Document ID: FDA-2013-N-0222-0001
Agency: fda
Document Type: Notice
Title: International Conference on Harmonisation: Proposed Change to Rodent Carcinogenicity Testing of Pharmaceuticals
Posted Date: 2013-03-18T04:00Z

[Federal Register Volume 78, Number 52 (Monday, March 18, 2013)]
[Notices]
[Pages 16681-16684]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2013-06145]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2013-N-0222]

International Conference on Harmonisation; Proposed Change to 
Rodent Carcinogenicity Testing of Pharmaceuticals; Request for Comments

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice; request for comments.

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SUMMARY: The Food and Drug Administration (FDA or the Agency) is 
considering a proposed change to the International Conference on 
Harmonisation (ICH) Sl guidance on rodent carcinogenicity testing. The 
goal of this potential change is to introduce a more comprehensive and 
integrated approach to address the risk of human carcinogenicity of 
small molecule pharmaceuticals, and to define conditions under which 2-
year rodent carcinogenicity studies add value to that assessment. The 
basis of this proposed change is the retrospective analyses of several 
datasets that reflect three decades of experience with such studies. 
The datasets suggest that knowledge of certain pharmacologic and 
toxicologic data can sometimes provide sufficient information to 
anticipate the outcome of 2-year rodent studies and their potential 
value in predicting the risk of human carcinogenicity of a given 
pharmaceutical. FDA is requesting public comment regarding a proposed 
change in approach to carcinogenicity assessment, on the prospective 
evaluation period intended to test this new approach, and on the 
proposed weight-of-evidence factors for carcinogenicity assessment.

DATES: Submit electronic or written comments on the proposed change by 
May 17, 2013.

ADDRESSES: Submit electronic comments on the proposed change to http://www.regulations.gov. Submit written comments to the Division of Dockets 
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, 
rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Todd Bourcier, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 22, rm. 3102, Silver Spring, MD 20993-0002, 301-
796-1179.

SUPPLEMENTARY INFORMATION:

I. Background

    FDA is considering a change in the current ICH S1 guidance on 
rodent carcinogenicity testing.\1\ The goal of this potential change is 
to introduce a more comprehensive and integrated approach to address 
the risk of human carcinogenicity of small molecule pharmaceuticals, 
and to define conditions under which 2-year rodent carcinogenicity 
studies add value to that assessment.
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    \1\ See the ICH S1 guidance documents, ``S1A The Need for Long-
Term Rodent Carcinogenicity Studies of Pharmaceuticals'' (ICH S1A), 
``S1B Testing for Carcinogenicity of Pharmaceuticals'' (ICH S1B), 
and ``S1C(R2) Dose Selection for Carcinogenicity Studies of 
Pharmaceuticals'' (ICH S1C), available on the Internet at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm or http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.
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    Datasets evaluated by the ICH S1 expert working group (S1 EWG) 
suggest that knowledge of pharmacologic targets and pathways together 
with toxicological and other data can, in certain cases, provide 
sufficient information to anticipate the outcome of 2-year rodent 
studies and their potential value in predicting the risk of human 
carcinogenicity of a given pharmaceutical. It is hypothesized that 
consideration of this information can provide sufficient information to 
conclude that a given pharmaceutical in certain cases presents a 
negligible risk or, conversely, a likely risk of human carcinogenicity 
without conducting a 2-year rodent study. It is envisioned that 
sponsors of such pharmaceuticals would provide drug regulatory agencies 
(DRAs) a carcinogenicity assessment document (CAD) that could justify a 
``waiver request'' that would seek to omit the conduct of 2-year rodent 
studies. The CAD would address the overall carcinogenic risk of the 
investigational drug as predicted by the endpoints discussed in this 
document and a rationale for why the conduct of 2-year rodent studies 
would or would not add value to that assessment.
    Prospective evaluation of this proposed hypothesis is necessary to 
justify proceeding with revision of the ICH S1 guidance. A prospective 
evaluation period would be sought wherein sponsors would be requested 
to submit CADs to DRAs for all investigational pharmaceuticals with 
ongoing or planned 2-year rodent studies. DRAs from each region would 
independently review the submitted assessments to evaluate the degree 
of concordance with sponsors and between regulatory regions. During 
this prospective evaluation period, the waiver requests would not to be 
granted and rather are intended solely for gathering experience and 
hypothesis testing. Submitted assessments would be compared to the 
outcome of the 2-year rodent studies to evaluate the accuracy and 
relevance of the predictions to the actual experimental results. 
Experience from this prospective evaluation period is considered 
critical to informing the S1 EWG's efforts in revising the current 
paradigm of assessing the carcinogenicity of small molecules as 
described in the ICH S1 guidance. FDA is requesting public comment 
regarding the proposed change in approach to carcinogenicity 
assessment, on the prospective evaluation period intended to test this 
new approach, and on the weight-of-evidence (WOE) factors proposed for 
inclusion in CADs.

II. Past Experience With Carcinogenicity Assessment

    The strategy of testing for carcinogenic potential was the first 
safety topic addressed by ICH. The main topics were the need to conduct 
a study (ICH S1A), the selection criteria for the rodent species (ICH 
S1B), and the criteria for selecting the maximum dose (ICH S1C). During 
the discussion in that period, the relevance of the lifetime 
carcinogenicity studies in rats and mice was already highly debated, 
but in the absence of an alternative, the outcome of the negotiations 
did not really change the basic strategy of testing pharmaceuticals for 
human use in two rodent species. A proposal to not use the mouse as a 
second species did not receive sufficient support, although it paved 
the way to introduce transgenic mice with a 6- to 9-month treatment as 
an appropriate alternative (ICH S1B).
    In the following years, considerable resources have been spent to 
evaluate the approaches using the transgenic mice (Ref. 1). Also, other 
models and approaches received attention, especially the possibility to 
predict the outcome of carcinogenicity studies on the basis of the 
results of 3- to 6-month studies (Ref. 2).

[[Page 16682]]

    In this framework, researchers from a U.S.-based company started a 
project with 60 company-owned and marketed compounds (Ref. 3) with the 
outcome that a negative histopathology result in rats (i.e., no 
evidence of hyperplasia in any organ) might be predictive for the 
absence of tumors in a 2-year study. This led to the conduct of a much 
broader project involving 13 companies.

A. Carcinogenicity Studies

    In 2011, PhRMA published a database analysis (Ref. 4) confirming 
the conclusion of an earlier paper. Based on a dataset of 182 
compounds, it could be concluded that negative histopathology in a 
chronic rat study together with a negative result in genotoxicity and 
negative evidence of a hormonal mechanism would be useful in predicting 
a negative outcome of the carcinogenicity study for these compounds. 
This conclusion could apply to around 30 percent to 40 percent of the 
compounds.
    In the discussion of these results with the DRAs, a question was 
raised regarding the impact of the pharmacological properties of the 
compounds--first, for the false negative compounds, but with 
consequences for all compounds. The European Union (EU) delegation has 
conducted an analysis and concluded that a majority of the tumor-
inducing compounds were found to induce these tumors in relation to 
their pharmacodynamic action. In addition, some compounds associated 
with hepatocellular hypertrophy or liver enzyme induction were prone to 
induce tumors not only in liver, but also in thyroid and testes.
    In addition to the PhRMA dataset, FDA conducted a similar study 
with 50 unique compounds, and the Japanese Pharmaceutical 
Manufacturers' Association (JPMA) conducted a study with 64 unique 
compounds from the PhRMA compound set. These datasets confirmed the 
earlier analysis of the PhRMA dataset with respect to negative 
predictivity, as well as the EU analysis regarding the relation with 
the pharmacology. From discussions held in formulating ICH S1B 
guidance, both the European Union (Ref. 5) and the United States (Ref. 
6) published a dataset of several hundreds of compounds with lifetime 
carcinogenicity studies in rats and mice. The EU delegation has used 
the background data of the European Union, as well as the published 
data from FDA relating the pharmacology of the compounds and the 
outcome of the rat carcinogenicity studies. This analysis fully 
confirmed the conclusions reached earlier on the PhRMA database.

B. Conclusions From Analyses Conducted

    From the analysis of the various datasets (PhRMA, FDA, JPMA, and EU 
+ FDA), it can be concluded that based on pharmacology, genotoxicity, 
and chronic toxicity data (usually present at the end of phase 2 in the 
development of a new pharmaceutical), the outcome of the 2-year rat 
carcinogenicity study can be predicted with reasonable assurance at the 
two extremes of the spectrum. Negative predictions can be made when 
predictive carcinogenic signals are absent and positive predictions can 
be made when such signals are present. An in-between category of 
compounds still remains for which the outcome of the carcinogenicity 
studies cannot be predicted with sufficient certainty.

III. Proposal

    The processes initiated by this prospective proposal are expected 
to improve pharmaceutical carcinogenicity evaluations, reduce use of 
animals in accordance with the 3Rs (reduce/refine/replace) principle, 
reduce the use of other drug development resources, and reduce 
timelines to market authorization in some cases, all without compromise 
to patient safety. Analyses of the datasets described in section II 
suggest that a carcinogenicity assessment could be completed for 
certain pharmaceuticals without conducting a 2-year rat carcinogenicity 
study. From these databases, it can be shown that pharmacologic and 
toxicologic data from numerous sources, including toxicology studies of 
6-month duration or shorter, can be integrated to predict with 
sufficient certainty that a given pharmaceutical will fall into one of 
three main categories:
     Category 1--so likely to be tumorigenic in humans that a 
product would be labeled as such, and a 2-year rat study would not add 
value;
     Category 2--the available sets of pharmacologic and 
toxicologic data indicate that tumorigenic potential for humans is 
uncertain, and a 2-year rat study is likely to add value to human risk 
assessment; and
     Category 3a--so likely to be tumorigenic in rats but not 
in humans through prior-established and well-recognized mechanisms 
known to be human irrelevant that a 2-year rat study would not add 
value; or
     Category 3b--so likely not to be tumorigenic in either 
rats or humans that no 2-year rat study is needed.
    A set of proposed WOE (see Appendix 1 of this document) factors has 
been developed. During the prospective evaluation period sponsors would 
be encouraged to apply the available WOE for each pharmaceutical prior 
to 2-year rat study completion and to assign a pharmaceutical candidate 
to category 1, 2, 3a, or 3b in a CAD with respect to the expected value 
and need for 2-year rat carcinogenicity testing. Sponsors would submit 
the CAD to the DRAs explaining and justifying their position that a 
waiver decision is, or is not, appropriate for each pharmaceutical 
before knowing the outcome of carcinogenicity testing.

IV. Scope and Process for a Prospective Evaluation Period

A. Objective

    The intent of the prospective evaluation period is to gain 
experience and generate data that would address critical aspects of 
proposed changes to the ICH S1 guidance that could not be answered by 
retrospective analysis of the existing datasets. Specifically, these 
critical aspects include how well the WOE will predict the outcome and 
value of 2-year rat carcinogenicity study results, and how often the 
DRAs are in accordance with sponsors and with each other regarding the 
need to conduct a 2-year rat study based on the arguments put forth in 
CADs.
    Sponsors would be requested to submit CADs for all investigational 
small molecule pharmaceuticals subject to a 2-year rat carcinogenicity 
study under current ICH S1A guidance, as well as for those with ongoing 
rat carcinogenicity studies, provided that dosing has not exceeded an 
18-month duration. The date that the document was authored would be 
specified in the CAD in relation to the start of the study and would 
state that the assessment was not influenced by any signal from the 
ongoing study. The results of the prospective evaluation period would 
inform future revisions to the ICH S1 guidances. CADs submitted under 
the prospective evaluation period would not be considered regulatory 
documents or a substitute for the standard carcinogenicity assessment. 
This request would not be applicable to investigational biologic 
pharmaceuticals that follow the ICH S6 and S6 Addendum guidance 
documents.\2\
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    \2\ See the ICH guidance documents, ``S6 Preclinical Safety 
Evaluation of Biotechnology-Derived Pharmaceuticals'' and ``S6 
Addendum to Preclinical Safety Evaluation on Biotechnology-Derived 
Pharmaceuticals,'' available at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm or 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.

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[[Page 16683]]

B. Content of Submitted CADs

    Submissions would assess the carcinogenic potential for the 
investigational pharmaceutical under study, guided by the WOE approach 
described in Appendix 1 of this document. The CAD would address each 
factor considered pertinent to carcinogenic potential and would not 
provide a general summary of the nonclinical profile of the 
pharmaceutical. Not all factors in Appendix 1 would be expected to be 
applicable or available in all cases.
    In addition to addressing the WOE in Appendix 1, the CAD would 
include the following critical elements:
    1. Prediction of the actual tumor outcome from the planned or 
ongoing 2-year rat study (positive/tumor target organs or absence of 
tumors);
    2. Projected value of the anticipated 2-year rat outcome to the 
overall carcinogenicity assessment and human risk implications; and
    3. Categorical assignment with explicit statement and explanation 
as to whether the CAD supports: (1) Conduct of the 2-year rat study, or 
(2) a waiver request from conducting the 2-year study.

C. Evaluation of CADs

    The intent of the prospective evaluation period is to generate data 
relevant to future changes to the ICH S1 guidance. As such, submitted 
CADs would have no impact on the drug development program in any 
region. Actual waivers of the 2-year rat study would not be granted, 
nor would CADs be used to support regulatory actions on development 
programs.
    Each DRA would independently review submitted CADs at the time of 
receipt for the adequacy of the prediction and would only provide 
feedback to sponsors when the assessments inadequately address the 
three critical elements cited in section IV.B of this document. DRAs 
would convene to assess the concordance in predictions between DRAs and 
sponsors and among DRAs.
    The CADs would again be evaluated, based on the following three 
points, after the DRAs have received results of the corresponding 2-
year rat study:
    1. Accuracy of the prediction compared to the 2-year rat tumor 
outcome using the WOE described in Appendix 1 of this document;
    2. Accuracy of the sponsor's and the DRAs' original categorical 
assignments relative to actual overall study outcome; and
    3. Regulatory impact when the predicted tumor outcome may differ 
from the actual tumor outcome.
    The DRAs would maintain product confidentiality in conducting 
independent analyses of the attributes data, as well as of the type of 
compounds. Summary of anonymized results and the extent of sponsor 
participation would be periodically reviewed by the ICH S1 EWG. 
Concordance in interpretations between DRAs and sponsors and among the 
DRAs would be analyzed at study termination. Final results of the 
prospective evaluation period would be reviewed by the S1 EWG to inform 
revision of the current ICH S1 guidance. Publication in a peer-reviewed 
toxicological journal is planned.
    The prospective evaluation period would end after approximately 50 
CADs have been received by the DRAs. The goal of 50 CADs could change, 
depending on the diversity of compounds addressed and the number of 
pharmaceutical companies that would participate. For example, a narrow 
focus on few drug classes and/or participation by few pharmaceutical 
companies could introduce bias into the study and necessitate an 
increase in the number of CADs. Based on analysis of the number of rat 
study protocols and final rat study reports received by FDA since 2010, 
it is estimated that a 2-year data collection period would be needed to 
reach the goal of 50 CADs. Success of this effort hinges on the active 
participation by pharmaceutical companies in submitting CADs to DRAs 
for review.

D. Process of Submitting CADs

    Sponsors would be requested to submit CADs to FDA; the EU European 
Medicines Agency; and the Japanese Ministry of Health, Labour and 
Welfare. We would request that CADs be sent to all three DRAs, whether 
or not development programs are established in each region. CADs would 
be requested for all investigational small molecule pharmaceuticals 
subject to 2-year rat carcinogenicity study under the current ICH S1 
guidance, as well as for those with ongoing rat carcinogenicity 
studies, provided that dosing has not exceeded the 18-month duration. 
We would encourage that the final results of the 2-year rat study be 
submitted when available, irrespective of the timing of the marketing 
application.

V. Comments

    Interested persons may submit comments regarding the proposed 
change in approach to carcinogenicity assessment, on the prospective 
evaluation period intended to test this new approach, and on the WOE 
factors proposed for inclusion in carcinogenicity assessment documents. 
Submit either electronic comments regarding this document to http://www.regulations.gov or written comments to the Division of Dockets 
Management (see ADDRESSES). It is only necessary to send one set of 
comments. Identify comments with the docket number found in brackets in 
the heading of this document. Received comments may be seen in the 
Division of Dockets Management (see ADDRESSES) between 9 a.m. and 4 
p.m., Monday through Friday, and will be posted to the docket at http://www.regulations.gov.

VI. References

    The following references have been placed on display in the 
Division of Dockets Management (see ADDRESSES) and may be seen by 
interested persons between 9 a.m. and 4 p.m., Monday through Friday, 
and are available electronically at http://www.regulations.gov.

1. Cohen, S.M., D. Robinson, and J. MacDonald, ``Alternative Models 
for Carcinogenicity Testing'', Toxicological Sciences, vol. 64, pp. 
14-19, 2001.
2. Cohen, S.M., ``Human Carcinogenic Risk Evaluation: An Alternative 
Approach to the Two-Year Rodent Bioassay'', Toxicological Sciences, 
vol. 80, pp. 225-229, 2004.
3. Reddy, M.V., F.D. Sistare, J.S. Christensen, et al., ``An 
Evaluation of Chronic 6- and 12-Month Rat Toxicology Studies as 
Predictors of 2-Year Tumor Outcome'', Veterinary Pathology, vol. 47, 
pp. 614-629, 2010.
4. Sistare, F.D., D. Morton, C. Alden, et al., ``An Analysis of 
Pharmaceutical Experience With Decades of Rat Carcinogenicity 
Testing: Support for a Proposal to Modify Current Regulatory 
Guidelines'', Toxicologic Pathology, vol. 39, pp. 716-744, 2011.
5. Van Oosterhout, J.P.J., J.W. Van der Laan, E.J. De Waal, et al., 
``The Utility of Two Rodent Species in Carcinogenic Risk Assessment 
of Pharmaceuticals in Europe'', Regulatory Toxicology and 
Pharmacology, vol. 25, pp. 6-17, 1997.
6. Contrera, J.F., A.C. Jacobs, and J.J. DeGeorge, ``Carcinogenicity 
Testing and the Evaluation of Regulatory Requirements for 
Pharmaceuticals'', Regulatory Toxicology and Pharmacology, vol. 25, 
pp. 130-145, 1997.

Appendix 1. Weight-of-Evidence Factors for Consideration in a 
Carcinogenicity Assessment Document

    Each of the following factors should be considered in formulating a 
prediction in the outcome and value of conducting a 2-year rat 
carcinogenicity study and an overall integrated assessment of the 
carcinogenic risk for humans. Some factors can be appropriate for both, 
others more

[[Page 16684]]

appropriate for one or the other purpose.
     Knowledge of Intended Drug Target and Pathway 
Pharmacology, Secondary and Off-Target Pharmacology, and Drug Target 
Distribution in Rats and Humans
    Target and pathway related mechanistic/pharmacologic and understood 
secondary pharmacologic characteristics can contribute to the 
prediction of outcomes of carcinogenicity studies and can improve 
prediction of potential human carcinogens. The CAD is expected to 
convey a thorough and critical assessment of the sponsor's knowledge of 
all such characteristics, including a comprehensive literature review 
specifically addressing carcinogenicity risk. Examples of such data 
sources include the following:
    [cir] Prior experience with other molecules in the drug class
    [cir] Experience with human genetic polymorphisms in the target or 
pathway
    [cir] Clinical trial data
    [cir] Genetically engineered rodent models
    [cir] Unintended pharmacology
    [cir] Hormonal perturbation
    [cir] Targeted tissue genomic biomarker measurements
     Genetic Toxicology Study Results
    The criteria in ICH S2(R1) \3\ will be used to evaluate genetic 
toxicology data using a weight-of-evidence approach.
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    \3\ See the ICH guidance ``S2(R1) Genotoxicity Testing and Data 
Interpretation for Pharmaceuticals Intended for Human Use,'' 
available at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm or 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.
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     Histopathologic Evaluation of Repeated-Dose Rat Toxicology 
Studies
    Histopathologic risk factors of neoplasia should be evaluated in 
the 6-month chronic rat study. Findings seen only in shorter-term 
repeated dose rat toxicity studies are generally considered of less 
value for 2-year rat study outcome prediction, but should be addressed. 
Histopathologic findings of particular interest include cellular 
hypertrophy, diffuse and/or focal cellular hyperplasia, persistent 
tissue injury and/or chronic inflammation, preneoplastic changes, and 
tumors. It is important to note that liver tumors are observed at 
relatively high frequency in the rat, sometimes with Leydig cell and 
thyroid follicular cell tumors. Hepatocellular hypertrophy associated 
with increased liver weight often results from hepatic enzyme 
induction, the latter being a well-understood mechanism of rodent 
specific tumorigenesis at these sites with little relevance to humans 
(Refs. 1 and 2).
     Exposure Margins in Chronic Rat Toxicology Studies
    A high exposure margin in a chronic rat toxicology study absent of 
any carcinogenic risk factors can provide additional support for a 
carcinogenicity study waiver. The inability to achieve high exposure 
margins in a chronic rat toxicology study because of limitations of 
tolerability, pharmacology, or absorption would not preclude a 
carcinogenicity study waiver.
     Evidence of Hormonal Perturbation
    Evidence of hormonal perturbation should be considered from both 
repeated-dose and reproductive toxicology studies. Such evidence can 
come from weight, gross and/or microscopic changes in endocrine organs, 
or parameters from reproductive toxicology studies. Serum hormone 
levels can be useful to address findings but are not always essential.
     Immune Suppression
    Immunosuppression can be a causative factor for tumorigenesis in 
humans. As such, immunotoxicological parameters should be examined 
according to the ICH S8 guidance.\4\
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    \4\ See the ICH guidance ``S8 Immunotoxicity Studies for Human 
Pharmaceuticals,'' available at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm or 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.
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     Special Studies and Endpoints
    Data from special stains, new biomarkers, emerging technologies, 
and alternative test systems can be submitted with scientific rationale 
to help explain or predict animal and/or human carcinogenic pathways 
and mechanisms when they would contribute meaningfully.
     Results of Non-Rodent Chronic Study
    Assessment of carcinogenic risk factors in the non-rodent 
toxicology studies should be considered for human risk assessment 
regardless of results in the chronic rat study.
     Transgenic Mouse Study
    A transgenic mouse carcinogenicity study (usually rasH2 or p53+/- 
mouse) is not required for the WOE argument. However, if conducted on a 
case-by-case basis, a transgenic mouse carcinogenicity study can 
contribute to the WOE.

References

    The following references have been placed on display in the 
Division of Dockets Management (see ADDRESSES) and may be seen by 
interested persons between 9 a.m. and 4 p.m., Monday through Friday, 
and are available electronically at http://www.regulations.gov.

1. Cook, J.C., G.R. Klinefelter, J.F. Hardisty, et al., ``Rodent 
Leydig Cell Tumorigenesis: A Review of the Physiology, Pathology, 
Mechanisms and Relevance to Humans'', Critical Reviews in 
Toxicology, vol. 29, pp. 169-261, 1999.
2. McClain, R.M., ``The Significance of Hepatic Microsomal Enzyme 
Induction and Altered Thyroid Function in Rats: Implications for 
Thyroid Gland Neoplasia'', Toxicologic Pathology, vol. 17, pp. 294-
306, 1989.

    Dated: March 12, 2013.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2013-06145 Filed 3-15-13; 8:45 am]
BILLING CODE 4160-01-P