any record keeping, 
labeling or other specific requirement on firms that handle only 
protein materials from nonruminant sources. An example would be a 
rendering operation that is part of a swine slaughter operation. 
However, if these firms would use or intend to use animal protein 
products containing ruminant tissues in ruminant feed, or caused such 
use or intended use, the feed would be adulterated under the act.
    The agency has also tentatively decided to require farmers (those 
responsible for feeding ruminant animals) only to make available copies 
of invoices and labeling for feed purchases. Farmers would not be 
required to maintain written procedures for handling animal protein 
products. These minimal requirements would apply even if the farmers 
were feeding both ruminant and nonruminant animals. Purchase records 
would be used primarily for traceback purposes. Because only minimal 
requirements would be placed on farmers, the proposed rules require 
that labeling for the animal protein and feed products caution against 
feeding the products to ruminants. Comments on these two tentative 
decisions are encouraged.

B. Outline of the Proposed Regulation

    The proposed regulation places two general requirements on persons 
that manufacture, blend, process, and distribute animal protein 
products and feeds made from such products. The first requirement is to 
place cautionary labeling on the protein and feed products. The second 
is a requirement to provide FDA with access to sales and purchase 
invoices, for compliance purposes. For example, an invoice obtained 
from a feed manufacturer for a protein product not labeled with the 
cautionary statement could be used to trace back to the supplying 
renderer to ensure that it manufactures and distributes animal protein 
product from nonruminant sources.
    Firms (renderers, blenders, and feed manufacturers and 
distributors) that handle animal protein products from both ruminant 
and nonruminant sources, and that intend to keep the products separate, 
would have certain additional requirements related to their source of 
nonruminant material; the need for separate facilities or cleanout 
procedures; and the need for SOP's. The same requirements would apply 
to firms that handle feeds containing animal protein products from both 
ruminant and nonruminant sources, and that intend to keep the feeds 
separate. Requirements would be greater for these operations because of 
the greater risk they would present for the possibility of ruminant 
protein being fed to ruminants.
    The proposed rule provides that some or all of the regulatory 
requirements would not apply if innovations such as development of test 
methods and deactivation processes for TSE agents were scientifically 
validated and put into commercial use. Provisions for use of such 
methods do not imply that the agency believes that such agents are or 
will be in the animal protein products. The objective is to minimize 
the risk that the agent would occur in the products, regardless of the 
level of risk. Certain minimal but additional requirements would be 
imposed in such circumstances. For example, because the innovations 
likely would be applied by renderers, the renderers would need to 
certify to downstream customers that the methods were being utilized.
    Section 589.2000(a) presents definitions of certain words used in 
the regulation. The definition of ``protein derived from ruminant and 
mink tissues'' excludes blood from bovines, milk proteins, and 
gelatins. Thus, those products are not subject to the regulatory 
provisions of the regulation. The proposed rule does not apply to any 
nonprotein animal tissues such as tallow or other fats. ``Renderer'' 
includes firms, not traditionally considered to be included within the 
definition of that term, but that collect animal tissues from various 
sources and subject them to minimal processing before offering the 
materials for use in animal feed. Also, ``feed manufacturers'' is 
defined to include both off-farm and on-farm feed manufacturing 
operations.
    Section 589.2000(b) declares that protein derived from ruminant and 
mink tissues is not GRAS when intended for use in the feed of ruminant 
animals. The use or intended use of such material in ruminant animal 
feed causes the feed to be adulterated.
    Section 589.2000(c) establishes regulatory requirements for 
renderers that manufacture products that contain or may contain protein 
derived from ruminant and mink tissues. (``May contain'' allows for the 
fact that the renderer may not be able to determine the species of some 
incoming material). These renderers typically process both ruminant and 
nonruminant materials, but do not attempt to separate ruminant from 
nonruminant materials. Section 589.2000(e) covers renderers that intend 
to separate such materials. As mentioned, renderers that process 
exclusively nonruminant materials are not covered by the specific 
requirements of the regulation. Section 589.2000(c) applies to animal 
protein products intended for use in animal feeds, as well as animal 
feeds containing such products.
    Two requirements would be placed on renderers covered by 
Sec. 589.2000(c). First, they would be required to label their products 
to indicate that they contain (or may contain) protein derived from 
ruminant and mink tissues, and that the materials should not be fed to 
ruminant animals or used to manufacture feed for ruminants. Second, the 
renderers would be required to maintain copies of sales invoices for 
all their animal protein products, and to make those copies readily 
available for inspection. As an example, FDA would use the invoices to 
follow up with customers to verify that the customers are not using the 
products to manufacture ruminant feed. Because sales invoices are 
normal business records, the agency believes that the additional burden 
imposed by this requirement would be minimal.
    Section 589.2000(c) renderers would be exempted from the labeling 
and record requirements if they used a manufacturing method that 
deactivates the agent that causes TSE's, or a test method that detects 
the presence of the agent that causes TSE's. Both methods would have to 
be validated by FDA, and made available to the public. The regulation 
would require ``routine'' use. That is, renderers would be required to 
use the test method on all incoming material or in each batch it 
manufactures.
    Section 589.2000(c) renderers would be exempted from the record 
requirements (but not the labeling requirement) if they used a safe 
method to mark the presence of the materials. The marking could be 
visible to the naked eye, e.g., through use of a dye, or by a nonvisual 
means. One ANPRM comment recommended use of a colored uniform fine iron 
product to identify specific feed ingredients. If the marking is not 
visible, the marking agent must be detectable by a method that has been 
validated by FDA, and made available to the public. The mark must be 
permanent, i.e., it must be visible in mixed feed as used on the farm.
    Section 589.2000(d) establishes regulatory requirements for persons 
other than renderers and persons responsible for feeding ruminants that 
handle animal protein products or feeds containing such products. This 
includes protein blenders, and feed manufacturers and distributors. 
However, as in the case of renderers, those firms that would otherwise 
be included in Sec. 589.2000(d) but that handle both ruminant and 
nonruminant

[[Page 571]]

materials and intend to separate the materials would be covered by 
Sec. 589.2000(e) instead. Protein blenders, and feed manufacturers and 
distributors, that handle only nonruminant materials are excluded from 
the regulatory requirements of the proposed rule.
    Persons covered by Sec. 589.2000(d) would be subject to the same 
requirements as renderers, i.e., labeling and records. The records 
would include invoices both to cover purchases and sales of animal 
protein products and feeds containing those products. For on-farm 
mixers, production records could be substituted for sales invoices.
    Section 589.2000(d) firms would be exempt from the labeling and 
record requirements if they purchased materials from renderers that 
certified the use of deactivation or detection methods as described in 
Sec. 589.2000(c). They would also be exempt from the labeling and 
record requirements if they purchased materials from persons other than 
renderers who certified that they purchased materials from renderers 
who certified the use of deactivation and detection methods as 
described in Sec. 589.2000(c). Paragraph (d) firms would also be exempt 
if they used the deactivation or detection methods described in 
Sec. 589.2000(c), where use of such method is appropriate for the 
particular firm.
    Paragraph (d) firms would be exempt from the record requirements if 
they purchased visibly-marked materials, or purchased from renderers 
that certified the use of marking methods as described in 
Sec. 589.2000(c). They would also be exempt from the record 
requirements if they used the marking methods as described in 
Sec. 589.2000(c).
    Section 589.2000(e) establishes regulatory requirements for 
renderers, protein blenders, feed manufacturers and distributors, and 
independent haulers that handle both ruminant and nonruminant 
materials, and intend to keep the products separate. Section 
589.2000(e) establishes four kinds of requirements. First, the firms 
would have the same labeling and recordkeeping requirements as 
specified in paragraphs (c) and (d) of Sec. 589.2000, except that the 
labeling requirement would apply only to the ruminant and mink 
materials. Second, a renderer's source of nonruminant protein materials 
would be limited to single-species facilities, i.e., facilities 
slaughtering only swine. A renderer could purchase nonruminant protein 
from more than one single-species facility. The agency believes that 
this restriction is necessary because of its understanding that it is 
not likely to be feasible for mixed species slaughterhouses to 
undertake the additional compliance costs, and possibly additional 
facility costs, that would be required to assure separation of ruminant 
and nonruminant materials. The restriction would therefore help assure 
that enforcement of Sec. 589.2000(e) would be practicable. However, the 
agency specifically requests comments on this provision.
    Third, the firms would be required to establish separate equipment 
and facilities for the two kinds of materials, or cleanout procedures 
to prevent cross contamination. Fourth, the firms would need to 
establish written SOP's specifying the cleanout procedures, if used, 
and specifying procedures for separating the materials from the time of 
receipt until the time of shipment. Although Sec. 589.2000(e) applies 
to several different kinds of firms, the agency's preliminary 
expectation is that only feed manufacturers and distributors will find 
it feasible to separate ruminant and nonruminant materials. As an 
example, a feed manufacturer might obtain ruminant materials from an 
independent renderer and swine materials from a packer/renderer, and 
use these materials to manufacture feed both for ruminants and 
nonruminants. The feed manufacturer would be required to meet the 
criteria listed previously, including the use of separate equipment and 
facilities or cleanout procedures, and the establishment of SOP's. The 
requirements of Sec. 589.2000(e) would be applicable in the 
transportation process, whether the material is hauled by the feed 
manufacturer or another party such as an independent hauler. The 
requirement for separate facilities, procedures or SOP's would not 
apply to a firm, e.g., a feed mill or hauler, that handles only 
nonruminant materials, or only ruminant materials. Nor would it apply 
to a firm that handles both ruminant and nonruminant materials but does 
not attempt to separate the two kinds of materials.
    The paragraph (e) firms would be exempted from the labeling and/or 
record keeping requirements, and the requirements related to sourcing, 
facilities and SOP's, if they meet the appropriate criteria for 
exemption. That is, renderers covered by Sec. 589.2000(e) would be 
exempt from the labeling and recordkeeping requirements if they used 
deactivation or detection methods, and from the recordkeeping 
requirements if they used marking methods. Blenders and feed 
manufacturers and distributors would be exempt in a similar manner.
    Section 589.2000(f) establishes requirements for those who are 
responsible for feeding ruminant animals. The only requirement 
contained in this paragraph is that those persons make available to FDA 
copies of purchase invoices and labeling for all incoming feeds. 
However, Sec. 589.2000(f) does not apply to the feed manufacturing 
portion of farms and feedlots that have on-farm feed manufacturing 
operations. Section 589.2000 (d) and (e) would apply in those 
instances. Furthermore, persons who feed or intend to feed ruminant 
protein to ruminant animals would be subject to regulatory action for 
using or intending to use an unapproved feed additive as established in 
Sec. 589.2000 (b).
    Section 589.2000(g) establishes that violations of Sec. 589.2000 
(c) through (f) would cause animal protein products or feed containing 
animal protein products to be adulterated under sections 402(a)(4) or 
402(a)(2)(d) of the act, or misbranded under section 403(a)(1).
    Section 589.2000(h) establishes inspection and records retention 
requirements for persons covered by section 589.2000 (c) through (f). 
Records that are required under those paragraphs would need to be kept 
for a minimum of 2 years. The agency believes that this time period is 
adequate for purposes of verifying compliance with the regulation's 
procedural requirements. The agency invites comments on the need for a 
longer retention period related to the BSE incubation period, 
especially the practicality of using such records for epidemiologic 
investigation.
    Section 589.2000(h) also requires that written procedures required 
by the regulation be made available for inspection and copying by FDA. 
The written procedures referred to are those specified in 
Sec. 589.2000(e)(3). Affected firms would be required to have a copy of 
the current procedures available at all times.

VII. Specific Protein Sources

    A number of comments discussed the exemption of certain tissues, 
including fluids, from any prohibitory rule. Most commentors favored 
the exemption of one or more tissues, including milk products; blood 
products; skeletal muscle and gelatin; and a variety of other tissues 
including both protein and nonprotein materials. Most of the comments 
cited published studies as well as positions taken by the European 
Union, European Commission, WHO and the government of France. The 
agency's comments on the status of milk, gelatin and blood follow. In 
addition, we discuss a comment on the use of canine and feline derived 
protein.

[[Page 572]]

A. Milk Proteins

    Data available to the agency suggests that milk proteins do not 
transmit the TSE agent. Research with oral exposure, intracerebral, and 
intraperitoneal administration of milk or mammary glands from BSE-
infected bovine to normal and BSE-sensitive mice has not demonstrated 
the development of TSE's (Refs. 42 and 52). An expert group under the 
auspices of WHO recommended that all countries prohibit the use of 
ruminant tissues in ruminant feed. The WHO expert group also declared 
that milk and milk products, including such products from the United 
Kingdom, are safe for human consumption. In addition, OIE has 
recommended, because of lack of infectivity, that restriction of import 
or transit of milk products from healthy animals from BSE countries 
need not be instituted. Therefore, the proposed rules provide that 
protein derived from ruminant tissues does not include milk proteins 
derived from bovine, ovine, caprine, and cervine.

B. Gelatin Proteins

    Data available to the agency suggest that gelatin does not transmit 
the TSE agent. The WHO has concluded that gelatin in the food chain is 
considered to be safe, as the conventional manufacturing process for 
gelatin has been demonstrated to significantly inactivate any residual 
infective activity that may have been present in source tissues (Ref. 
2). FDA concurs with this statement and the scientific information on 
which it is based. Thus, the proposed rule excludes gelatin from 
protein derived from ruminant tissues.

C. Blood Meal Proteins

    Data available to the agency suggests that bovine blood components 
do not transmit the TSE agent (Refs. 56, 78, and 94). Therefore, the 
proposed rule does not include blood meal from bovine as a protein 
derived from ruminant tissues.

D. Canine and Feline Derived Proteins

    One comment suggesting that canine- and feline-derived proteins 
should not be fed to ruminants because of the finding of FSE in 
domestic cats in the United Kingdom. The agency is also aware of an 
ethically-based objection by some to the rendering of the carcasses of 
pet animals. TSE has not been diagnosed in dogs or other canines. FSE 
has not been diagnosed in the United States. The agency has considered 
the information provided by the comments and the published scientific 
literature (Refs. 26 and 27), and has preliminarily determined that 
there is no measurable risk of the spread of TSE's from canine- or 
feline-derived proteins to ruminants in the United States. However, the 
agency is inviting further comment on this issue.

VIII. Environmental Impact

    FDA has carefully considered the potential environmental effects of 
this proposed rule and of five possible alternative actions. In doing 
so, the agency reviewed ANPRM comments submitted by a number of 
organizations and individuals. The comments were mostly concerned with 
the volume of material (e.g., dead animals and slaughter byproducts) 
that would be affected, and the nonrendering or rendering alternative 
means by which these materials could be disposed of, or utilized, 
safely. Comments suggested a number of uses for the processed 
materials, other than ruminant feed, including use in nonruminant 
animal feed and fertilizers, and disposal methods such as on-farm 
burial, landfilling, and incineration.
    In the environmental assessment that accompanies this proposed 
rule, FDA evaluated the environmental consequences of six different 
options. These included: No action; ruminant and mink-to-ruminant 
prohibition (the proposed action); partial ruminant and mink-to-
ruminant prohibition; mammalian-to-ruminant prohibition; prohibition of 
feeding tissues from any animal species in which TSE has been detected 
in the United States; and sheep and goat specified offal prohibition.
    The environmental assessment considered each of the alternatives in 
the context of two scenarios. The first assumes that BSE does not occur 
in the United States, regardless of the alternative selected. The 
second scenario assumes that BSE does occur in the United States, again 
regardless of the alternative selected. In the first scenario, the 
assessment considered environmental impacts related to on-farm 
disposal, landfill, incineration, and industry wastes produced. The 
second scenario considered environmental impacts related to production 
losses and impacts, wildlife exposure, on-farm disposal, landfill, and 
incineration.
    In the first scenario (no BSE), the ``no action'' alternative does 
not have environmental consequences because it is the ``status quo'' or 
baseline alternative. Environmental impacts for the other alternatives 
ranged from slight to moderate increases in environmental effects. For 
the proposed option (ruminant-to-ruminant) there would be moderate 
increases in environmental effects from on-farm disposal and landfill 
use, and slight increases in the other effects. Increases in waste 
disposal (on-farm, landfill, etc.) are anticipated to be temporary, 
however, as the markets are expected to adjust quickly to the more 
restricted uses of the ruminant materials.
    In the second scenario (occurrence of BSE), the greatest negative 
environmental effect would occur in the case of the ``no action'' 
alternative. This is because the likely spread of the BSE agent through 
animal feed before the first BSE case is diagnosed would result in 
disposal of large numbers of animals by means other than rendering. 
Similar large impacts would occur with the sheep and goat, and TSE 
animal, options. Minimum environmental consequences would occur with 
the proposed option (ruminant-to-ruminant), because the spread of the 
BSE agent would have been controlled. Minimum to small effects would 
result from the remaining two options, partial ruminant prohibition and 
mammalian-to-ruminant prohibition.
    The agency has concluded that the proposed rule will not have a 
significant impact on the human environment, and that an environmental 
impact statement is not required. FDA's finding of no significant 
impact (FONSI) and the evidence supporting that finding, contained in 
an environmental assessment (EA) prepared under 21 CFR 25.31, may be 
seen in the Dockets Management Branch (address above) between 9 a.m. 
and 4 p.m., Monday through Friday. FDA invites comments and submission 
of data concerning the EA and FONSI.

IX. Analysis of Impacts

    FDA has examined the impacts of the proposed rule under Executive 
Order 12866, under the Regulatory Flexibility Act (5 U.S.C. 601-612), 
and under the Unfunded Mandates Reform Act (Pub. L. 104-4). Executive 
Order 12866 directs agencies to assess all costs and benefits of 
available regulatory alternatives and, when regulation is necessary, to 
select regulatory approaches that maximize net benefits (including 
potential economic, environmental, public health and safety, and other 
advantages; and distributive impacts and equity). The Regulatory 
Flexibility Act requires agencies to analyze regulatory options that 
would minimize any significant impact of a rule on small entities. The 
Unfunded Mandates Reform Act requires that agencies prepare an 
assessment of anticipated costs and benefits before proposing any rule 
that may result in an annual expenditure by State, local, and tribal 
governments, in the aggregate, or by the private sector, of 
$100,000,000 (adjusted annually for inflation). FDA

[[Page 573]]

concludes that this proposed rule is consistent with the principles set 
forth in the Executive Order and in these two statutes.
    A study of the impacts on industry of the proposed rule (on file 
with the Docket Management Branch (Ref. 114)) conducted for FDA by the 
Eastern Research Group (ERG), a private consulting firm, and the 
discussion in the remainder of this section, demonstrate that the 
proposed rule constitutes an economically significant rule as described 
in the Executive Order. The agency has further determined that the 
proposed rule will have a significant impact on a substantial number of 
small entities. The proposal makes no mandates on government entities 
and is estimated to result in aggregate net annual costs ranging from 
$21.4 to $48.2 million to the private sector.

A. The Need for Regulation

    Although BSE has not been diagnosed in the United States, the need 
for regulatory action is based on a need to protect U.S. livestock from 
the risk of contracting BSE. In its guidelines for the preparation of 
Economic Impact Analyses, the Office of Management and Budget (OMB) 
directs Federal regulatory agencies to determine whether a market 
failure exists, and if so, whether that market failure could be 
resolved by measures other than new Federal regulation. In this 
instance, private incentive systems for both suppliers and purchasers 
may fail in markets for cattle, rendering, and ruminant feed. The 
potential for market failure among the suppliers in these sectors 
results from the externality that could be created by individual 
suppliers imposing economic hardships on other suppliers within the 
industry. The potential for market failure among the purchasers results 
from the inadequate information that would be available to purchasers 
of potentially infective products.
    Any renderer, feed manufacturer, or cattle producer that permits 
animal protein derived from ruminants and mink to be placed in ruminant 
feed increases the risk that other renderers, feed manufacturers, or 
cattle producers will suffer the severe economic consequences that 
would follow an outbreak of BSE in the United States. The industry is 
aware of this risk, as evidenced by the existence of voluntary programs 
aimed at reducing the transmission of the infectious agent. These 
include an adult sheep rendering ban recommended by the NRA, a 
recommended ban on the feeding of rendered ruminant protein to 
ruminants by the NCBA and others, and scrapie-free certification 
programs by individual sheep producers. Although the benefits of such 
programs--the reduction or elimination of the risk of an outbreak of 
BSE and the increased consumer confidence in the safety of the 
industries' products--accrue to all members of these industries, 
compliance with these measures is incomplete, because individual 
noncomplying members can avoid the costs of risk reduction measures 
while still enjoying the benefits of compliance by others in the 
industry.
    If purchasers could easily identify the risks of infective agent 
contamination associated with products from specific suppliers, they 
could more easily take defensive actions to reduce these risks (e.g., 
refusing products from cattle known to have consumed specified ruminant 
proteins). Purchasers are unlikely to obtain the information they need, 
however, for several reasons. First, the long incubation period for BSE 
creates a lag between the actual onset and the recognition of the 
disease and could lead to a suboptimal level of risk prevention by the 
concerned parties during the incubation period. By the time the first 
signs of disease are observed, many animals may have been already 
exposed. Moreover, renderers sell their product to feed manufacturers 
who frequently combine proteins from many different plant sources and 
animal species to produce cattle feed. Ruminant producers, therefore, 
have no sure way of knowing whether a particular batch of feed is free 
from potentially infective proteins and cannot easily avoid purchasing 
risky feed. Finally, if renderers or feed manufacturers do not believe 
that BSE is an important threat they may choose not to take preventive 
action, regardless of the risk levels perceived by epidemiological 
experts or consumers.

B. Benefits

    The proposed rule would reduce the risk of an outbreak and 
subsequent proliferation of BSE disease in the United States. It may 
also forestall the loss of consumer confidence in the U.S. beef market 
due to concerns about BSE and its implications. Thus, the benefits of 
this proposal would include the value of reduced risks to human and 
animal health and to the economic stability of the U.S. livestock and 
livestock dependent industries compared to the ``no action'' option. In 
technical terms, these benefits measure the expected value of the 
future disease-related costs that might be averted by the proposed 
rule. Specifically, they are calculated as a product of three factors: 
(1) The probability that, in the absence of this rule, BSE would be 
introduced and proliferate in the United States, (2) the costs, both 
direct and indirect, that would be associated with the spread of BSE in 
the United States, and (3) the extent to which the proposed rule would 
reduce the likelihood of BSE proliferation.
    BSE has not been detected in the United States and the probability 
that it currently exists is remote. Nevertheless, it is possible that 
BSE could develop in the future. Once developed, BSE could remain 
undetected for several years because of its long incubation period and 
because, at present, it can be diagnosed reliably only by microscopic 
brain examination after death. During the period between introduction 
and diagnosis, the disease could spread as it apparently did in the 
U.K. via intake of infective feed. If regulation was delayed until 
after discovery, the costs would be substantial. By addressing the 
central risk factors associated with BSE, FDA believes that the 
proposed rule would eliminate the vast majority of the BSE-related 
risks and costs.
    BSE was first detected in the U.K. in November 1986, and a ban on 
ruminant offal in ruminant feed was imposed in the U.K. in July 1988 
(Ref. 115). An analysis of cattle born before and after the feed ban 
went into effect suggests that the feed ban significantly decreased 
disease transmission (Ref. 116). This analysis found that the incidence 
of confirmed BSE roughly doubled each year for animals born between 
July 1985 and July 1988, but declined precipitously in animals born in 
August 1988 compared to the previous year and continued to fall 
thereafter. Because BSE has a long incubation period, however, a 
decrease in the incidence was not evident until several years after the 
initial feed ban was implemented. The incidence of BSE peaked in 1992 
at 36,681 detected cases, or approximately 0.3 percent of the UK's 11.5 
million cattle. Despite a sharp decrease in the incidence rate since 
then, by the end of 1996, more than 165,000 cases of BSE will have been 
detected, with one-third of all U.K. cattle herds infected (Refs. 115 
and 117).
    The likelihood that BSE will someday be developed in the United 
States cannot be estimated with any confidence, although U.S. risk 
factors are believed to be significantly smaller than existed in the 
United Kingdom of the early 1980's. As described previously, the 
various remaining modes include transmission from scrapie-infected 
sheep or other animals with TSE, e.g., through meat and bone meal; 
introduction via imported

[[Page 574]]

animals; and spontaneous introduction (which in some TSE's has been 
hypothesized to occur at a rate of about 1 case per million per year). 
USDA import controls and the voluntary bans on sheep offal and ruminant 
tissues in ruminant foods reduce the risk of disease introduction but 
cannot completely eliminate it.
    Although FDA cannot quantitatively estimate the risk of a 
significant BSE outbreak in the United States, the agency has used the 
U.K. experience, modified to account for major differences in 
circumstances, to assess the consequences of the potential spread of 
the disease within the United States. If BSE were introduced in this 
country, the pattern of disease spread would presumably be similar to 
that in the United Kingdom, with most symptomatic disease appearing in 
older cattle (the average time for BSE symptoms is approximately 5 
years after infection (Ref. 115)). The rate of spread of symptomatic 
disease would probably differ, however, because compared with the pre-
BSE U.K. dairy industry, U.S. dairy cows are younger and are exposed to 
meat and bone meal in feed later in life than was true in the United 
Kingdom (Ref. 118). United Kingdom dairy animals were historically fed 
meat and bone meal as calves, whereas U.S. dairy cows ingest meat and 
bone meal primarily as adults.
1. Methodology
    To develop an illustrative estimate of the number of cattle that 
might be lost to BSE infection if the disease were to occur in the 
United States in the absence of regulation, FDA extrapolated from the 
experience in the United Kingdom, but adjusted for the differences in 
cattle age and potential age of exposure to meat and bone meal. This 
extrapolation assumes that the detection of BSE in this country would 
quickly lead to a ruminant-to-ruminant feed prohibition but that, as in 
the United Kingdom, BSE incidence would nonetheless continue to 
increase for 6 years due to the disease's long incubation time (hence 
several years of disease spread before the diagnosis of the first 
case). To account for the difference in cattle age-related risk 
factors, FDA assumed that, if BSE occurred in the United States, the 
affected animals would be predominately dairy cows of age 4 or more, 
rather than age 3 and up as in the U.K. (due to the differences in age 
of exposure.) The difference of 1 year is based on the agency's 
estimate that U.S. cattle are first exposed to meat and bone meal 1 
year later than U.K. cattle. Therefore, the onset of the clinical 
disease is estimated to start 1 year later. Accordingly, only 47 
percent of U.S. dairy cows are age 4 and up (about 4.8 million cows), 
while 90 percent of United Kingdom cows are age 3 and up (about 2.6 
million cows). Thus, a lower percentage of U.S. cattle were assumed to 
be at risk of symptomatic BSE, and the projected rate of death was 
proportionately lower. Based on the relative size of the U.S. and U.K. 
dairy cattle populations, these projections suggest that if BSE were 
introduced in the United States and spread in a similar manner, the 
disease would destroy 299,000 U.S. cattle over 11 years (4.8 x 2.6 x 
162,000 U.K. BSE deaths). (These calculations assume that a feed 
prohibition would be implemented very soon after the first case is 
diagnosed, and that the prohibition would immediately begin to affect 
the underlying rate of new infection. If a feed prohibition were not 
implemented at that time, the number of cattle deaths would be much 
higher.)
    Other adjustments could be made to this estimate, but their effect 
on the direction of the results would be uncertain. For example, 
compared with U.K. practices before 1988, U.S. dairy cattle consume a 
higher proportion of concentrated feed that contains meat and bone 
meal. On the other hand, most U.S. concentrate contains a lower 
percentage of meat and bone meal (and a higher percentage of vegetable-
based proteins). If BSE infectivity in feed is highly dose-dependent, 
these factors could cause FDA's cost estimate to be either too high or 
too low, if one of the factors is dominant over the other.
    The risks and costs associated with BSE when it occurs are 
primarily of three types. First, there is the possible risk and 
associated cost of ruminant-to-human transmission of TSE disease. The 
proposed rule would reduce this risk by eliminating the main routes by 
which ruminants might acquire transmissible TSE, greatly reducing any 
risk incurred by the human consumption of ruminant-derived products. 
Thus, the proposed rule would reduce the risk of future mortality, 
morbidity, and health care costs due to human TSE. Second, there is the 
risk of livestock losses. These losses include not only the deaths of 
BSE-infected animals, but also the loss and disposal costs of other 
animals that would be destroyed, either to contain the immediate spread 
of disease or to restore consumer confidence in the safety of beef and 
dairy products. Third, there are the costs associated with decreased 
domestic sales and exports of beef and other bovine-derived products 
until consumer and international confidence could be restored.
2. Reduced Risk to Public Health
    As discussed earlier, scientists believe that the nv-CJD cases 
identified in the U.K. may have been associated with the BSE epidemic. 
If indeed there were such an association, and if BSE were to occur in 
this country, there would be a risk of spreading BSE-related human TSE 
in the United States The proposed rule therefore might avert human 
deaths in the United States, although the number of deaths cannot be 
estimated. The proposed rule would also save the health care and other 
costs associated with treating individuals with the disease.
3. Reduced Risk of Direct Livestock Losses
    For estimating the present value of livestock losses if BSE 
occurred in the United States, FDA assumed that the first case of BSE 
would not be detected--even in the absence of the proposed rule--for 4 
years. Based on an estimated value of $502 per animal (Ref. 119) and 
disposal costs of $4 per animal, direct losses from the death of 
299,000 BSE-infected cattle would reach $151 million over 11 years 
(starting 4 years from now). At a discount rate of 7 percent, the total 
present value of these losses is $75 million.
    In addition to the animal losses from direct infection, a 
significant outbreak would probably lead to the eradication of high-
risk animals to restore consumer confidence. Switzerland, for example, 
has proposed slaughtering all cattle born before that country 
implemented a feed ban, or approximately one-eighth of its national 
herd (Ref. 120). The United Kingdom has begun a program to destroy and 
incinerate all animals over age 30 months as they reach the end of 
their useful life, or about 1 million animals in 1996 and a total of 
4.7 million over 6 years. In addition, the United Kingdom has a program 
to slaughter some unmarketable male dairy calves (126,000 had been 
slaughtered as of August 1996) and up to 147,000 additional ``high-
risk'' animals (Refs. 115 and 121). Even if the U.K. eradication of 
animals were limited to a one-time total of 1 million cattle (about 8.7 
percent of their cattle stock), similar measures in the United States, 
if they occurred immediately upon detection of the disease, would 
result in the one-time destruction of $4.58 billion worth of cattle, 
with a present value of $3.49 billion.
4. Costs of Future Regulation
    Moreover, the ability to control a BSE outbreak once it occurred 
would require putting in place restrictions on the use

[[Page 575]]

of ruminant proteins in ruminant feeds that would be at least as 
restrictive as the measure under this proposed rule. Presumably, the 
total costs of implementing a ruminant-to-ruminant feed prohibition at 
that point would be at least as great as the low estimates for this 
proposed rule, or $21.4 million per year. The present value of these 
future regulatory costs would total approximately $240 million. 
Moreover, this estimate may vastly understate the economic impact 
because the market value of ruminant-derived proteins could disappear 
if there were an actual outbreak.
5. Reduced Risk of Losses in Domestic Sales and Exports
    If BSE were to emerge in the United States, the news could greatly 
reduce both domestic sales and exports of bovine products. In the 
United Kingdom, domestic consumption fell by more than 20 percent 
between 1988 and 1990 and has not yet fully recovered (Ref. 122), 
presumably due to continuing concerns about possible links between BSE 
and CJD. If U.S. consumers acted similarly, U.S. producers of beef 
products could lose over $9 billion in annual sales (Ref. 123). 
Alternatively, U.S. consumers might demonstrate considerably less 
concern, as the U.K. experience may have improved the ability of U.S. 
risk managers to communicate both the extent of the risk of contracting 
CJD from the consumption of beef and the responsiveness of the 
government's safety policies. Nonetheless, it remains probable that the 
uncertainty surrounding a serious BSE outbreak would lead U.S. 
consumers to reduce their consumption and spending on beef by a 
significant amount. Also, at the same time that U.K. domestic sales of 
beef were declining due to the fear of BSE, the volume of U.K. exported 
beef fell by nearly 16 percent (Ref. 122). Based on U.S. beef exports 
in 1994 of approximately $2.2 billion (Ref. 109), a proportional 
decline of this magnitude would reduce U.S. exports by up to $0.3 
billion per year.
    While the values of such lost domestic and international sales 
would reduce the profits of the U.S. beef industry and the enjoyment of 
some U.S. consumers of beef, they do not provide an accurate measure of 
societal costs, because competitor industries, such as poultry, pork, 
and seafood, would gain new profits. Thus, the net costs that would 
result from such potential shifts in consumer spending cannot be 
precisely discerned without extensive economic modeling. While FDA 
examined a partial equilibrium model for projecting the approximate 
losses of consumer and producer surplus within the market for beef 
products, the agency could not adequately quantify the likely effects 
on the markets for substitutes of beef. Consequently, FDA could not 
estimate the net economic cost of these lost sales. Nevertheless, the 
magnitude of these potential costs could be substantial and the agency 
requests public comment on how the appropriate measurement 
methodologies could be developed and applied.
    Finally, even in the absence of evidence of BSE in the United 
States, consumer concern about BSE could affect beef consumption and 
expenditures. Thus, one benefit of implementing the proposed rule now 
is that it might prevent a loss of consumer confidence in the beef 
market, irrespective of the actual risk of BSE. FDA did not attempt to 
quantify this potential loss, but believes that it also may be 
substantial, particularly in light of the recent increased U.S. 
publicity of BSE and its hypothesized links to CJD.
6. Total Losses Averted
    In summary, the losses averted by the proposed rule include the 
expected value of the costs associated with BSE itself, and the 
potential value of forestalling a drop in domestic and international 
demand for U.S. beef due to BSE-related causes. The first component 
largely reflects the statistical probability that BSE could occur and 
spread within the United States and the potential $3.7 billion cost of 
destroying BSE-exposed livestock. The second primarily measures the 
expected loss to U.S. consumers and producers that would result from 
reduced sales. While FDA has not quantified these latter costs, 
plausible scenarios indicate that they could reach billions of dollars. 
Moreover, these figures have not included the possibility of lost lives 
and treatment costs associated with treating human TSE.
    Finally, the expected benefits of the proposed rule are slightly 
lower than the sum of the expected value of all the costs associated 
with BSE, because the rule would not totally eliminate all of the 
related risk (e.g., due to the possibility of spontaneous introduction 
of disease and the possible incomplete compliance with the rule). FDA 
believes, however, that any remaining risk would be extremely small. In 
addition, because the rate of BSE infection and the associated costs 
would probably vary geographically (as scrapie does now) (Ref. 98) , 
the benefits would vary across regions of the country.
7. Comparison of Alternatives
    As described elsewhere in this document, FDA is considering five 
alternatives to the proposed rule, in addition to other options that 
might be offered in the comments. The first three of these alternatives 
are: (1) No action (relying on voluntary industry activities), (2) 
prohibit only materials from U.S. species in which TSE has been 
diagnosed, and (3) a prohibition on proteins from specified sheep and 
goat offal in ruminant feed. Compared with the proposed action, 
prohibiting proteins from all U.S. TSE species provides similar 
reductions in the risk that BSE might be introduced, with a sheep/goat 
specified offal protein ban and no action providing progressively less 
risk reduction. The TSE species alternative, however, would be 
significantly less effective in limiting the spread of BSE (e.g., after 
spontaneous introduction) until BSE was diagnosed and cattle were added 
to the list of TSE species. Likewise, the two other alternatives would 
be significantly less effective in inhibiting the spread of ruminant-
to-ruminant transmission of disease once BSE is introduced. Thus, the 
expected value of the benefits of each of the three rejected options is 
substantially lower than the proposed rule, although the amount of 
difference cannot be estimated precisely.
    The agency is also considering two other alternatives: (1) A 
mammalian-protein-to-ruminant prohibition, and (2) a partial ruminant-
to-ruminant prohibition which would exclude all ruminant and mink 
tissues except certain bovine tissues. Compared with the proposed rule, 
both alternatives offer similar benefits in substantially inhibiting 
the initial introduction of BSE. The extent of inhibition of the spread 
of disease (and associated costs), however, would be different.
    The mammalian protein alternative would further reduce the spread 
of disease compared with the proposed rule, by reducing the risk of 
cross-contamination within rendering and processing plants. Thus, this 
alternative would bring the expected value of the BSE-related costs 
even closer to zero than would the proposed measure. However, the 
incremental benefit is small if cross- contamination under the proposed 
measure does not pose a substantial risk.
    The partial ruminant-to-ruminant prohibition would be less 
effective than the proposed measure, because it would be more 
administratively difficult to enforce. Thus, this alternative would not 
reduce the expected value of the

[[Page 576]]

BSE-related costs as much as the proposal. Again, however, the exact 
difference cannot be estimated, but would vary depending on the likely 
level of compliance under the alternative.

C. Industry Impacts

    The ERG study examines the composition, size, and scale of economic 
activity for the various affected industry sectors and provides 
estimates of the cost and high and low market impacts (depending on the 
size of the price change for restricted meat and bone meal of five 
regulatory options (see Table 1).

                      Table 1.--Estimated Costs of Alternative Regulatory Prohibitions \1\                      
                                                                                                                
                                                              Ruminant-to-   Partial                            
                                                  Mammalian-    ruminant   ruminant-to- Sheep/Mink-  Sheep/Goat-
                                                 to-ruminant   (proposal)    ruminant   to-ruminant  to-ruminant
                                                                                                                
Annualized Impacts----------------------------------------------------------------------------------------------
(4) ($  million)                                                                                                
----------------------------------------------------------------------------------------------------------------
                                      Low Market Impact Scenario ($25/ton)                                      
                                                                                                                
----------------------------------------------------------------------------------------------------------------
Capital Costs..................................         8.8          1.0          3.2           0.0          0.0
Operating/Disposal Costs.......................        10.1          0.1         14.4           5.1          0.2
Transportation.................................        10.7          7.6          5.3           0.0          0.0
Documentation..................................         1.9          1.5          0.5           0.0          0.0
Substitution Costs.............................         9.7          8.0          3.7           0.0          0.0
Renderer Revenue Losses........................        76.4         63.2         28.8           4.2          0.1
Nonruminant Gains..............................       (72.6)       (60.0)       (27.4)          0.0          0.0
                                                ----------------------------------------------------------------
      Totals...................................        45.0         21.4         28.5           9.3          0.3
                                                                                                                
----------------------------------------------------------------------------------------------------------------
                                     High Market Impact Scenario ($100/ton)                                     
                                                                                                                
----------------------------------------------------------------------------------------------------------------
Capital Costs..................................         8.8          8.2          4.9           0.0          0.0
Operating/Disposal Costs.......................        10.1         10.1         16.9           5.1          0.2
Transportation.................................        10.7          7.6          5.3           0.0          0.0
Documentation..................................         1.9          1.8          0.7           0.0          0.0
Substitution Costs.............................         9.7          8.0          3.7           0.0          0.0
Renderer Revenue Losses........................       305.6        252.8        115.4           4.2          0.1
Nonruminant Gains..............................      (290.3)      (240.2)      (109.6)          0.0          0.0
      Totals...................................        56.5         48.3         37.3           9.3          0.3
----------------------------------------------------------------------------------------------------------------
\1\ Totals may not match text due to rounding error.                                                            

1. The Proposed Rule
    The proposed alternative would prohibit the use of ruminant and 
mink protein in ruminant feeds. Currently, only about 10 percent of the 
meat and bone meal supply is used in ruminant feed, but over 80 percent 
of the meat and bone meal contains some ruminant material. ERG forecast 
that because no mixed-species slaughtering or rendering establishments 
would find it profitable to separate ruminant from nonruminant offal, 
most would continue to contain ruminant material. ERG estimated that 
affected renderers and feedmills would incur total direct compliance 
costs ranging from $10.2 to $27.6 million per year. Renderers would 
bear annual costs of about $6.3 million and feed mills would bear 
annual costs of from $3.8 to $21.3 million. Arrayed by compliance 
category, transportation costs were estimated at $7.6 million; 
documentation costs for activities to ensure control of ruminant feed 
constituents ranged from $1.5 to $1.8 million; and capital costs and 
operating costs ranged from $1.0 to $8.2 million and $0.1 to $10.1 
million, respectively, due primarily to the need for some feedmills to 
expand their capacity to offer both ruminant and nonruminant feed 
products under a high market impact scenario.
    Because consumer response to the rule is uncertain, ERG could not 
develop a precise projection of future meat and bone meal prices. ERG 
estimated, however, that the regulatory prohibition of marketing 
ruminant meat and bone meal to ruminants would lower the price of this 
product by from $25 to $100 per ton, decreasing rendering industry 
revenues by from $63.2 to $252.8 million per year. In contrast, a lower 
MBM price would increase sales of meat and bone meal to the nonruminant 
sector and the resulting increased profits for that sector would 
offset, at an aggregate level, most revenue losses. Although ERG did 
not quantify this effect, FDA determined that the assumption of a fixed 
supply of meat and bone meal and a linear demand for nonruminant feed 
implies that purchasers of mixed-species meat and bone meal for 
nonruminant uses would save from $60.0 to $240.2 million annually, 
because of the lower meat and bone meal costs. This estimate assumes a 
total meat and bone meal supply of 2.5 million tons, changes in price 
ranging from $25 to $100 per ton, and an increase in nonruminant 
consumption of meat and bone meal of about 250,000 tons. In addition, 
manufacturers of ruminant feed would incur higher costs if they could 
not use ruminant proteins. In an analysis prepared for the feed 
industry, protein substitutes, such as soybean meal and other minerals 
necessary to provide the same nutritional level as that provided by the 
meat and bone meal, were estimated to cost approximately $31.75 per ton 
more than meat and bone meal (Ref. 125). FDA believes that this 
estimate is overstated, because it assumes that soybean meal alone 
sells for $20 per ton more than meat and bone meal. In fact, their 
respective market prices are currently similar. Nevertheless, FDA used 
the reported $31.75 per ton differential to estimate that the higher 
price of alternative proteins would increase ruminant feed costs by 
about $8.0 million per year.
    As a result, FDA estimates that the aggregated annualized costs of 
this proposal, comprised of both the direct compliance costs and the 
various indirect gains and losses, would total

[[Page 577]]

from $21.4 to $48.2 million. Although the greatest initial burden would 
fall on the rendering and feed manufacturing sectors, ERG noted that 
the final distribution of these impacts would shift; renderers would 
pass back the economic impacts to slaughterers, who, in turn, would 
pass them back to cattle producers. FDA judged, however, that of the 
small renderers dependent upon farmers' and ranchers' dead stock for 
their raw materials, 20 to 25 would be likely to close. ERG also 
forecast that these impacts would cause a decline in prices for 
slaughter-weight cattle of $1 to $5 per head. In the long run, ERG 
foresaw a modest reduction in the size of the U.S. cattle herd.
    In response to its ANPRM, FDA received comments on the possible 
impacts of the proposal from both individuals and industry. The 
submission from the American Feed Industry Association (AFIA) contained 
an analysis of the animal feed market that was based on the assumption 
that the proposal would taint the safety of all meat and bone meal 
(both ruminant and nonruminant), to the extent that even nonruminant 
animal producers would refuse to purchase the product. This loss of 
wholesale value was estimated at $523 million. Further, the AFIA 
comment estimated the cost for disposing of this meat and bone meal at 
$349 million and for substituting to higher priced feeds at $74 million 
annually.
    FDA questions the conclusions of the AFIA report, largely because 
the proposed rule does not prohibit the use of ruminant proteins in 
nonruminant feeds and there is no evidence that this market would 
disappear. As noted earlier, nonruminant feed use currently constitutes 
about 90 percent of the meat and bone meal market. While some 
nonruminant producers may be wary of ruminant MBM after the proposal 
becomes final, the broad media coverage of BSE in the United Kingdom 
and the voluntary prohibition of ruminant MBM in ruminant feeds have 
already provided nonruminant producers with substantial information on 
the relevant risks. The implications of the ERG study are that most of 
the major nonruminant sectors that use ruminant meat and bone meal in 
their feeds would continue this practice, particularly at sharply lower 
MBM prices. Because ERG believed that all stocks of meat and bone meal 
would find a commercial outlet within the nonruminant feed sector, they 
projected no additional disposal costs and far smaller revenue losses 
than AFIA.
2. Partial Ruminant-to-Ruminant Prohibition
    ERG also estimated the economic impact of a partial ruminant-to-
ruminant prohibition, which would prohibit only the use of proteins 
from designated ruminant tissues in ruminant feeds. ERG projected that 
cattle packer/renderers and approximately one-half of the large cattle 
packers would choose to separate the designated and nondesignated 
tissues. As shown in Table 1, this change in processing would lead to 
increased costs from capital investments, increases in operating and 
transportation expenses, training, and documentation activities. 
Further, ERG projected, under the high market impact scenario, that 
some feedmills would expand their facilities to offer both restricted 
and nonrestricted meat and bone meal. They estimated the annualized 
direct compliance costs for this option at from $23.5 to $27.9 million. 
In addition, ERG projected that this option would cause price declines 
of from $25 to $100 per ton for the meat and bone meal derived from 
designated tissues, leading to decreases in renderer revenues of from 
$28.8 to $115.4 million per year. As discussed previously, FDA again 
assumed a fixed supply of meat and bone meal and a linear demand for 
nonruminant feed to calculate that purchasers of mixed-species meat and 
bone meal for nonruminant uses would save from $27.4 million to $109.6 
million annually because of the lower meat and bone meal costs. Adding 
additional protein substitution costs of $3.7 million and other 
indirect costs raises the estimated net aggregate costs for this 
alternative to $28.6 to $37.4 million.
3. Mammalian-to-Ruminant Prohibition
    The third option assessed was the prohibition of mammalian protein 
in ruminant feeds. ERG projected that slaughtering and rendering 
establishments would have no reason to separate offal because very few 
of these establishments process both mammals and nonmammals. They 
estimated annualized direct compliance costs for this option at $31.6 
million. ERG forecast that, regardless of the size of the price decline 
for restricted meat and bone meal, some feedmills would expand their 
capacity to offer both restricted and nonrestricted meat and bone meal, 
resulting in increased capital and plant operating costs. The majority 
of the remaining regulatory costs are composed of documentation costs. 
Assuming that a regulatory prohibition on marketing restricted meat and 
bone meal to ruminants would cause the price of the restricted meat and 
bone meal to fall by from $25 to $100 per ton, ERG projected that this 
option would reduce renderer revenues by from $76.4 to $305.6 million 
per year. Alternatively, under the same assumptions as applied above, 
FDA found that purchasers of mixed-species meat and bone meal for 
nonruminant uses would save from $72.6 million to $290.3 million 
annually, because of the lower meat and bone meal costs. Adding 
additional protein substitution costs of $9.7 million and other 
indirect costs raises the estimated net aggregate costs for this third 
option to from $45.1 to $56.6 million.
4. Other Regulatory Alternatives
    FDA also considered two less restrictive options for controlling 
the spread of an outbreak of BSE in the United States: A prohibition of 
all sheep, goat, mink, deer, and elk proteins in ruminant feed; and a 
prohibition of sheep and goat proteins in ruminant feed. The first of 
these alternatives would require that ruminants not be fed proteins 
from any species in which a TSE was diagnosed in the United States, 
which includes sheep, goats, mink, deer, and elk. ERG anticipated 
minimal regulatory impacts for sheep, lamb, and goat producers because 
most renderers already require that sheep, lamb, and goat offal be 
excluded from mixed species meat and bone meal. ERG estimated that this 
alternative could restrict the use of up to 34,150 tons of offal 
annually from the various species, or about 0.3 percent of all 
mammalian offal rendered. Using an estimated cost of $150/ton for 
landfill disposal, ERG calculated that the disposal costs for this 
alternative could equal $5.1 million. Furthermore, ERG estimated that 
the meat and bone meal and tallow manufactured from offal generates 
revenues of about $500/ton of processed material. Under this option, 
meat and bone meal production would fall by 8,450 tons per year, 
reducing industry revenues by an estimated $4.2 million annually.
    The final alternative would restrict only sheep and goat protein 
from use in ruminant feed. This alternative is similar to the agency's 
1994 proposal, which pertained only to adult sheep and goats. Most 
sheep and goats are currently excluded by renderers from being rendered 
into mixed species meat and bone meal. ERG estimated that this 
alternative would restrict the use of up to 1,200 tons of offal, or 
about 0.01 percent of all mammalian offal rendered. At $150/ton for 
landfill disposal, the disposal costs would equal $0.2 million. ERG 
calculated that

[[Page 578]]

production of meat and bone meal under this option would be restricted 
by only 300 tons per year, leading to revenue losses of about $0.1 
million.
    ERG noted that the disposal costs presented for the latter two 
alternatives are high-end estimates because of the likelihood of onsite 
disposal for deer and elk taken by hunters. Further, these alternatives 
were not expected to have a measurable effect on the price of meat and 
bone meal because they would affect only 0.3 percent and 0.01 percent 
of the meat and bone meal markets, respectively. In contrast to the 
first three options, these rules would not change the demand for meat 
and bone meal, but would restrict the supply of meat and bone meal. Any 
postregulation increase in price, therefore, would increase revenues of 
renderers and costs of purchasers of meat and bone meal by an almost 
equal amount. ERG reported that this decrease in supply would have a 
negligible effect on meat and bone meal prices.

D. Small Business Impacts

    The Regulatory Flexibility Act requires agencies to prepare a 
regulatory flexibility analysis if a rule would have a significant 
impact on a substantial number of small entities. The discussion in 
this section, as well as in other sections of this document, and the 
ERG report, constitute the agency's compliance with this requirement.
    The Regulatory Flexibility Act asks for a succinct statement of the 
purpose and objectives of the rule. As explained previously in this 
document, FDA is proposing this measure to address the risk to U.S. 
livestock associated with feeding ruminant proteins to ruminants. 
Existing epidemiological evidence suggests a link between an outbreak 
of BSE in the United Kingdom and the practice of feeding products to 
cattle that included ruminant proteins. This rule would prohibit that 
practice. Thus, the need for regulatory action is based on the need to 
prevent the spread of BSE and thereby to protect the health of animals 
and to minimize any risk that might be posed to humans from BSE.
    The Regulatory Flexibility Act also requires a description of the 
affected small entities. The ERG study includes counts of entities in 
each class of industry that are involved in ruminant production and 
meat preparation. The vast majority of all of these firms are 
considered small businesses according to size standards set by the 
Small Business Administration. There are 282 rendering plants, of which 
204 have fewer than 500 employees, including all of the 152 independent 
renderers. ERG also estimated that 30,000 feedmills, all with fewer 
than 500 employees, could be affected by this rule. An estimated 1.4 
million enterprises are engaged in ruminant production. These include 
businesses engaged in the production of beef and dairy cattle, 
including farmers and ranchers, stocker operators, and cattle feeders, 
and other ruminant producers. The slaughtering industry contains more 
than 4,000 establishments. Of this total, however, only 130 are packer/
renderers that could have compliance requirements and about 52 of these 
establishments have fewer than 500 employees. ERG estimated that almost 
300,000 small establishments are engaged in meat processing. These 
businesses would have no direct compliance activities, but could be 
affected indirectly by altered renderer practices. Also, about 150,000 
small producers of nonruminant animals could gain from lower feed 
costs.
    The RFA also requires a description of the recordkeeping 
requirements of the proposed rule. The ERG report presents detailed 
estimates of these costs. ERG found that the rule would require certain 
feed manufacturers to develop new written operating procedures. In 
addition, affected firms would have to retain invoices but FDA believes 
this activity is already generally accepted business practice.
    Finally, the Regulatory Flexibility Act asks for an evaluation of 
any regulatory overlaps and regulatory alternatives that would minimize 
costs to small entities. FDA is unaware of any significant regulatory 
conflicts with other Federal rules. FDA examined five regulatory 
alternatives in addition to no action: (1) The ruminant-to-ruminant 
prohibition; (2) the partial ruminant-to-ruminant prohibition; (3) the 
mammalian-to- ruminant prohibition; (4) the prohibition of all sheep, 
goat, mink, deer, and elk proteins in ruminant feed; and (5) the 
prohibition of specified sheep and goat proteins in ruminant feed. The 
ERG report provides a detailed comparison of the respective impacts of 
these alternatives and found that the estimated direct compliance costs 
are lower under the proposed rule ($10.2 to $27.6 million) than under 
two of the alternative rules ($23.5 to $27.9 million for the partial 
ruminant-to-ruminant option, $31.6 million for the mammalian-to-
ruminant option). The other alternatives would not be nearly as 
effective at reducing the risk of an outbreak and spread of BSE, but 
are considerably less costly. As many of the above projections are 
uncertain, FDA particularly invites additional data or comment on the 
effects of the proposed and alternative rules on any group of small 
businesses.

E. Unfunded Mandates Analysis

    Based on the ERG study, FDA estimated that aggregate expenditures 
by the private sector that result from the proposed rule, issued under 
21 CFR 589.2000, will range from $10.2 to $27.6 million per year. As 
described in section IX.B. of this document, the benefits of this 
measure accrue both to the general public (through decreased risks to 
health) and to the livestock and associated industries. The costs of 
the measure are borne by the private sector, primarily the rendering 
and animal feed industries. Because FDA anticipates no significant 
additional costs to State, local, or tribal governments, this 
regulatory action does not require an assessment under the Unfunded 
Mandates Reform Act.

X. The Paperwork Reduction Act of 1995

    This proposed rule contains recordkeeping requirements that are 
subject to public comment and review by OMB under the Paperwork 
Reduction Act of 1995 (Pub. L. 104-13). Therefore, in accordance with 5 
CFR part 1320, a description of reporting requirements is given in 
Table 2 of this document, with an estimate of the annual collection of 
information burden. Included in the estimate is the time for reviewing 
instructions, gathering and maintaining the data needed, and completing 
and reviewing the collection of information.
    With respect to the following collection of information, FDA is 
soliciting comments on: (1) Whether the proposed collection of 
information is necessary for proper performance of FDA's functions, 
including whether the information will have practical utility; (2) the 
accuracy of FDA's estimate of the burden of the proposed collection of 
information, including the validity of the methodology and assumptions 
used; (3) ways to enhance the quality, utility, and clarity of the 
information to be collected; and (4) ways to minimize the burden of the 
collection of information on those who are to respond, including 
through the use of automated collection techniques or other forms of 
information technology, when appropriate.
    Title: Substances Prohibited from Use in Animal Food or Feed; 
Animal Proteins Prohibited in Ruminant Feed.
    Description: The proposed rule (Sec. 589.2000) provides that 
protein derived from ruminant and mink tissues is not GRAS for use in 
ruminant feed and is a food additive subject to section 409 of the act. 
Proteins derived from

[[Page 579]]

animal tissues contained in such feed ingredients in distribution 
cannot be readily determined by recipients engaged in the manufacture, 
processing and distribution, and use of animal feeds and feed 
ingredients. To achieve the public and animal health objectives of this 
proposed rule, the agency believes that manufacturers, processors, 
distributors, and users must be responsible for ensuring and 
appropriately maintaining the identity of the specific nature of the 
components of animal protein products and animal feeds containing these 
products.
    Thus, under the agency's authority in section 701(a) (21 U.S.C. 
371(a)) of the act to issue regulations for the efficient enforcement 
of the act, this proposed rule places three general requirements on 
persons that manufacture, blend, process and distribute products that 
contain or may contain protein derived from ruminant and mink tissues, 
and feeds made from such products. The first requirement is for 
cautionary labeling of these products with direct language developed by 
FDA. The second requirement is for these establishments to provide FDA 
with access to their purchase and sales invoices for compliance 
purposes. FDA believes that maintenance of such records is a usual and 
customary part of normal business activities for such firms. These two 
requirements are not within the scope of the Paperwork Reduction Act. 
The third requirement is recordkeeping which requires that the firms 
develop standard operating procedures if they intend to keep ruminant 
and mink material separate from nonruminant material. The agency is 
aware that the certification procedures provided in Sec. 589.2000(d) of 
the regulation could be interpreted as imposing a paperwork burden on 
certain industry segments. However, the agency notes that the 
certification procedures apply only where new technology (e.g., a 
deactivation method) is developed. The agency was unable to estimate 
when such technology might be developed, what its characteristics and 
costs would be, and other essential information needed to make 
realistic estimates of any paperwork burden. Therefore, such costs are 
not included in this proposed rule. However, the agency specifically 
requests comments and information related to the factors that would 
determine the extent of any paperwork burden.
    The recordkeeping burden in Table 2 has been estimated using the 
typical average size establishment that is expected to handle animal 
protein from both ruminant and nonruminant sources, or feeds containing 
these products, and intend to keep them separate. FDA's preliminary 
estimate is that only a fraction of feed manufacturers and distributors 
will separate their products. Independent renderers were excluded from 
the burden estimates based on information provided for the economic 
estimate. Packer/renderers were excluded because they are single 
species processors.
    Under these recordkeeping requirements, for which records must be 
made available for FDA inspection, an estimated 2,000 feed mills would 
handle both restricted and nonrestricted products and would develop 
standard operating procedures for keeping ruminant and mink material 
separate from nonruminant material from the time of receipt to time of 
shipment. The estimate in the burden chart is based on the time 
required to develop and establish the written procedures and is a one 
time requirement. The 2,000 firms will also incur annual operating cost 
estimated at $10 million, because of the flushing, sequencing and other 
procedures that will be required. It is estimated that 1,000 of the 
firms may incur capital cost for the construction of separate 
facilities. These costs have been annualized for 10 years, at $7.119 
million per year. The remaining firms are expected to be able to meet 
the regulation's requirements without incurring capital cost.
    The agency has submitted copies of the proposed rule to OMB for its 
review of these requirements. Interested persons are requested to send 
comments regarding this collection of information by February 18, 1997, 
but not later than March 4, 1997 to the Office of Information and 
Regulatory Affairs, OMB (address above), Attn: Desk Officer for FDA.
    Description of Respondents: Distributors, feed manufacturers, 
blenders and renderers.

                                                   Table 2.--Estimated Annual Recordkeeping Burden \1\                                                  
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                            No. of                                                                                      
                                                            record                    Total      Hours per                 Capital cost   Operating cost
                     21 CFR section                        keepers/    Frequency      annual       record    Total hours   (annualized)      (yearly)   
                                                            firms                    records                                                            
--------------------------------------------------------------------------------------------------------------------------------------------------------
589.2000 (e)(1)(iv)....................................        2,000            1        2,000           14       28,000      $7,119,000    $10,000,000 
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ Costs are only incurred under the high-impact scenario.                                                                                             

XI. Federalism

    FDA has analyzed this proposal in accordance with the principles 
and criteria set forth in Executive Order 12612 and has determined that 
this proposal does not warrant the preparation of a Federalism 
Assessment.

XII. References

    The following references have been placed on display in the Dockets 
Management Branch (address above) and may be seen by interested persons 
between 9 a.m. and 4 p.m., Monday through Friday.

    1. Transcript, FDA and USDA Symposium, ``Tissue Distribution, 
Inactivation and Transmission of Transmissible Spongiform 
Encephalopathies,'' Riverdale, MD, 1996.
    2. WHO, ``Report of a WHO Consultation on Public Issues Related 
to Human and Animal Transmissible Spongiform Encephalopathies,'' 
With the participation of FAO and OIE, Geneva, Switzerland, WHO/EMC/
DIS/96.147, 2-3 April 1996.
    3. Centers for Disease Control and Prevention, Memorandum, July 
25, 1996.
    4. USDA, APHIS, ``Bovine Spongiform Encephalopathy: Implications 
for the United States, a Follow-up,'' 1996.
    5. Personal Communications, Will Hueston, 1996.
    6. Walker, K. D., et al., ``Comparison of bovine spongiform 
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Technique,'' Office Internationale Epizootics, 11(2):491-537, 1992.
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June 1993.

[[Page 580]]

    12. Davis, A., USDA-APHIS-U.S., personal communication, April 
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of Scrapie in the Serum of Affected Mice and Rats,'' Veterinary 
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Record, 83:109, 1968.
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Scrapie,'' Archives of Virology, 82:105-109, 1984.
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Through the Incubation Period of Hamsters Peripherally Injected with 
Scrapie,'' Archives of Virology, 108:145-149, 1989.
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Creutzfeldt-Jacob Disease from Human Blood,'' Lancet, 2:896-897, 
1985.
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Creutzfeldt-Jacob Disease,'' Science, 200:1069-1070, 1978.
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Agent in Mice, National Institute of Neurological Diseases and 
Blindness Monograph No. 2,'' Slow, Latent, and Temperate Virus 
Infections, 195-202, 1965.
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Spongiform Encephalopathy to Mice by Feeding Them with Extraneural 
Tissues of Affected Cattle,'' Veterinary Record, 132:545-547, 1993.
    52. Taylor, D. M., C. E. Ferguson, C. J. Bostock, and M. Dawson, 
``Absence of Disease in Mice Receiving Milk from Cows with Bovine 
Spongiform Encephalopathy,'' Veterinary Record, 136:592, 1995.
    53. Ministry of Agriculture Fisheries and Food (MAFF), ``Reports 
of a Decline in the Incidence of BSE,'' Veterinary Record, p. 26, 
1995.
    54. Hadlow, W. J., et. al., ``Virologic and Neurohistopathologic 
Findings in Dairy Goats Affected with Natural Scrapie,'' Veterinary 
Pathology, 17:187-199, 1980.
    55. Hotchin, J., et al., ``Disappearance of Scrapie Virus from 
Tissue of the Mouse,'' Intervirology, 19:205-212, 1983.
    56. Ministry of Agriculture, Fisheries and Food, ``Bovine 
Spongiform Encephalopathy in Great Britain: A Progress Report,'' 
November 1995.
    57. Diedrich, J. F., et al., ``Increased Expression of Heat 
Shock Protein, Transferrin, and B2-Microglobulin in Astrocytes 
During Scrapie,'' Microbial Pathogenisis, 15:1-6, 1993.
    58. Forloni, G., et al., ``Neurotoxicity of a Prion Protein 
Fragment,'' Nature, 362:543-546, 1993.
    59. Fairbairn, D. W., et al., ``Spongiform Encephalopathies and 
Prions: An Overview of Pathology and Disease Mechanisms,'' FEMS 
Microbiology Letters, 123:233-240, 1994.
    60. Brown, D. R., et al., ``Role of Microglia and Host Prion 
Protein in Neurotoxicity of a Prion Protein Fragment,'' Nature, 
380:345-347, 1996.
    61. Hsiao, K., ``Mutation of the Prion Protein in Libyan Jews 
With Creutzfeldt-Jakob Disease,'' New England Journal of Medicine, 
324:1091-1097, 1991.
    62. Onodera, T., et al., ``Isolation of Scrapie Agent from the 
Placenta of Sheep with Natural Scrapie in Japan,'' Microbiology and 
Immunology, 37:311-316, 1993.
    63. Foster, J. D., et al., ``Transmission of Bovine Spongiform 
Encephalopathy to sheep and goats,'' Veterinary Record, 133(14):339, 
1993.
    64. Goldman, W., et al., ``PrP genotype and agent effects in 
scrapie: change in allelic interaction with different isolates of 
agent in sheep, a natural host of scrapie,'' Journal of General 
Virology, 75(5):989, 1994.
    65. Foster, J. D., et al., ``Detection of BSE infectivity in 
brain and spleen of experimentally infected sheep,'' Veterinary 
Record, 138:546, 1996.
    66. Gordon, W. S., ``Transmission of Scrapie and Evidence of 
Spread of Infection in Sheep at Pasture,'' Report at Scrapie 
Seminar, Washington, DC, January 27-30, 1964; ARS 91--53:8-18, 1966.
    67. Wisniewski, H., et al., ``Mites as Vectors for Scrapie,'' 
Lancet, 347:1114, 1996.

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    68. Goldfarb, L. G., R. B. Petersen, M. Tabaton, P. Brown, A. C. 
LeBlanc, P. Montagna, P. Cortelli, J. Julien, C. Vital, and W. W. 
Pendelbury, et al., ``Fatal Familial Insomnia and Familial 
Creutzfeldt-Jakob Disease: Disease Phenotype Determined by a DNA 
polymorphism,'' Science, 258(5083): 806-808, 1992.
    69. Ghetti, B., S. R. Dlouhy, G. Giaccone, O. Bugiani, B. 
Frangione, M. R. Farlow, and F. Tagliavini, Gerstmann-Straussler-
Scheinker Disease and the Indiana Kindred, Brain Pathology, 5:61-75, 
1995.
    70. Kitamoto, T., M. Ohta, K. Doh-ura, S. Hitoshi, Y. Terao, and 
J. Tateishi, ``Novel Missense Variants of Prion Protein in 
Creutzfeldt-Jakob Disease or Gerstmann-Straussler Syndrome,'' 
Biochemical and Biophysical Research Communication, 191: 709-714, 
1993.
    71. Oda, T., T. Kitamoto, J. Tateishi, T. Mitsuhashi, K. 
Iwabuchi, C. Haga, E. Oguni, Y. Kato, I. Tominaga, and K. Yanai, et 
al., ``Prion Disease with 144 Base Pair Insertion in a Japanese 
Family Line,'' Acta Neuropathologica, 90:80-86, 1995.
    72. Tateishi, J., and T. Kitamoto, ``Inherited Prion Diseases 
and Transmission to Rodents,'' Brain Pathology, 5:53-59, 1995.
    73. Ikeda, T., M. Horiuchi, N. Ishiguro, Y. Muramatsu, G. D. 
Kai-Uwe, and M. Shinagaw, ``Amino Acid Polymorphisms of PrP with 
Reference to Onset of Scrapie in Suffolk and Corriedale Sheep in 
Japan,'' Journal of Genetic Virology, 76:2577-2581, 1995.
    74. Belt, P. B., I. H. Muileman, B. E. Schreuder, J. Bos-de-
Ruijter, A. L. Gielkens, and M. A. Smits, ``Identification of Five 
Allelic Variants of the Sheep PrP Gene and Their Association with 
Natural Scrapie,'' Journal of Genetic Virology, 76:509-517, 1995.
    75. Westaway, D., V. Zuliani, C. M. Cooper, M. Da-Costa, S. 
Neuman, A. L. Jenny, L. Detwiler, and S. B. Prusiner, ``Homozygosity 
for Prion Protein Alleles Encoding Glutamine-171 Renders Sheep 
Susceptible to Natural Scrapie,'' Genes and Development, 8:959-969, 
1994.
    76. Clouscard, C., P. Beaudry, J. M. Elsen, D. Milan, M. 
Dussaucy, C. Bounneau, F. Schelcher, J. Chatelain, J. M. Launay, and 
J. L. Laplanche, ``Different Allelic Effects of the Codons 136 and 
171 of the Prion Protein Gene in Sheep with Natural Scrapie,'' 
Journal of Genetic Virology, 76:2097-2101, 1995.
    77. Hunter, N., W. Goldmann, G. Smith and J. Hope, ``Frequencies 
of PrP Gene Variants in Healthy Cattle and Cattle with BSE in 
Scotland,'' Veterinary Record, 135:400-403, 1994.
    78. Kimberlin, R. H., ``Bovine Spongiform Encephalopathy,'' 
Scientific and Technical Review, 11:347-390, 1992.
    79. Schmerr, et al., Journal of Chromatography, in press.
    80. Beekes, M., et al., ``Western Blot Mapping of Disease-
Specific Amyloid in Various Animal Species and Humans with 
Transmissible Spongiform Encephalopathies Using a High-yield 
Purification Method,'' Journal of General Virology, 76:2567-2576, 
1995.
    81. Banissi-Sabourdy, C., et al., ``Electroanalytical 
Characterization of Alzheimer's Disease and Ovine Spongiform 
Encephalopathy by Repeated Cyclic Volummetry at a Capillary Graphite 
Paste Electrode,'' Bioelectrochemistry and Bioenergetics, 28:127-
147, 1996.
    82. Gibbs, C. J., et al., personal communications, 1996.
    83. Schreuder, B. E. C., et al, ``Preclinical Test for Prion 
Diseases,'' Nature, 381:563, 1996.
    84. Hsich, g., et al, ``The 14-3-3 Brain Protein in 
Cerebrospinal Fluid as a Marker for Transmissible Spongiform 
Encephalopathies,'' NEJM, 335:924, 1996.
    85. Taylor, D. M., S. L. Woodgate, and M. J. Atkinson, 
``Inactivation of the Bovine Spongiform Encephalopathy Agent by 
Rendering Procedures,'' Veterinary Record, 9(137):605-610, 1995.
    86. Taylor, D. M. and R. Bradley, personal communication, 1996.
    87. Collee, J. G., ``Food Borne Illness-Bovine Spongiform 
Encephalopathy,'' Lancet, 336:1300-1303, 1990.
    88. Fraser, H., et al., ``Transmission of Bovine Spongiform 
Encephalopathy and Scrapie to Mice,'' Journal of General Virology, 
73:1891-1897, 1992.
    89. Robinson, M. M., ``Bovine Spongiform Encephalopathy,'' 
Foreign Animal Disease, pp. 134-138, 1992.
    90. Spongiform Encephalopathy Advisory Committee, United 
Kingdom, statement, March 20, 1996.
    91. WHO, ``Scientific Consultation on Human and Animal 
Spongiform Encephalopathies,'' Geneva, Switzerland, 16- 17 May 1996, 
Press Release WHO/38.
    92. Lasmezas, C. I., et al, ``BSE Transmission to Macaques,'' 
Nature, 381:743, 1996.
    93. Collinge, J., et al., ``Molecular analysis of prion strain 
variation and the aetiology of `new variant' CJD,'' Nature, 383:685, 
1996.
    94. World Health Organization, ``Report of a WHO Consultation on 
Public Health Issues Related to Human and Animal Transmissible 
Spongiform Encephalopathies,'' WHO/CDS/PH/95.145, 1995.
    95. Hueston, Will, USDA, personal communication, 1996.
    96. Centers for Disease Control and Prevention, ``Surveillance 
for Creutzfeld-Jakob Disease--United States,'' Morbidity and 
Mortality Weekly Report, 45(31):665, 1996.
    97. USDA, ``Animal and Plant Health Inspection Service, 
Emergency Programs Activities, Bovine Spongiform Encephalopathy 
(BSE) Surveillance Program,'' in Foreign Animal Disease Report, No. 
20-3/4, pp. 1-2, 1992, and poster display at U.S. Animal Health 
Association annual meeting, October 30, 1993.
    98. USDA, APHIS, ``Qualitative Analysis of BSE Risk Factors in 
the United States,'' 1991.
    99. USDA, APHIS, ``Bovine Spongiform Encephalopathy: 
Implications for the United States,'' 1993.
    100. Holman, R. C., A. S. Khan, J. Kent, T. W. Strine, and L. B. 
Schonberger, ``Epidemiology of Creutzfeldt-Jakob Diseases in the 
United States,'' 1979-1990: Analysis of National Mortality Data, 
Neuroepidemiology, 14:174-181, 1995.
    101. CDC, ``World Health Organization Consultation on Public 
Health Issues Related to Bovine Spongiform Encephalopathy and the 
Emergence of a New Variant of Creutzfeldt-Jakob Disease,'' Morbidity 
and Mortality Weekly Report, 45/(14):295-303, 1996.
    102. Office Internationale Epizootics, International Animal 
Health Code, Chapter 3.2.13 on BSE, pp. 231-235, July 1993.
    103. European Community decisions, 96/362/EC.
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to Animal Protein Producers, 1989.
    105. FDA, ``Report of Findings of Directed Inspections of Sheep 
Rendering Facilities,'' January 1993.
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Animal Health Organizations regarding a voluntary Ban on Ruminant 
Derived Protein in Ruminant Feed Recommendations, press release 
March 29, 1996.
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Service Announce Additional Steps, Support for Industry Efforts to 
Keep U.S. Free of BSE,'' March 29, 1996.
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Animal Science), April 8, 1996, letter to Gary Weber, National 
Cattleman's Beef Association.
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Comment No. 280, June 13, 1996.
    110. Anonymous, Comment No. 279, June 13, 1996.
    111. Andrews, C. D., et al., ``Detection of Beef, Sheep, Deer, 
and Horse Meat in Cooked Meat Products by Enzyme-Linked 
Immunosorbent Assay,'' Journal of Association of Analytical Chemist 
International, 75:572-576, 1992.
    112. Berger, R. G., et al., ``Detection of Poultry and Pork in 
Cooked and Canned Meat Foods by Enzyme-Linked Immunosorbent 
Assays,'' Journal of Association of Analytical Chemist 
International, 71:406-410, 1988.
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Spongiform Encephalopathies,'' in ``The Report of the Expert Group 
on Animal Feedingstuffs to the Minister of Agriculture, Fisheries, 
and Food, the Secretary of State for Health and the Secretaries of 
State for Wales, Scotland, and Northern Ireland,'' 1992.
    114. Eastern Research Group, ``Cost Analysis of Regulatory 
Options to Reduce the Risk of an Outbreak of Bovine Spongiform 
Encephalopathy (BSE),'' July 1996.
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to eradicate BSE in the United Kingdom,'' May 1996.
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Cattle Born After the Introduction of the 'Feed ban','' Veterinary 
Record, 134:274-275, 1994.
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Foods, Animal Pharm, March 1994.
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Encephalopathy: A Qualitative Economic Assessment, USDA Livestock 
Marketing Information Center, May 10, 1996.
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357:p.6, Sept. 20, 1996.

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    121. United Kingdom, Ministries of Agriculture, Fisheries and 
Foods, BSE: Government Measures to Assist the Beef industry, Aug. 
19, 1996.
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of BSE on the United Kingdom Beef Industry,'' Outlook on 
Agriculture, Vol. 24,3, pp. 151-154, 1995.
    123. Duewer, L.A., USDA, Economic Research Service, personal 
communication, October 31, 1996; Putnam, Judith J., and J. E. 
Allshouse, Food Consumption Prices and Expenditures, 1970-94, USDA, 
Economic Research Service, Statistical Bulletin No. 928, Table 45, 
1996.
    124. Marsh, J. M., Derived Demand Elasticities: Marketing Margin 
Methods versus an Inverse Demand Model for Choice Beef, Western 
Journal of Agricultural Economics, vol.16 no.2, pp.382-391, 1991.
    125. Lenard, Thomas M., Preliminary Economic Analysis of a 
Ruminant-to-Ruminant Feeding Ban, Prepared for American Feed 
Industry Association. Comments submitted to FDA Docket No. 96N-0135.

XIII. Request for Comments

    Interested persons may, on or before February 18, 1997, submit to 
the Dockets Management Branch (address above) written comments 
regarding this proposal. Two copies of any comments are to be 
submitted, except that individuals may submit one copy. Comments are to 
be identified with the docket number found in brackets in the heading 
of this document. Received comments may be seen in the office above 
between 9 a.m. and 4 p.m., Monday through Friday.

List of Subjects in 21 CFR Part 589

    Animal feeds, Animal foods, Food additives.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, it is 
proposed that 21 CFR part 589 be amended as follows:

PART 589--SUBSTANCES PROHIBITED FROM USE IN ANIMAL FOOD OR FEED

    1. The authority citation for 21 CFR part 589 continues to read as 
follows:

    Authority: Secs. 201, 402, 409, 701 of the Federal Food, Drug, 
and Cosmetic Act (21 U.S.C. 321, 342, 348, 371).

    2. New Sec. 589.2000 is added to subpart B to read as follows:


Sec. 589.2000  Animal proteins prohibited in ruminant feed.

    (a) Definitions. (1) Protein derived from ruminant and mink tissues 
means any protein-containing portion of ruminant animals or mink, 
excluding blood from bovines, milk proteins and gelatin.
    (2) Renderer means any firm or individual that processes slaughter 
byproducts, animals unfit for human consumption, meat scraps or food 
waste. The term includes persons who collect such materials and subject 
them to minimal processing, or distribute them to firms other than 
renderers whose intended use for the products may include animal feed. 
The term includes renderers that also blend animal protein products.
    (3) Blender means any firm or individual which obtains processed 
animal protein from more than one source or from more than one species, 
and subsequently mixes (blends) or redistributes an animal protein 
product.
    (4) Feed manufacturer and distributor includes manufacturers and 
distributors of complete and intermediate feeds intended for animals, 
and includes on-farm in addition to off-farm feed manufacturing and 
mixing operations.
    (5) Nonruminant protein includes protein from nonruminant animals 
and from vegetable sources.
    (b) Food additive status. The Food and Drug Administration has 
determined that protein derived from ruminant and mink tissues is not 
generally recognized as safe for use in ruminant feed because it may 
contain transmissible spongiform encephalopathy (TSE)-infective 
material, and is a food additive subject to section 409 of the Federal 
Food, Drug, and Cosmetic Act (the act). In the absence of a regulation 
providing for its safe use as a food additive under section 409 of the 
act, the use or intended use in ruminant feed of any material that 
contains protein derived from ruminant and mink tissues causes the feed 
to be adulterated and in violation of the act, unless it is the subject 
of an effective notice of claimed investigational exemption for a food 
additive under Sec. 570.17 of this chapter. The Food and Drug 
Administration has determined that ruminant and mink derived protein is 
not prior sanctioned for use in ruminant feeds.
    (c) Requirements for renderers that are not included in paragraph 
(e) of this section. (1) Renderers that manufacture products that 
contain or may contain protein derived from ruminant and mink tissues 
and that are intended for use in animal feed shall take the following 
measures to ensure that materials identified in paragraph (b) of this 
section are not used in the feed of ruminants:
    (i) Label the materials as follows: ``Contains (or may contain) 
protein derived from ruminant and mink tissues. Do not feed to ruminant 
animals, and do not use to manufacture feed intended for ruminant 
animals''; and
    (ii) Maintain copies of sales invoices for the materials, and make 
the copies available for inspection and copying by the Food and Drug 
Administration.
    (2) Renderers described in paragraph (c)(1) of this section will be 
exempted from the requirements of paragraphs (c)(1)(i) and (c)(1)(ii) 
of this section if they:
    (i) Use exclusively a manufacturing method that has been validated 
by the Food and Drug Administration to deactivate the agent that causes 
TSE's and whose design has been made available to the public; or
    (ii) Use routinely a test method that has been validated by the 
Food and Drug Administration to detect the presence of the agent that 
causes TSE's and whose design has been made available to the public. 
Products found to contain the agent that causes TSE's shall be labeled 
``Not for Use in Animal Feed.'' Records of the test results shall be 
made available for inspection by the Food and Drug Administration.
    (3) Renderers described in paragraph (c)(1) of this section who are 
not exempted under paragraph (c)(2)(i) or paragraph (c)(2)(ii) of this 
section will be exempted from the requirements of paragraph (c)(1)(ii) 
of this section if they use a permanent method, approved by FDA, to 
mark the presence of the materials. If the marking is by the use of an 
agent that cannot be detected on visual inspection, the renderer must 
use an agent whose presence can be detected by a method that has been 
validated by the Food and Drug Administration and whose design has been 
made available to the public.
    (d) Requirements for protein blenders, and feed manufacturers and 
distributors, that are not included in paragraph (e) of this section. 
(1) Protein blenders, and feed manufacturers and distributors, that 
manufacture, blend, process and distribute products that contain or may 
contain protein derived from ruminant and mink tissues shall:
    (i) Comply with paragraph (c)(1) of this section, and
    (ii) Maintain copies of invoices for purchase of animal protein 
products or feeds containing such products, and make copies available 
for inspection and copying by the Food and Drug Administration.
    (2) Protein blenders, and feed manufacturers and distributors, 
shall be exempt from paragraphs (d)(1)(i) and (d)(1)(ii) of this 
section if they:
    (i) Purchase animal protein products from renderers that certified 
compliance with paragraph (c)(2) of this section or purchase such 
materials from parties

[[Page 583]]

that certify that the materials were purchased from renderers that 
certified compliance with paragraph (c)(2); or
    (ii) Comply with the requirements of paragraph (c)(2) of this 
section where appropriate.
    (3) Protein blenders, and feed manufacturers and distributors, 
shall be exempt from paragraph (c)(1)(ii) of this section if they:
    (i) Purchase animal protein products that are marked or purchase 
such materials from renderers that certified compliance with paragraph 
(c)(3) of this section, or purchase such materials from parties that 
certify that the materials were purchased from renderers that certified 
compliance with paragraph (c)(3) of this section; or
    (ii) Comply with the requirements of paragraph (c)(3) of this 
section where appropriate.
    (4) Copies of certifications as described in paragraphs (d)(2) and 
(d)(3) of this section, shall be made available for inspection and 
copying by the Food and Drug Administration.
    (e) Requirements for persons that intend to separate ruminant/mink 
and nonruminant/mink materials. (1) Renderers, protein blenders, feed 
manufacturers and distributors, haulers and others that manufacture, 
process, blend and distribute both protein products derived from 
ruminant and mink tissues or feeds containing such products, and 
protein products from other animal tissues or feeds containing such 
products, and that intend to keep those products separate shall:
    (i) Comply with paragraphs (c)(1) or (d)(1) of this section as 
appropriate except that the labeling requirement shall apply only to 
products derived from ruminant and mink tissues or feeds containing 
such products;
    (ii) In the case of a renderer, obtain nonruminant (excluding mink) 
materials only from single-species facilities;
    (iii) Provide for measures to avoid commingling or cross-
contamination:
    (A) Maintain separate equipment or facilities for the manufacture, 
processing, or blending of such materials; or
    (B) Use clean-out procedures or other means adequate to prevent 
carry-over of ruminant and mink derived protein into animal protein 
products or feeds that may be used for ruminants; and
    (iv) Maintain written procedures specifying the clean-out 
procedures or other means, and specifying the procedures for separating 
ruminant and mink materials from nonruminant materials (excluding mink) 
from the time of receipt until the time of shipment.
    (2) Renderers, blenders, and feed manufacturers and distributors 
will be exempted from appropriate requirements of paragraph (e)(1) of 
this section, if they meet the appropriate criteria for exemption under 
paragraphs (c)(2) or (c)(3), and (d)(2) or (d)(3) of this section.
    (f) Requirements for establishments and individuals that are 
responsible for feeding ruminant animals. Establishments and 
individuals that are responsible for feeding ruminant animals shall 
maintain copies of purchase invoices and labeling for all feeds 
received, and make the copies available for inspection and copying by 
the Food and Drug Administration.
    (g) Adulteration and misbranding. (1) Animal protein products, and 
feeds containing such products, that are not in compliance with 
paragraphs (c) through (f) of this section, excluding labeling 
requirements, will be deemed adulterated under section 402(a)(2)(C) or 
402(a)(4) of the act.
    (2) Animal protein products, and feeds containing such products, 
that are not in compliance with the labeling requirements of paragraphs 
(c) through (f) of this section will be deemed misbranded under section 
403(a)(1) of the act.
    (h) Inspection; records retention. (1) Records that are to be made 
available for inspection and copying, as required by this section, 
shall be kept for a minimum of 2 years.
    (2) Written procedures required by this section shall be made 
available for inspection and copying by the Food and Drug 
Administration.


    Dated: December 27, 1996.
David A. Kessler,
Commissioner of Food and Drugs.

Donna E. Shalala,
Secretary of Health and Human Services.
[FR Doc. 97-37 Filed 1-2-97; 8:45 am]
BILLING CODE 4160-01-F