United States
Environmental Protection
Agency
Toxic Substances
Public Meeting
October 15-16, 1979
Melrose Park, Illinois
Proposed Health
Effects Test
Standards
Toxic Substances
Control Act
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Location:
Holiday Inn — Chicago West
1900 North Mannheim Road
Melrose Park, Illinois
60160
(312)681-3100
For Further Information Contact:
Industry Assistance Office
Office of Toxic Substances
(TS-799)
401 M Street, SW
Washington, DC
20460
Call Toll Free:
(800) 424-9065
Or in Washington:
554-1404
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Public Meeting:
TSCA Health Effects Test Standards
as Proposed in the Federal Register
May 9 & July 26, 1979
Agenda
October 15, 1979
9:00 -9:15 a.m.
9:15 -10:15 a.m.
10:15 -10:30 a.m.
10:30 -Noon
12:00 -1:00 p.m.
1:00 -2:00 p.m.
2:00 -3:00 p.m.
3:00 -3:15 p.m.
3:15 -4:00 p.m.
4:00 -5:00 p.m.
October 16, 1979
9:00 -9:15 a.m.
9:15 -10:45 a.m.
10:45 -11:00 a.m.
11:00 -Noon
12:00 -1:00 p.m.
1:00 -2:00 p.m.
2:00 -2:15 p.m.
2:15 -3:15 p.m.
3:15 -4:30 p.m.
Introduction
Subpart A—General Requirements
Coffee Break
Subpart A—General Requirements
Lunch
Subpart B—Good Laboratory Practices for
Health Effects
Subpart C—Acute and Subchronic Health
Effects
Coffee Break
Subpart I—Metabolism
Other Issues
Introduction
Subpart D—Chronic Health Effects
Coffee Break
Mutagenicity
Lunch
Subpart F—Teratogenicity
Coffee Break
Subpart F—Reproductive Health Effects
Other Issues
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Where to Find It
in the Federal Register
Part 772—Standards for Development of Test Data
-44066
-44066
-44067
-44067
-44070
-44071
-44071
-44072
•44075
•44077
Subpart A—General Requirements
§772.100-1 General July 26-44062
§772.100-2 General Standards for Health Effects July 26-44062
Subpart B—Good Laboratory Practice Standards
§772.110-1 Good Laboratory Practice Standards
for Health Effects May 9-27362
Subpart C—Acute & Subchronic Health Effects
§772.112-10 General July 26-
§772.112-21 Acute Oral Toxicity Study July 26-
§772.112-22 Acute Dermal Toxicity Study July 26-
§772.112-23 Acute Inhalation Toxicity Study July 26-
§772.112-24 Primary Eye Irritation Study July 26-
§772.112-25 Primary Dermal Irritation Study July 26-
§772.112-26 Dermal Sensitization Study July 26-
§772.112-31 Subchronic Oral Dosing Studies July 26-
§772.112-32 Subchronic 90-Day Dermal Toxicity Study July 26-
§772.112-33 Subchronic Inhalation Toxicity Study July 26-
Subpart D—Chronic Health Effects
§772.113-1 General May 9-27350
§772.113-2 Oncogenic Effects Test Standards May 9—27354
§772.113-3 Non-Oncogenic Chronic Effects Test Standards May 9—27357
§772.113-4 Combined Chronic Effects Test Standards May 9—27359
Subpart E—Mutagenic Effects
§772.114-1 General July 26—44080
§772.114-2 Standards for Detecting Gene Mutations July 26—44081
§772.114-3 Test Standards for Detecting Heritable
Chromosomal Mutations July 26—44083
§772.114-4 Test Standards for Detecting Effects on
DNA Repair or Recombination as an Indicator
of Genetic Damage July 26—44084
Subpart F—Teratogenic/Reproductive Health Effects
§772.116-1 General July 26—44087
§772.116-2 Teratogenic Effects Test Standards July 26—44087
§772.116-3 Reproductive Effects Test Standards July 26—44089
Subpart I—Other Health Effects
§772.119-1 General Metabolism Test Standards July 26—44092
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EPA Participants
Moderator:
John B. Pitch, Jr.
Director
Industry Assistance Office
Office of Toxic Substances
Sarah S. Shapley
Industrial Liaison
Industry Assistance Office
Office of Toxic Substances
Panel Chairman:
Panel Members:
Dr. Carl R. Morris
Chairman, Health Effects Subgroup
Section 4 Work Group
Health Review Division
Office of Testing and Evaluation
Office of Toxic Substances
Dr. NorbertP. Page
Director of Scientific Affairs
Office of Testing and Evaluation
Office of Toxic Substances
Dr. Larry L. Hall
Senior Toxicologist
Office of Research and Development
Dr. Adrienne J. Zahner
Pathologist
Carcinogen Assessment Group
Office of Research and Development
Dr. Richard N. Hill
Acting Director
Health Effects and Science Policy
Office of Toxic Substances
Dr. William H. Preston
Chairman, Pesticide Registration
Guidelines Work Group
Office of Pesticides Programs
Mr. Alan H. Carpien
Attorney, Toxic Substances Division
Office of General Counsel
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Proposal Highlights
Section 4 Testing Requirements
A Section 4(a) Test Rule Will Specify
• Chemical Substance(s) to Test
• Person(s) to Test (Sponsor)
• Standards for Testing
— Reference Code of Federal Regulations (CFR) TSCA
Standards
— Special Modifications and Provisions
• Deadlines for Submission of Data to EPA
EPA Approach As Proposed
• Establish Generic Test Standards in CFR for Future
Reference
• Test Rules Will Reference CFR and Provide for Specific
Modifications
Subpart A—General Requirements for
Health Effects
§772.100-2
Contents
• Applicable to All Health Effects Studies. Additional
Requirements in Each Test Standard.
• Specific Personnel Requirements
— Pathologists
— Veterinarians
- Others
• Study Plan Submissions (when specified)
• Test or Control Substance Concentration
• Dietary Requirements
• Contaminant Analysis of Feeds and/or Vehicles
• Clinical Observations
• Pathology Procedures
• Reporting of Data
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Proposal Highlights
Subpart B—Good Laboratory Practice
Standards for Health Effects
§772.110-1
EPA/FDA Interaction
• Under EPA/FDA interagency agreement, FDA is authorized
to conduct Good Laboratory Practice inspections and does
inspections to support audits of FIFRA and TSCA health
effects studies.
• EPA provides scientific expertise for audits of toxicity tests
and directs all regulatory follow-up relating to FIFRA and
TSCA.
• All adverse inspection/audit findings will be disseminated
to other regulatory agencies.
EPA approach on Environmental Effects
• EPA is currently developing Good Laboratory Practices for
ecological effects and chemical fate testing under FIFRA
and TSCA.
• EPA will conduct inspections/audit for ecological effects
and chemical fate testing.
Purposes of a Data Audit
• To determine whether "raw data" are internally consistent
as well as consistent with test reports submitted to EPA
• To obtain information provided in final report
• To determine whether protocol was followed in conduct of
study
• To determine whether errors were made or practices
employed which may have affected the study's validity
• To determine whether data were altered or whether final
report did not disclose all material facts regarding actual
test procedures or results
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Proposal Highlights
Good Laboratory Practice Standards for
Health Effects
§772.110-1
Contents
Personnel Qualifications
Quality Assurance Unit
Protocol and Conduct of the Study
Time of Completion
Test Substance Specifications
Facilities Requirements
— Physical
— Operational
Animal Care and Handling
Handling of Potentially Toxic Substances and Wastes
Proposal Highlights
Subpart C—Acute and Subchronic Health
Effects
§772.112-10
General
• Scope and Purpose/Applicability—Data Development for
Section 4 of TSCA
• Definitions
(1) "Acute effects" means short-term health effects
following a single administration of a test substance.
(2)"Subchronic effects" means health effects following
continuous or repeated administration of a test substance
over a period of approximately 90 days.
• Good Laboratory Practices—Standards for Acute and
Subchronic Health Effects. The GLP in Subpart B, in
§772.110-1, apply to Subpart C.
• Specific Personnel Requirements—The requirements in
Subpart A, §772.110-2 (b), apply to Subpart C.
• Test or Control Substance Concentration—The
requirements in Subpart A, §772.100-2(b)(3), apply to
Subpart C.
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Proposal Highlights
Subpart
Section
772.112-21
772.112-22
772.112-23
772.112-24
772.112-25
772.112-26
C— Acute
Test
Oral
(Gavage)
Dermal
(24 hours)
Inhalation
(1-4 hours)
Eye
irritation
Dermal
irritation
Dermal
sensitization
Studies
Species
Rat
Rabbit
Rat
Rabbit
Rabbit
*— Key Points
Age, Sex,
Number
Young adults,
Both sexes,
Minimum 5/group
Young adults,
Both sexes,
Minimum 5/group
Young adults,
Both sexes,
Minimum 5/group
Young adults,
Minimum 9/group
Young adults,
Minimum 6/group
Guinea pig Young adults,
Minimum 10/group
Dose
Levels
3 + Control (if
vehicle/diluent)
3 + Control
4 + Control
1
1 + Control (if
vehicle/diluent)
Sequential
3/week x 3 weeks,
total 10 treatments
Clinical
Exam
Observation (12
hour cycle, 14
days)
Observation (12
hour cycle,
14 days)
Observation (12
hour cycle,
14 days)
Observation (at
daysl, 2,3,4,
7,10, &13)
Observation (daily
until irritation ends
or is irreversible)
Observation
(at least 6 weeks)
Pathology
Exam
Detailed
gross
Detailed
gross
Histopath
(skin)
Detailed
gross
Histopath
(respiratory
system)
'Conduct of all studies wilt conform with Good Laboratory Practices for Hea/th Effects.
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Proposal Highlights
Subpart C— Subchronic Studies*— Key Points
Section Test
772.112-31 Oral
Rat— 90 days
772.112-32 90-Day Dermal
772.112-33 90-Day
Inhalation
(Minimum 5
days/week)
Age, Sex, Dose
Species Number Levels
2 mammalian: Rat— 6 weeks 3 + Controls
rat and Dog— 4-6 months
non-rodent
Both sexes
Rat— 20/group
Dog— 6/group
Rabbit Young adults, 3 + Controls
Both sexes,
10/group
Rat Young adults, 3 + Controls
Both sexes, (vehicle and
10/group negative)
Clinical
Exam
Observation
(12 hour cycle)
Hematology
Blood chemistry
Cholinesterase
Inhibition tests
Urinalysis
Others as
appropriate
Observation
(12 hour cycle)
Hematology
Blood chemistry
Cholinesterase
Inhibition tests
Others as
appropriate
Observation
(12 hour cycle)
Hematology
Blood chemistry
Cholinesterase
Others as
appropriate
Detailed
Exam
Detailed
gross
Histopath.
Tissues as
specified
Detailed
gross
Histopath.
Tissues as
specified
Detailed
gross
Histopath.
Tissues
as specified
'Conduct of alt studies will conform with Good Laboratory Practices for Health Effects.
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Proposal Highlights
Subpart D—Chronic Health Effects
Oncogenicity Test Standards
§772.113-2
Test Animals
• Both Sexes
• Two Rodent Species—Laboratory Rat and Mouse
Duration
• 24-30 Months
Route(s)
• Major Human Exposure
• Designated in Specific Test Rules
Dose Levels
• Minimum 3 + Matched Controls
• High Dose (HD)—Slightly Toxic Range
• Median Dose (MD)-1/4-1/2 HD
• Low Dose (LD)—1/2 or less MD but not less than 10 % of the
HD
• Minimum 90-day Preliminary Toxicity Study as Basis for
Dose Levels
Number of Animals
• Minimum 50/Group
• 50 Animals/Group x 4 Doses x 2 Species x 2 Sexes =800
Animals
Age at Start
• Weanlings—Maximum 6 weeks
Clinical Examination
• Observation (12 hour cycle)
• Hematology
Pathology Examination
• Detailed Gross
• Microscopic Exam (Approximately 30 Tissues/Animal)
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Data Reporting
Study Plan Submission to EPA
• 90 Days Before Initiation of Study
Conduct of Study
• GLP for Health Effects
• Use of Standardized Diets/Contaminant Analysis
Proposal Highlights
Subpart D—Chronic Health Effects
Non-Oncogenic Chronic Effects Test
Standards
§772.113-3
Test Animals
• Both Sexes
• Two Mammalian Species—Rat (R) and Non-Rodent (N)
(Dog/Other)
Duration
• 24-30 Months
Number of Animals
• R: Minimum 50/Group (plus at least 8 additional for clinical
laboratory testing)
• N: Minimum 6/Group
Age at Start
• Weanlings
• R: Maximum 6 weeks
• N: Maximum 10 weeks
Route(s)
• Major Human Exposure
• Designated in Specific Test Rules
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Dose Levels
• Minimum 3 + Matched Controls
• Highest Dose—"Moderate Toxicity"
— Mortality must not exceed 50 percent before 18 months.
— Minimal mortality but significant toxicologic effects.
• Second Dose—"Slight Toxicity"
• Lowest Dose—No Observable Evidence of Toxicity (other
than tumors)
• Minimum 90-day Preliminary Toxicity Study as Basis for
Dose Levels
Clinical Examination
• Observation (12 hour cycle) • Urinalysis
• Hematology • Function Tests
• Blood Chemistry • Residue Analysis
Pathology Examination
• Detailed Gross
• Microscopic Exam (Approximately 40 Tissues/Animal)
Data Reporting
Study Plan Submission to EPA
• 90 Days Before Initiation of Study
Conduct of Study
• GLP for Health Effects
• Use of Standardized Diets/Contaminant Analysis
Proposal Highlights
Subpart D—Chronic Health Effects
Combined Chronic Effects Test Standards
§772.113-4
Test Animals
• Both Sexes
• Three Mammalian Species—Mouse (M), Rat (R),
Non-Rodent/Dog (N)
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Duration
• 24-30 Months
Route(s)
• Major Human Exposure
• Designated in Specific Test Rules
Dose Levels
• Matched Controls
• R + N: Upper Dose "Moderate Toxicity"
— R: Mortality must not exceed 50 percent before 18
months.
— N: Minimal mortality but significant toxicologic effects.
• M +R + N: Second Dose—"Slight Toxicity"
• M +R + N: Third Dose —1/4-1/2 Second Dose
• M + R + N: Fourth Dose—No Observable Evidence of
Toxicity (other than tumors)
• Minimum 90-day Preliminary Toxicity Study as Basis for
Dose Levels
Numbers of Animals
• M: Minimum 50/Group (Plus at least 8 additional for clinical
laboratory testing)
• R: Minimum 50/Group (Plus at least 8 additional for clinical
laboratory testing)
• N: Minimum 6 Group
Age at Start
• Weanlings
• R + M: Maximum 6 weeks
• N: Maximum 10 weeks
Clinical Examination
• Observation (12 hour cycle) • Urinalysis
• Hematology • Function Tests
• Blood Chemistry • Residue Analysis
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Pathology Examination
• Detailed Gross
• Microscopic Exam (Approximately 40 Tissues/Animal)
Data Reporting
Study Plan Submission to EPA
• 90 Days Before Initiation of Study
Conduct of Study
• GLP for Health Effects
• Use of Standardized Diets/Contaminant Analysis
Proposal Highlights
Subpart E—Mutagenic Effects
§772.114
Purpose
• Assess potential hazard of chemical substances to interact
with genetic mechanisms with resultant heritable change
(mutation).
Tests Required
• Gene Mutations
— Bacteria
— Eukaryotic Micro-Organisms
— Insects
— Mammalian Somatic Cells in Culture
— Mammals In Vivo
• Heritable Chromosomal Mutations
— In Vivo Cytogenetics (Mammals)
— Chromosomal Damage (Insects)
— Dominant Lethal (Mammals)
— Heritable Translocation (Mammals)
• DNA Repair or Recombination
— DNA Repair (Bacteria)
— Unscheduled DNA Synthesis (Mammalian Cells)
— Eukaryotic Micro-Organisms
— Sister Chromatid Exchange (Mammalian Cells)
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Proposal Highlights
Subpart F—Teratogenic/Reproductive
Effects
§772.116-1
General
• Scope and Purpose/Applicability—Data development for
Section 4 of TSCA
• Definitions
(1) "Teratogenic" means the potential of a test substance to
produce defects in offspring resulting from perinatal
exposure.
(2) "Reproductive effects" means impairment of
reproduction.
(3) "Developmental effects" means adverse health effects
during any or all phases of development and maturation
following a single, continuous or repeated
administration of a test substance.
(4) "Reproductive toxicity" means the total or accumulated
toxicity of a test substance during any or all phases of
conception, development and maturation.
• Good Laboratory Practice Standards for
Teratogenic/Reproductive Health Effects—The GLP in
Subpart B, §772.110-1, apply to Subpart F
• Specific Personnel Requirements—The requirements in
Subpart A, §772.110-2(b), apply to Subpart F
• Submission of Study Plan—The sponsor(s) of a study must
submit a detailed study plan to the Agency at least 90 days
before the initiation of a "reproduction study." The
requirement for study plan submission in Subpart A,
§772.110-2(b)2, applies to the reproduction studies in
Subpart F Study plans for teratogenicity studies are
not required prior to their initiation.
• Test or Control Substance Concentration—The
requirements in Subpart A, §772.100-2(b)(3), apply to
Subpart F
• Dietary Requirements—The requirements specified in
Appendix B, Subpart A, apply to Subpart F.
• Contaminant Analysis of Feeds and/or Vehicles—The
requirements specified in Appendix B, Subpart A, apply to
Subpart F
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Proposal Highlights
Subpart F—Teratogenic Effects
§772.116-2
Test Animals
• Two Mammalian Species—Rat, Mouse, Hamster or Rabbit
Number of Animals
• Rat, Mouse or Hamster: 20/Group
• Rabbit: 12/Group
Age at Start
• Young Adults
Dose Levels
• Minimum 3 + Matched Controls
• High Dose (HD)—Some fetal and/or maternal toxicity but
not more than 10 percent maternal
fatality.
• Median Dose (MD)
• Lowest Dose (LD)—No Observable Evidence of Toxicity
• Body Weight on First Day of Administration as Basis for
Dose Levels
Clinical Examination
• Observation (12 hour cycle)
Pathology Examination
• Detailed Gross on Female and Fetuses
Data Reporting
Conduct of Study
• GLP for Health Effects
• Use of Standardized Diets/Contaminant Analysis
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Proposal Highlights
Subpart F—Reproductive Effects
§772.116-3
Test Animals
• 1 Mammalian Species—Rat
Number of Animals
• Minimum 20 Females/Dose
• Minimum 10 Fertile Males/Dose
Dose Levels
• Minimum 3 + Matched Controls
• Highest Dose (HD)—"Moderate Toxicity" but not more than
10 percent fatality
• Median Dose (MD)
• Lowest Dose (LD)— No Observable Evidence of Toxicity
Duration
• 2 Generations, Fo and F, (continuous exposure)
• F2 —In Vivo and Through Nursing
Clinical Examination
• Observation (at least 12 hour cycle)
Pathology Examination
• Detailed Gross
• Histopathology
Data Reporting
Study Plan Submission to EPA
• 90 Days Before Initiation of Study
Conduct of Study
• GLP for Health Effects
• Use of Standardized Diets/Contaminant Analysis
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Comparative Table of TSCA and FIFRA Proposals
Section of TSCA Proposal Test Standards
Subpart A
Subpart B
Subpart C
Subpart D
Subpart E
Subpart F
Subpart I
772.100 General
772.110-1 GLP for Health Effects
772.112-21 Acute Oral Toxicity
772.112-22 Acute Dermal Toxicity
772.112-23 Acute Inhalation Toxicity
772.112-24 Primary Eye Irritation
772.112-25 Primary Dermal Irritation
772.112-26 Dermal Sensitization
772.112-31 Subchronic Oral Dosing
772.112-32 Subchronic 90-Day Dermal Toxicity
772.112-33 Subchronic Inhalation Toxicity
772.113-1 General
772.113-2 Oncogenic Effects
772.113-3 Non-Oncogenic Chronic Toxicity
772.113-4 Combined Chronic Toxicity
772.114-1 General
772.114-2 Gene Mutations
772.114-3 Heritable Chromosomal Mutations
772.114-4 DNA Repair
772.116-1 General
772.116-2 Teratogenicity
772.116-3 Reproduction
772.119-1 Metabolism
Section of FIFRA Proposal
163.80-2.-3
(In Draft)
163.81-1(b)&(c)
163.81-2(c)&(d)
163.81-3(b)&(c)
163.81-4(c)&(d)
163.81-5(c)&(d)
163.81 -6(b)&(c)
163.82-1 (c)&(d)
163.82-3(c)&(d)
163.82-4(c)&(d)
163.80-2,-3
163.83-2(c)&(d)
163.83-1 (c)&(d)
163.83- 1(b) and 163.83-2(b)
163.84-1 (a),(d),(e)&(f)
163.84-2
163.84-3
163.84-4
163.83-3(b)&(c)
163.83-4(b)&(c)
163.85-1 (a),(c),(d)&(e)
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