Draft Risk Evaluation for Perchloroethylene (Ethene, 1,1,2,2-Tetrachloro) CASRN: 127-18-4 Systematic Review Supplemental File: Data Quality Evaluation of Human Health Hazard Studies


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vvEPA

United States	Office of Chemical Safety and

Environmental Protection Agency	Pollution Prevention

Draft Risk Evaluation for
Perchloroethylene
(Ethene, l,l»2,2-Tetrachloro)

CASRN: 127-18-4

Systematic Review Supplemental File:

Data Quality Evaluation of Human Health Hazard Studies

Animal Studies

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April 2020

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Table of Contents

1.	Acute Toxicity Studies	4

1.1.	Animal toxicity evaluation results of Beliles et al 1980 for acute inhalation
studies on genotoxicity in vivo outcomes	4

1.2.	Animal toxicity evaluation results of Dow et al 1950 for an acute and repeat
inhalation exposures study on mortality, body weight, respiratory, cardiovascular,
hepatic, renal, hematological and immune, reproductive, neurological/behavior,
endocrine, gastrointestinal, musculoskeletal, ocular and sensory outcomes	7

1.3.	Animal toxicity evaluation results of Dow et al 1983 for an acute eye irritation
study in rabbits on irritation outcomes	14

1.4.	Animal toxicity evaluation results of Dow et al 1983 for an acute dermal
lethality study in rabbits on mortality and irritation outcomes	17

1.5.	Animal toxicity evaluation results of Dow et al 1983 for an acute dermal
irritation study on irritation outcomes	20

1.6.	Animal toxicity evaluation results of Dow et al 1983 for an acute oral toxicity
study in rats on mortality and acute toxicity/poisoning outcomes	23

2.	Short - Term Toxicity Studies	26

2.1.	Animal toxicity evaluation results of Beliles et al 1980 for 3-week gestational
inhalation studies on genotoxicity in vivo (mechanistic) outcomes	26

2.2.	Animal toxicity evaluation results of Boverhof et al 2013 for a 4-week inhalation
(perc) study on mortality, nutrition and metabolic/adult exposure body weight,
hematological and immune, hepatic, renal, and respiratory outcomes	29

2.3.	Animal toxicity evaluation results of Carney et al 2006 for a gestational
exposure study on reproductive, growth (early life) and development, nutrition and
metabolic/adult exposure body weight, mortality outcomes	34

2.4.	Animal toxicity evaluation results of Nelson et al 1979 for a
neurodevelopmental inhalation study (gd 7-13) study on growth (early life) and
development outcomes	41

2.5.	Animal toxicity evaluation results of Nelson et al 1979 for a
neurodevelopmental inhalation study (gd 14-20) on growth (early life) and
development and neurological/behavior outcomes	46

2.6.	Animal toxicity evaluation results of NTP 1986 for 1-day inhalation studies in
rats and mice on acute toxicity, neurological/behavioral, mortality, nutrition and
metabolic/adult exposure body weight outcomes	51

2.7.	Animal toxicity evaluation results of NTP 1986 for 14-day inhalation studies in
rats and mice on neurological/behavioral, mortality, nutrition and metabolic/adult
exposure body weight outcomes	54

2.8.	Animal toxicity evaluation results of NTP 1986 for 14-day inhalation studies in
rats and mice (histology) on reproductive, hematological and immune, renal, hepatic,
cardiovascular, endocrine, gastrointestinal, respiratory, skin and connective tissue,
thyroid outcomes	58

2.9.	Animal toxicity evaluation results of Seo et al 2012	62

3.	Subchronic Toxicity Studies	66

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3.1.	Animal toxicity evaluation results of Buben et al 1985 for a 6 week gavage study
of perc in mice study on hepatic outcomes	66

3.2.	Animal toxicity evaluation results of E. I. Dupont De Nemours 1941 for a 10
week inhalation study in dogs on neurological/behavior, cardiovascular,
hematological and immune outcomes	70

3.3.	Animal toxicity evaluation results of Natl Institute of Health 1977 for a 6-week
oral (rats and mice) study on mortality and metabolic/adult exposure body weight
outcomes	74

4.	Chronic T oxicity Studies	80

4.1.	Animal toxicity evaluation results of Dow et al 1978 for a 12 month inhalation
study in rats, with lifetime observation on renal, hepatic, nutrition and
metabolic/adult exposure body weight, hematological and immune outcomes	80

4.2.	Animal toxicity evaluation results of Halogenated Solvents, Indust for a
multigen inhalation study in rats on reproductive, renal, hepatic, growth (early life)
and development, neurological/behavior, nutrition and metabolic/adult exposure
body weight outcomes	86

4.3.	Animal toxicity evaluation results of NTP 1986 for 13-week inhalation studies
in rats and mice on reproductive, hematological and immune, neurological/behavior,
renal, hepatic, cardiovascular, endocrine, gastrointestinal, mortality, nutrition and
metabolic/adult exposure body weight, respiratory, skin and connective tissue, and
thyroid outcomes	91

4.4.	Animal toxicity evaluation results of Tinston et al 1994 for a multigeneration
inhalation study on reproductive, growth (early life) and development, and renal
outcomes	95

5.	Cancer Studies	98

5.1.	Animal toxicity evaluation results of Dow et al 1978 for a 12 month inhalation
study in rats, with lifetime observation (cancer) on cancer outcomes	98

5.2.	Animal toxicity evaluation results of Jisa et al 1993 for a cancer bioassay study
on cancer; nutrition and metabolic/adult exposure body weight outcomes	104

5.3.	Animal toxicity evaluation results of Natl Institute of Health 1977 for a 78-week
cancer bioassay (rats and mice) study on cancer, mortality, respiratory, hepatic, renal,
thyroid, cardiovascular, neurological/behavior, nutrition and metabolic/adult
exposure body weight, hematological and immune, skin and connective tissue, and
gastrointestinal outcomes	107

5.4.	Animal toxicity evaluation results of NTP 1986 for 2-year cancer biossay,
inhalation studies in rats and mice on cancer, reproductive, hematological and
immune, neurological/behavior, renal, hepatic, cardiovascular, endocrine,
gastrointestinal, mortality, nutrition and metabolic/adult exposure body weight,
respiratory, skin and connective tissues, thyroid outcomes	115

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1. Acute Toxicity Studies

1.1. Animal toxicity evaluation results of Beliles et al 1980 for acute inhalation studies

on genotoxicity in vivo outcomes

Study reference:

Beliles, R. P.,Brusick, D. J.,Mecler, F. J. (1980). Teratogenic-mutagenic risk of workplace contaminants:
trichloroethylene, perchloroethylene, and carbon disulfide

HERO ID: 58331

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

Test Substance

1. Test Substance
Identity

Identified by chemical
name and synonym

High

2. Test Substance
Source

Manufacturer and lot
number given.

High

3. Test Substance
Purity

91% pure, impurities
were not characterized

Medium

Test Design

4. Negative and
Vehicle Controls

Filtered air controls;
control animals exposed
in a different room.

High

5. Positive Controls

Positive controls
(reference mutagens)
were used for all
studies.

High

6. Randomized
Allocation

randomly assigned to
groups

High

Exposure
Characterization

7. Preparation and
Storage of Test
Substance

Method and equipment
used to generate the test
substance as a vapor
were reported and
appropriate.

High

8. Consistency of

Exposure
Administration

See footnote at end of
page.1

High

9. Reporting of
Doses/Concentratio
ns

Target and analytical
concentrations were
provided. Range of
measure concentration
did not deviate more
than 10%.

High

10. Exposure
Frequency and
Duration

Acute duration
appropriate for
dominant lethal and
spermhead abnormality.

High

1 Metrics that received a "High" rating met the criteria as discussed in the Applications of Systematic Review for
TSCA Risk Evaluation.

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Study reference:

Beliles, R. P.,Brusick, D. J.,Mecler, F. J. (1980). Teratogenic-mutagenic risk of workplace contaminants:
trichloroethylene, perchloroethylene, and carbon disulfide



HERO ID: 58331











Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score



11. Number of
Exposure Groups
and Dose Spacing

2 exposure
concentrations (100 and
500ppm)

Medium

2

1

2



12. Exposure Route
and Method

Dynamic chamber,
whole body, assumed
that Perc does not
condense.

High

1

1

1



13. Test Animal
Characteristics

Species, strain and
source were reported;
starting age and bw not
given.

Medium

2

2

4

Test Organism

14. Adequacy and

Consistency of
Animal Husbandry
Conditions

well reported

High

1

1

1



15. Number per
Group

6-10/group

High

1

1

1



16. Outcome
Assessment
Methodology

Dominant lethal assay,
spermhead abnormality,
chromosomal aberration
in rat bone marrow,

High

1

2

2

Outcome
Assessment

17. Consistency of
Outcome
Assessment

See footnote at end of
page.1

High

1

1

1

18. Sampling
Adequacy

See footnote at end of
page.1

High

1

1

1



19. Blinding of
Assessors

Blinding was not
reported, but most
outcomes were not
subjective.

Medium

2

1

2



20. Negative Control
Response

See footnote at end of
page.1

High

1

1

1

Confounding /
Variable Control

21. Confounding
Variables in Test
Design and
Procedures

None related to
genotoxicity

High

1

2

2

22. Health
Outcomes Unrelated
to Exposure

None related to
genotoxicity

High

1

1

1

1 Metrics that received a "High" rating met the criteria as discussed in the Applications of Systematic Review for
TSCA Risk Evaluation.

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Study reference:

Beliles, R. P.,Brusick, D. J.,Mecler, F. J. (1980). Teratogenic-mutagenic risk of workplace contaminants:
trichloroethylene, perchloroethylene, and carbon disulfide

HERO ID: 58331

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

Data Presentation
and Analysis

23. Statistical
Methods

Statistics were well
described and
appropriate

High

1

1

1

24. Reporting of
Data

All outcomes were
reported.

High

1

2

2

High: >=1 and <1.7
Medium: >=1.7 and <2.3
Low: >=2.3 and <=3

Sum of scores:



31

36

Overall Score = Sum of Weighted Scores/Sum
of Metric Weighting Factors:

1.1613

Overall Score:
Nearest *:

1.2

Overall Quality Level:

High

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1.2. Animal toxicity evaluation results of Dow et al 1950 for an acute and repeat

inhalation exposures study on mortality, body weight, respiratory, cardiovascular,
hepatic, renal, hematological and immune, reproductive, neurological/behavior,
endocrine, gastrointestinal, musculoskeletal, ocular and sensory outcomes

Study reference:

Dow Chem, Co (1950). Vapor toxicity of tetrachloroethylene for laboratory animals and human subjects
HERO ID: 4214242

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

Test Substance

1. Test Substance
Identity

Tetrachoroethylene
identified by name and
structure.

High

2. Test Substance
Source

"* samples of
commercial product" -

manufacturer not
identified. Confirmed
identity in lab.

Medium

3. Test Substance
Purity

99.9%C

High

Test Design

4. Negative and
Vehicle Controls

No controls reported for
acute studies. In repeat-
exposure study, authors
indicated untreated and
air-exposed controls
were used "for each
experiment". It is not
clear if they were all
concurrent because
exposure duration varied
drastically in different
exposure groups within
the same species.

Unacceptable

5. Positive Controls

Not Rated

6. Randomized
Allocation

Animals were "carefully
selected on the basis of

general appearance,
body weight, and growth

during a preliminary
period of observation".

Low

Exposure
Characterization

7. Preparation and
Storage of Test
Substance

Vaporization method
reported with limited
details. Storage not
reported.

Medium

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Study reference:

Dow Chem, Co (1950). Vapor toxicity of tetrachloroethylene for laboratory animals and human subjects
HERO ID: 4214242

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score



8. Consistency of

Exposure
Administration

Exposure durations
varied widely between
exposure groups within

the same species
(unclear if each duration
had a concurrent control
group). Only guinea pigs

had two exposure
groups (and presumably
a control group) with the
same duration (exposed
14 days over an 18 day
period) for meaningful
dose-response analysis

(but data reporting
inadequate for analysis).
Different chambers were

used for different
concentrations in repeat-
exposure studies.

Unacceptable

4

1

4

9. Reporting of
Doses/Concentratio
ns

Only target levels were
reported. Air
concentrations were
monitored, and
reportedly within 10% of
target

Medium

2

2

4

10. Exposure
Frequency and
Duration

Exposure at different
concentrations in acute
studies ranged from
minutes to 14 hours.
Exposure at different
concentrations in repeat
exposure studies (7 hr/d,
5 d/wk) ranged from 18-
236d for various species.

Low

3

1

3

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Study reference:

Dow Chem, Co (1950). Vapor toxicity of tetrachloroethylene for laboratory animals and human subjects
HERO ID: 4214242

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score



11. Number of
Exposure Groups
and Dose Spacing

Acute exposure:: 4
exposure levels, no
control, (lack of control
addressed in prior Metric
4, not here)
Repeated exposure: All
exposure groups except
Monkeys had at lease 2
exposure groups plus

control. With the
exception of 2 (of 4)
guinea pig groups,
exposure groups were
not directly comparable
due to different
exposure durations.

Low

3

1

3

12. Exposure Route
and Method

Acute: glass, 160L, air

rate of 15-30 L/min
(which equates 6-12 air

changes per hour)..
Animals in groups of 5-
12.

Repeat: Metal chamber
about 450L for 100 ppm,
metal chamber of 1700 L
for 200 and 400 ppm,
glass chamber of 160L
for 1600 and 2500 ppm.
Air flow rate not
reported.

Unacceptable

4

1

4

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Study reference:

Dow Chem, Co (1950). Vapor toxicity of tetrachloroethylene for laboratory animals and human subjects
HERO ID: 4214242

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

Test Organism

13. Test Animal
Characteristics

Rat: Internal albino
colony originally
obtained from Wistar
Institute of Anatomy and

Biology in 1938
Gn Pig: Heterogeneous
stock purchased from
"commercial breeder"
Rabbit: Albino, internal
heterogeneous colony
(no further details)
Monkey: Rhesus - "newly
imported", no further
details.

No ages reported for any
species. Initial BW data
only available graphically
for a couple exposure
groups.

Low

3

2

6

14. Adequacy and

Consistency of
Animal Husbandry
Conditions

Diet for each species
reported. No other
husbandry conditions
reported.

Low

3

1

3

15. Number per
Group

Acute: 5-30 per dose per
duration
Repeat:
Rat: 5-22/sex per group
Rabbit: 2/sex per group
Guinea Pig: 5-15/sex per
group
Monkey - 2 M/group

Number varied widely
between exposure
groups.

Medium

2

1

2

Outcome
Assessment

16. Outcome
Assessment
Methodology

Acute: Mortality, clinical

signs, hepatic injury
Repeat: Mortalty, clinical
signs, BW, select organ
weight and histology,
hematology in some
animals

High

1

2

2

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Study reference:

Dow Chem, Co (1950). Vapor toxicity of tetrachloroethylene for laboratory animals and human subjects
HERO ID: 4214242

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score



17. Consistency of
Outcome
Assessment

Acute: Timing different
across exposure groups.
Unclear for repeat
exposure - all animals

were evaluated for
mortality, CS, BW, OW,
and "organic injury" -
assuming gross
necropsy; periodic
hematology was
performed on "several
groups of animals", not
further defined; clinical
chemistry was evaluated

in "many cases"; in
"many instances" organs
were examined
histologically.
Depending on which
groups were evaluated,
timing was different due
to different exposure
durations between
exposure levels.

Unacceptable

4

1

4

18. Sampling
Adequacy

Unclear how many
animals were evaluated
for several of the metrics
(see Metric 17)

Low

3

1

3

19. Blinding of
Assessors



Not Rated

NA

NA

NA

20. Negative Control
Response

Data reporting limited.
Where exposure group

data were reported
quantitatively, control
data were included.
Remaining data reported
qualitatively (change or
no change from control).

Low

3

1

3

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Study reference:

Dow Chem, Co (1950). Vapor toxicity of tetrachloroethylene for laboratory animals and human subjects
HERO ID: 4214242

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

Confounding /
Variable Control

21. Confounding
Variables in Test
Design and
Procedures

Acute: Anaesthetic

effects with
unconsciousness and
failure of respiration in

acute study at all
exposures except the
lowest (2000 ppm)
Repeat: CNS depression
also reported at highest

concentration (2500
ppm) in rat, mice, GP (no
mention of respiratory
depression)

Low

3

2

6



22. Health
Outcomes Unrelated
to Exposure

data on attrition and/or

health outcomes
unrelated to exposure
for each study group
were not reported
because only substantial
differences among
groups were noted

Medium

2

1

2

Data Presentation
and Analysis

23. Statistical
Methods

Acute- no statistics, data
for mortality adequate
for independent analsysi

Repeat: t-test was
reported used "wherever

possible"" Reported
only for guinea pig group
exposed to 0 or 200 ppm

for "as many as 158
Seven-hour Exposures in
220 days"

Low

3

1

3



24. Reporting of
Data

Only limited data sets
were reported
quantitatively, the
majority were reported
qualitatively only (even
with exposure-related
effects)

Low

3

2

6

High: >-1 and <1.7
Medium: >=1.7 and <2.3
Low: >=2.3 and <=3

Sum of scores:



29

76

Overall Score = Sum of Weighted Scores/Sum
of Metric Weighting Factors:

2.6207

Overall Score:
Nearest *:

2.61

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Study reference:

Dow Chem, Co (1950). Vapor toxicity of tetrachloroethylene for laboratory animals and human subjects
HERO ID: 4214242

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score



Overall Quality Level:

Unacceptable1

Study Quality
Comment:

Footnote 1: Consistent with our Application of A Systematic Review in TSCA Risk Evaluations document, if a metric
for a data source receives a score of Unacceptable (score = 4), EPA will determine the study to be unacceptable. In
this case, four of the metrics were rated as unacceptable. As such, the study is considered unacceptable and the

score is presented solely to increase transparency.

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1.3. Animal toxicity evaluation results of Dow et al 1983 for an acute eye irritation
study in rabbits on irritation outcomes

Study reference:

Dow Chem, Co (1983). Initial submission: perchloroethylene solvent formulation: acute toxicological properties
& industrial handling hazards, with cover letter dated 102591 (sanitized)

HERO ID: 4214440

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

Test Substance

1. Test Substance
Identity

Test substance identity

was reported by
unambiguous name, and
reference was made to
an appendix containing
the composition, but the
table was blanked out in
the appendix in the pdf.

Low

2. Test Substance
Source

Test substance source

was reported, but
without certification or
analytical verification of
identity.

Medium

3. Test Substance
Purity

Purity was not reported;
reference was made to
an appendix containing
the composition, but the
table was blanked out in
the appendix in the pdf.

Low

Test Design

4. Negative and
Vehicle Controls

Negative control group
not required for eye
irritation tests;
untreated eye serves as
control

Not Rated

5. Positive Controls

Positive controls not
typical for this study
type.

Not Rated

6. Randomized
Allocation

Animal allocation to
study groups was not
described.

Low

Exposure
Characterization

7. Preparation and
Storage of Test
Substance

No information on
preparation or storage of
test material was
provided.

Unacceptable

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Study reference:

Dow Chem, Co (1983). Initial submission: perchloroethylene solvent formulation: acute toxicological properties
& industrial handling hazards, with cover letter dated 102591 (sanitized)

HERO ID: 4214440

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

8. Consistency of

Exposure
Administration

Study does not clearly
state that undiluted test
material was used, but
based on the language
and approach to other
experiments in the
paper, it is likely that this
is the case.

Medium

9. Reporting of
Doses/Concentratio
ns

Exposure reported as
volume of test material;
concentration/purity of
of Perc in test material
was not reported.

Medium

10. Exposure
Frequency and
Duration

Dermal patches were left
in place for 24 hours
which is adequate.

High

11. Number of
Exposure Groups
and Dose Spacing

Single exposure level is
acceptable for eye
irritation testing.

High

12. Exposure Route
and Method

Route and method are
typical for this study
type.

High

Test Organism

13. Test Animal
Characteristics

Test animal source,
species, strain, and sex
were reported; age and
initial body weight were
not.

Medium

14. Adequacy and

Consistency of
Animal Husbandry
Conditions

Housing conditions,
acclimation, and
photoperiod were

reported, but
temperature and
humidity were not.

Medium

15. Number per
Group

9 rabbits were used; this
is more than required for
testing.

High

Outcome
Assessment

16. Outcome
Assessment
Methodology

Outcome assessment

methodology was
adequately reported;
Draize scoring method
was cited but scoring
details not provided.

Medium

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Study reference:

Dow Chem, Co (1983). Initial submission: perchloroethylene solvent formulation: acute toxicological properties
& industrial handling hazards, with cover letter dated 102591 (sanitized)

HERO ID: 4214440

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

17. Consistency of
Outcome
Assessment

Two exposure groups
were used (one with
eyes rinsed after 30 sec
and one with no rinsing)

Medium

18. Sampling
Adequacy

All exposed animals
were evaluated for all
outcomes.

High

19. Blinding of
Assessors

As there was no control
group blinding was not
possible/necessary.

Not Rated

20. Negative Control
Response

There was no negative
control group.

Not Rated

Confounding /
Variable Control

21. Confounding
Variables in Test
Design and
Procedures

No potentially
confounding factors
were identified. Eye
condition was examined
and determined to be
healthy before testing.

High

22. Health
Outcomes Unrelated
to Exposure

No health outcomes
unrelated to exposure
were reported.

High

Data Presentation
and Analysis

23. Statistical
Methods

Statistical analysis is not
typical for eye irritation
tests.

Not Rated

24. Reporting of
Data

Individual and group
irritation scores for each
time point were
reported.

High

Sum of scores:

High: >=1 and <1.7
Medium: >=1.7 and <2.3

Overall Score = Sum of Weighted Scores/Sum
of Metric Weighting Factors:

Overall Score:
Nearest *:

Low: >=2.3 and <=3

Overall Quality Level:

Low

Study Quality
Comment:

The reviewer upgraded this study's overall quality rating, changing its status from unacceptable to acceptable.
They noted: The only metric that was unacceptable was test storage and preparation which is of low concern in a
single exposure eye irritation test. Note: The study was initially assigned a rating of unacceptable (score = 4) with
a calculated score of 1.9 (shown solely for transparency). No calculated score is identified for the current rating in

the table above because the study was upgraded to low.

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1.4. Animal toxicity evaluation results of Dow et al 1983 for an acute dermal lethality
study in rabbits on mortality and irritation outcomes

Study reference:

Dow Chem, Co (1983). Initial submission: perchloroethylene solvent formulation: acute toxicological properties
& industrial handling hazards, with cover letter dated 102591 (sanitized)

HERO ID: 4214440

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

Test Substance

1. Test Substance
Identity

Test substance identity

was reported by
unambiguous name, and
reference was made to
an appendix containing
the composition, but the
table was blanked out in
the appendix in the pdf.

Low

2. Test Substance
Source

Test substance source

was reported, but
without certification or
analytical verification of
identity.

Medium

3. Test Substance
Purity

Purity was not reported;
reference was made to
an appendix containing
the composition, but the
table was blanked out in
the appendix in the pdf.

Low

Test Design

4. Negative and
Vehicle Controls

Negative controls not
common in lethality
studies

Not Rated

5. Positive Controls

Positive controls not
typical for this study
type.

Not Rated

6. Randomized
Allocation

There was only one
group

Not Rated

Exposure
Characterization

7. Preparation and
Storage of Test
Substance

No information on
preparation or storage of
test material was
provided.

Unacceptable

8. Consistency of

Exposure
Administration

Volume and skin surface
area of application were
not reported.

Medium

9. Reporting of
Doses/Concentratio
ns

Exposure reported as
mg/kg. Initial body
weights were not
reported.

Medium

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PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Dow Chem, Co (1983). Initial submission: perchloroethylene solvent formulation: acute toxicological properties
& industrial handling hazards, with cover letter dated 102591 (sanitized)

HERO ID: 4214440

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

10. Exposure
Frequency and
Duration

Exposure was for 24
hours which is adequate.

High

11. Number of
Exposure Groups
and Dose Spacing

Only one dose (200
mg/kg) was tested, and it

was well below the
recommended dose for a
limit test (2000 mg/kg).
An attempt was made to
test 2000 mg/kg but this

dose resulted in
significant animal pain.

Low

12. Exposure Route
and Method

Acute Percutaneous
Absorption

High

Test Organism

13. Test Animal
Characteristics

Test animal source,
species, strain, and sex
were reported; age and
initial body weight were
not.

Medium

14. Adequacy and

Consistency of
Animal Husbandry
Conditions

Housing conditions,
acclimation, and
photoperiod were

reported, but
temperature and
humidity were not.

Medium

15. Number per
Group

5 male rabbits were
used; this number is
consistent with
guidelines.

High

Outcome
Assessment

16. Outcome
Assessment
Methodology

Outcome assessment

methodologies for
mortality, body weight,
and necropsy were
reported. Irritation
responses were
described, but a scoring
system was not applied.

Low

17. Consistency of
Outcome
Assessment

Only a single group was
used.

Not Rated

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Dow Chem, Co (1983). Initial submission: perchloroethylene solvent formulation: acute toxicological properties
& industrial handling hazards, with cover letter dated 102591 (sanitized)

HERO ID: 4214440

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

18. Sampling
Adequacy

Although the protocol
called for only surviving

animals to be
necropsied, all exposed
animals survived, so all
were necropsied.

High

19. Blinding of
Assessors

As there was only one
group blinding was not
possible/necessary.

Not Rated

20. Negative Control
Response

Negative controls not
required for acute
lethality test

Not Rated

Confounding /
Variable Control

21. Confounding
Variables in Test
Design and
Procedures

No potentially
confounding factors
were identified, but
initial health conditions
were not reported.

Medium

22. Health
Outcomes Unrelated
to Exposure

No health outcomes
unrelated to exposure
were reported.

High

Data Presentation
and Analysis

23. Statistical
Methods

Statistical analysis is not
possible on a single
exposure group.

Not Rated

24. Reporting of
Data

Data reporting was
adequate for the type of
study.

Medium

High: >=1 and <1.7
Medium: >=1.7 and <2.3
Low: >=2.3 and <=3

Sum of scores:

Overall Score = Sum of Weighted Scores/Sum
of Metric Weighting Factors:

Overall Score:
Nearest *:

Overall Quality Level:

Low

Study Quality
Comment:

The reviewer upgraded this study's overall quality rating, changing its status from unacceptable to acceptable.
They noted: The only metric that was unacceptable was test substance preparation and storage, which is of low
concern for single dose dermal administration. Note: The study was initially assigned a rating of unacceptable
(score = 4) with a calculated score of 2.2 (shown solely for transparency). No calculated score is identified for the
current rating in the table above because the study was upgraded to low.

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PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

1.5. Animal toxicity evaluation results of Dow et al 1983 for an acute dermal irritation
study on irritation outcomes

Study reference:

Dow Chem, Co (1983). Initial submission: perchloroethylene solvent formulation: acute toxicological properties
& industrial handling hazards, with cover letter dated 102591 (sanitized) #journal#, #volume#(#issue#), #Pages#

HERO ID: 4214440

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

Test Substance

1. Test Substance
Identity

Test substance identity

was reported by
unambiguous name, and
reference was made to
an appendix containing
the composition, but the
table was blanked out in
the appendix in the pdf.

Low

2. Test Substance
Source

Test substance source

was reported, but
without certification or
analytical verification of
identity.

Medium

3. Test Substance
Purity

Purity was not reported;
reference was made to
an appendix containing
the composition, but the
table was blanked out in
the appendix in the pdf.

Low

Test Design

4. Negative and
Vehicle Controls

Negative control groups
not required for dermal
irritation test

Not Rated

5. Positive Controls

Positive controls not
typical for this study
type.

Not Rated

6. Randomized
Allocation

There was only one
group

Not Rated

Exposure
Characterization

7. Preparation and
Storage of Test
Substance

No information on
preparation or storage of
test material was
provided.

Unacceptable

8. Consistency of

Exposure
Administration

Skin surface area tested
was not reported.

Low

9. Reporting of
Doses/Concentratio
ns

See footnote at end of
page.1

High

1 Metrics that received a "High" rating met the criteria as discussed in the Applications of Systematic Review for
TSCA Risk Evaluation.

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PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

HERO ID: 4214440

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

10. Exposure
Frequency and
Duration

Dermal patches were left
in place for 24 hours
which is adequate.

High

11. Number of
Exposure Groups
and Dose Spacing

Only one exposure level
was tested, but it
reflected the highest

concentration
(undiluted) possible.

Medium

12. Exposure Route
and Method

See footnote at end of
page.1

High

Test Organism

13. Test Animal
Characteristics

Test animal source,
species, strain, and sex
were reported; age and
initial body weight were
not.

Medium

14. Adequacy and

Consistency of
Animal Husbandry
Conditions

Housing conditions,
acclimation, and
photoperiod were

reported, but
temperature and
humidity were not.

Medium

15. Number per
Group

6 rabbits were used; this
is more than required for
testing.

High

Outcome
Assessment

16. Outcome
Assessment
Methodology

Outcome assessment

methodology was
inadequately reported
(lacking irritation scoring
details)

Unacceptable

17. Consistency of
Outcome
Assessment

Only a single group was
used.

Not Rated

18. Sampling
Adequacy

All exposed animals
were evaluated for all
outcomes.

High

19. Blinding of
Assessors

As there was only one
group blinding was not
possible/necessary.

Not Rated

20. Negative Control
Response

There was no negative
control group.

Not Rated

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PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

HERO ID: 4214440

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

Confounding /
Variable Control

21. Confounding
Variables in Test
Design and
Procedures

No potentially
confounding factors
were identified, but
initial health conditions
were not reported.

Medium

22. Health
Outcomes Unrelated
to Exposure

No health outcomes
unrelated to exposure
were reported.

High

Data Presentation
and Analysis

23. Statistical
Methods

Statistical analysis is not
typical for this study
type.

Not Rated

24. Reporting of
Data

Individual skin irritation
scores were not
reported.

Unacceptable

High: >=1 and <1.7
Medium: >=1.7 and <2.3
Low: >=2.3 and <=3

Sum of scores:

Overall Score = Sum of Weighted Scores/Sum
of Metric Weighting Factors:

2.3043

Overall Score:
Nearest *:

2.31

Overall Quality Level:

Unacceptable1

Study Quality
Comment:

Footnote 1: Consistent with our Application of A Systematic Review in TSCA Risk Evaluations document, if a metric
for a data source receives a score of Unacceptable (score = 4), EPA will determine the study to be unacceptable. In
this case, three of the metrics were rated as unacceptable. As such, the study is considered unacceptable and the

score is presented solely to increase transparency.

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PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

1.6. Animal toxicity evaluation results of Dow et al 1983 for an acute oral toxicity study
in rats on mortality and acute toxicity/poisoning outcomes

Study reference:

Dow Chem, Co (1983). Initial submission: perchloroethylene solvent formulation: acute toxicological properties
& industrial handling hazards, with cover letter dated 102591 (sanitized)

HERO ID: 4214440

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

Test Substance

1. Test Substance
Identity

Test substance identity

was reported by
unambiguous name, and
reference was made to
an appendix containing
the composition, but the
table was blanked out in
the appendix in the pdf.

Low

2. Test Substance
Source

Test substance source

was reported, but
without certification or
analytical verification of
identity.

Medium

3. Test Substance
Purity

Purity was not reported;
reference was made to
an appendix containing
the composition, but the
table was blanked out in
the appendix in the pdf.

Low

Test Design

4. Negative and
Vehicle Controls

Negative controls not
required for lethality
studies.

Not Rated

5. Positive Controls

Positive controls not
typical for this study
type.

Not Rated

6. Randomized
Allocation

Study did not report how
animals were allocated
to groups.

Low

Exposure
Characterization

7. Preparation and
Storage of Test
Substance

No information on
preparation or storage of
test material was
provided.

Unacceptable

8. Consistency of

Exposure
Administration

Some details of exposure
administration were not
reported (e.g., gavage
volume) but these are
unlikely to affect the
results.

Low

9. Reporting of
Doses/Concentratio
ns

Doses were reported
unambiguously as mg/kg
bw

High

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Dow Chem, Co (1983). Initial submission: perchloroethylene solvent formulation: acute toxicological properties
& industrial handling hazards, with cover letter dated 102591 (sanitized)

HERO ID: 4214440

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

10. Exposure
Frequency and
Duration

Single exposure is typical
for this study type.

High

11. Number of
Exposure Groups
and Dose Spacing

There were 5 nonzero
exposure groups, and
the maximum dose
administered (5000
mg/kg) is commonly
used in limit tests. Dose
range and spacing were
adequate to enable
calculation of LD50
values with reasonable
confidence limits.

High

12. Exposure Route
and Method

Acute oral/gavage

High

Test Organism

13. Test Animal
Characteristics

Test animal source,
species, strain, and sex
were reported; age and
initial body weight were
not.

Medium

14. Adequacy and

Consistency of
Animal Husbandry
Conditions

Housing conditions,
acclimation, and
photoperiod were

reported, but
temperature and
humidity were not.

Medium

15. Number per
Group

6 rats/sex/dose were
used.

Medium

Outcome
Assessment

16. Outcome
Assessment
Methodology

Outcome assessment
methodology was
reported, but outcomes

were limited to
mortality, clinical signs,
body weight, and gross
necrospsy.

Medium

17. Consistency of
Outcome
Assessment

There were no reported
inconsistencies in
outcome assessment.

High

18. Sampling
Adequacy

All exposed animals
were evaluated for all
outcomes.

High

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Dow Chem, Co (1983). Initial submission: perchloroethylene solvent formulation: acute toxicological properties
& industrial handling hazards, with cover letter dated 102591 (sanitized)

HERO ID: 4214440

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

19. Blinding of
Assessors

Most outcomes (apart
from clinical signs) were
not subjective.

Not Rated

20. Negative Control
Response

There was no negative
control group.

Not Rated

Confounding /
Variable Control

21. Confounding
Variables in Test
Design and
Procedures

No potentially
confounding factors
were identified, but food
intake was not measured
and could have affected
body weights.

Medium

22. Health
Outcomes Unrelated
to Exposure

No health outcomes
unrelated to exposure
were reported.

High

23. Statistical
Methods

Statistical analysis of

lethality data was
conducted, and data
enabling independent
analysis were reported.

Medium

Data Presentation
and Analysis

24. Reporting of
Data

Mortality and clinical
signs were reported in
detail, including time of
death/onset of
symptoms, but body
weights were not
reported.

Medium

Sum of scores:

High: >=1 and <1.7
Medium: >=1.7 and <2.3

Overall Score = Sum of Weighted Scores/Sum
of Metric Weighting Factors:

Overall Score:
Nearest *:

Low: >=2.3 and <=3

Overall Quality Level:

Low

Study Quality
Comment:

The reviewer upgraded this study's overall quality rating, changing its status from unacceptable to acceptable.
They noted: The only metric that was unacceptable was test substance preparation and storage, which is of low
concern for single dose gavage administration. The study was initially assigned a rating of unacceptable (score = 4)
with a calculated score of 2.0 (shown solely for transparency). No calculated score is identified for the current
rating in the table above because the study was upgraded to low.

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PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

2. Short-Term Toxicity Studies

2.1. Animal toxicity evaluation results of Beliles et al 1980 for 3-week gestational

inhalation studies on genotoxicity in vivo (mechanistic) outcomes

Study reference:

Beliles, R. P.,Brusick, D. J.,Mecler, F. J. (1980). Teratogenic-mutagenic risk of workplace contaminants:
trichloroethylene, perchloroethylene, and carbon disulfide

HERO ID: 58331

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

Test Substance

1. Test Substance
Identity

Identified by chemical
name and synonym

High

2. Test Substance
Source

Manufacturer and lot
number given.

High

3. Test Substance
Purity

91% pure, impurities
were not characterized

Medium

Test Design

4. Negative and
Vehicle Controls

Filtered air controls; "To

avoid exposure of
control animals to test
materials, all control
chambers were in a
different chamber room
than the exposure
chambers. No test
materials were taken
into the control rooms."

High

5. Positive Controls

Positive controls
(reference mutagens)

were used for all
studies. "However, the

contractor did not
attempt to verify the

purity of these
commercially available
samples."

High

6. Randomized
Allocation

"The animals were
randomly assigned to
experimental groups."

High

Exposure
Characterization

7. Preparation and
Storage of Test
Substance

Method and equipment
used to generate the test
substance as a vapor
were reported and
appropriate.

High

8. Consistency of

Exposure
Administration

Details of exposure
administration were
reported.

High

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PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Beliles, R. P.,Brusick, D. J.,Mecler, F. J. (1980). Teratogenic-mutagenic risk of workplace contaminants:
trichloroethylene, perchloroethylene, and carbon disulfide

HERO ID: 58331

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

9. Reporting of
Doses/Concentratio
ns

Target and analytical
concentrations were
provided. Range of
measure concentration
did not deviate more
than 10% target
concentration.

High

10. Exposure
Frequency and
Duration

The exposure frequency
and duration were

reported and
appropriate for this
study.

High

11. Number of
Exposure Groups
and Dose Spacing

2 exposure
concentrations (100 and
500ppm)

Medium

12. Exposure Route
and Method

Dynamic chamber,
whole body, assumed
that Perc does not
condense.

High

13. Test Animal
Characteristics

Species, strain and
source were reported;
starting age and body
weight not given.

Medium

Test Organism

14. Adequacy and

Consistency of
Animal Husbandry
Conditions

well reported

High

15. Number per
Group

6-10/group

High

Outcome
Assessment

16. Outcome
Assessment
Methodology

Dominant lethal assay,
spermhead abnormality,
chromosomal aberration
in rat bone marrow, rat
dominant lethal test
conducted.

High

17. Consistency of
Outcome
Assessment

See footnote at end of
page.1

High

1 Metrics that received a "High" rating met the criteria as discussed in the Applications of Systematic Review for
TSCA Risk Evaluation.

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Beliles, R. P.,Brusick, D. J.,Mecler, F. J. (1980). Teratogenic-mutagenic risk of workplace contaminants:
trichloroethylene, perchloroethylene, and carbon disulfide

HERO ID: 58331

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score



18. Sampling
Adequacy

See footnote at end of
page.1

High

1

1

1

19. Blinding of
Assessors

Blinding was not
reported, but most
outcomes were not
subjective.

Medium

2

1

2

20. Negative Control
Response



High

1

1

1

Confounding /
Variable Control

21. Confounding
Variables in Test
Design and
Procedures

None related to
genotoxicity

High

1

2

2

22. Health
Outcomes Unrelated
to Exposure

None related to
genotoxicity

High

1

1

1

Data Presentation
and Analysis

23. Statistical
Methods

Statistics were well
described and
appropriate

High

1

1

1

24. Reporting of
Data

All outcomes were
reported.

High

1

2

2

High: >=1 and <1.7
Medium: >=1.7 and <2.3
Low: >=2.3 and <=3

Sum of scores:



31

36

Overall Score = Sum of Weighted Scores/Sum
of Metric Weighting Factors:

1.1613

Overall Score:
Nearest *:

1.2

Overall Quality Level:

High

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PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

2.2. Animal toxicity evaluation results of Boverhof et al 2013 for a 4-week inhalation
(perc) study on mortality, nutrition and metabolic/adult exposure body weight,
hematological and immune, hepatic, renal, and respiratory outcomes

Study reference:

Boverhof, D. R.,Krieger, S. M.,Hotchkiss, J.,Stebbins, K. E.,Thomas, J.,Woolhiser, M. R. (2013). Assessment of the
immunotoxic potential of trichloroethylene and perchloroethylene in rats following inhalation exposure Journal
of Immunotoxicology, 10(3), 311-320

HERO ID: 2127872

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

1. Test Substance
Identity

The test substance was
identified definitively.

High

Test Substance

2. Test Substance
Source

The source of the test
substance was reported
incompletely (a batch/lot
number was not
reported).

Medium

3. Test Substance
Purity

The test substance purity
was acceptable
(reported to be 99.98%
pure).

High

4. Negative and
Vehicle Controls

A concurrent negative
control group (filtered
air only) was used and
was appropriate.

High

Test Design

5. Positive Controls

A positive control group

(injected with
cyclophosphamide) was
included in the antibody
response test and was
appropriate. A similar
positive control was not
included in the test for

evaluating organ
weights, histopathology,

hematology, and
bronchoalveolar lavage
(not applicable).

High

6. Randomized
Allocation

The study authors did
not report how animals
were allocated to study
groups.

Low

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PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

HERO ID: 2127872

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

Exposure
Characterization

7. Preparation and
Storage of Test
Substance

The test substance
preparation and method
and equipment used to
generate the test
substance as a vapor
were reported and
appropriate. The study
authors did not report
how the test substance
was stored

Medium

8. Consistency of

Exposure
Administration

Details of the exposure

administration were
reported and exposures

were administered
consistently across study
groups.

High

9. Reporting of
Doses/Concentratio
ns

Concentrations were
reported without
ambiguity. Test
concentrations in the

chambers were
analytically determined
at least once per hour
during the exposures
and mean analytical
concentrations were
reported. The analytical
method used to measure
chamber concentrations
was reported and
appropriate.

High

10. Exposure
Frequency and
Duration

The exposure frequency
and duration of exposure

were reported and
appropriate for the study
and outcomes of
interest.

High

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PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

HERO ID: 2127872

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

11. Number of
Exposure Groups
and Dose Spacing

The number of exposure
groups and
concentration spacing
were justified by the
study authors (based on
previous studies/animal

data) and considered
adequate to address the
purpose of the study.

High

12. Exposure Route
and Method

The route and method of
exposure were reported
and were suited to the

test substance. A
dynamic whole body
chamber was used and
acceptable for the test
substance vapor.

High

Test Organism

13. Test Animal
Characteristics

The test animal species,
strain, sex, and age were
reported and the test
animals were obtained
from a commercial
source. Initial body
weights and health
status at the start of the
study were not reported
although the animals
were certified Virus
Antibody Free by the
source.

Medium

14. Adequacy and

Consistency of
Animal Husbandry
Conditions

Husbandry conditions
were not sufficiently
reported to evaluate if
husbandry was adequate
and if differences
occurred between
control and exposed
groups.

Low

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

HERO ID: 2127872

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

15. Number per
Group

The number of animals

per group (8
females/dose group) was

less than the typical
number used in studies
of the same or similar
type (e.g., subchronic
toxicity study).

Medium

Outcome
Assessment

16. Outcome
Assessment
Methodology

The outcome assessment
methodology addressed
or reported the intended
outcomes of interest and
was sensitive for the
outcomes of interest.

High

17. Consistency of
Outcome
Assessment

Details of the outcome
assessment protocol
were reported and
outcomes were assessed
consistently across study
groups.

High

18. Sampling
Adequacy

Details regarding
sampling for the
outcomes of interest
were reported and the
study used adequate

sampling for the
outcomes of interest.

High

19. Blinding of
Assessors

No subjective outcomes
were reported.

Not Rated

20. Negative Control
Response

The biological response
of the negative control
group was reported and
acceptable.

High

Confounding /
Variable Control

21. Confounding
Variables in Test
Design and
Procedures

Respiratory rate was not
reported to have been
evaluated in this
inhalation study;
however, Perc is a
potential respiratory
irritant

Low

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PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

HERO ID: 2127872

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e., High, Medium, L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

22. Health
Outcomes Unrelated
to Exposure

Data on attrition and/or

health outcomes
unrelated to exposure
for each study group
were not reported
because only substantial
differences among
groups were noted.

Medium

Data Presentation
and Analysis

23. Statistical
Methods

Statistical methods were
clearly described and
appropriate for the
datasets.

High

24. Reporting of
Data

Data for most exposure-
related findings were
reported for most, but
not all, outcomes by
exposure group.
However, some
exposure-related data
were not reported
quantitatively (e.g.,
reduced body weights)
and incidence data for

histopathological
findings were reported
incompletely (only the

mid- and high-
concentrations; unclear

if any animals were
affected in the control or
low-concentration
groups).

Medium

High: >=1 and <1.7
Medium: >=1.7 and <2.3
Low: >=2.3 and <=3

Sum of scores:

Overall Score = Sum of Weighted Scores/Sum
of Metric Weighting Factors:

1.5333

Overall Score:
Nearest *:

1.5

Overall Quality Level:

High

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

2.3. Animal toxicity evaluation results of Carney et al 2006 for a gestational exposure
study on reproductive, growth (early life) and development, nutrition and
metabolic/adult exposure body weight, mortality outcomes

Study reference:

Carney, E. W.,Thorsrud, B. A.,Dugard, P. H.,Zablotny, C. L. (2006). Developmental toxicity studies in Crl:CD (SD)
rats following inhalation exposure to trichloroethylene and perchloroethylene Birth Defects Research, Part B:
Developmental and Reproductive Toxicology, 77(5), 405-412

HERO ID: 630415

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

Test Substance

1. Test Substance
Identity

tetrachloroethylene
(PERC)

High

2. Test Substance
Source

INEOS CHIor Ltd, no
batch number

Medium

3. Test Substance
Purity

>99%

High

Test Design

4. Negative and
Vehicle Controls

See footnote at end of
page.1

High

5. Positive Controls

Not required by cited
guidelines (OPPTS
870.370 and OECD414)

Not Rated

6. Randomized
Allocation

Animals were randomly
assigned to four groups

High

Exposure
Characterization

7. Preparation and
Storage of Test
Substance

The method and
equipment used to
generate the test
substance as a gas,
vapor, or aerosol were
NOT reported. It is not
clear if the vapor
generation method
reported for TCE was
also used for PERC
(different laboratories,

different chambers,
different flow rates, etc).
However, since analytical
concentrations were
reported, omission of
vapor generation details
is unlikely to have a
substantial impact on
results

Medium

1 Metrics that received a "High" rating met the criteria as discussed in the Applications of Systematic
Review for TSCA Risk Evaluation.

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

HERO ID: 630415

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

8. Consistency of

Exposure
Administration

The concentrations of
PERC were measured
multiple times each
exposure day using GC
analysis. Exposure
administration
consistent across groups.

(already downgraded
metric 7 to unacceptable

based on lack of
methods for generating
atmospheres, so that
was not used to grade
for this metric).

High

9. Reporting of
Doses/Concentratio
ns

Target and analytical
exposure levels were
reported..

High

10. Exposure
Frequency and
Duration

GD 6-19, 6 hr/d, 7 d/wk;
Both guidelines cited
indicate that animals
should be dosed until

the day prior to C-
section and sacrifice,
which was reported as
GD 20.

High

11. Number of
Exposure Groups
and Dose Spacing

3 exposure and 1
control. These test
concentrations were
based on the results
from the previously
discussed developmental

toxicity studies. The
highest exposure level of
600ppm (equivalent to
4.1mg PERC/L) exceeds
the limit concentration
of 2 mg/L specified in the
EPA prenatal
developmental toxicity
test guideline (OPPTS
870.3700).

High

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Carney, E. W.,Thorsrud, B. A.,Dugard, P. H.,Zablotny, C. L. (2006). Developmental toxicity studies in Crl:CD (SD)
rats following inhalation exposure to trichloroethylene and perchloroethylene Birth Defects Research, Part B:
Developmental and Reproductive Toxicology, 77(5), 405-412

HERO ID: 630415

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score



12. Exposure Route
and Method

Animals were whole
body exposed in 0.75-
cubic-meter exposure

chambers.
Chamber airflow was
maintained at
approximately 150
L/min. This resulted in
approximately 12 air
changes per hour.

High

1

1

1

Test Organism

13. Test Animal
Characteristics

CrhCD (SD) rats (Charles
River). Virgin female
rats. Initial BW not
reported (body weights
reported fro GD 3, 6, 9,
13,17, and 20).

Medium

2

2

4

14. Adequacy and

Consistency of
Animal Husbandry
Conditions

Housing adequately
described. Room
temperature and
humidity were
maintained
within laboratory specific
ranges(19-231C and
40-70% relative
humidity). A 12-hr
photoperiod was
maintained for all
animals. Food an water

available ad libitum
except during exposure
periods.

High

1

1

1

15. Number per
Group

22 dams/group; in
accordance with
guidelines

High

1

1

1

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

HERO ID: 630415

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

Outcome
Assessment

16. Outcome
Assessment
Methodology

Maternal toxicity -
clinical signs, BW, feed
consumption, mortality

Reproductive/Devt -
gravid uterine weights,

placenta weight, #
corpora lutea, uterine
implants, resorptions,
live/dead fetuses, fetal

weight, external,
skeletal, and visceral
malformations/variation
s

Although the current
OECD test guideline 414
(updated in 2018)
indicates that AGD
should be measured in
all live fetuses, the OECD
TG 414 version available

at the time of
publication of this study
was from 2001 and did

not require
measurement of AGD
and the cited OPPTS
guideline does not have
that requirement.

Medium

17. Consistency of
Outcome
Assessment

Consistent evaluation
across groups

High

18. Sampling
Adequacy

17-22 pregnant dams

High

19. Blinding of
Assessors

Blinding not done for
PERC and not required
by cited guidelines.

Not Rated

20. Negative Control
Response

Control data reported.
Historical control data
discussed when needed
to assess results.

High

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Carney, E. W.,Thorsrud, B. A.,Dugard, P. H.,Zablotny, C. L. (2006). Developmental toxicity studies in Crl:CD (SD)
rats following inhalation exposure to trichloroethylene and perchloroethylene Birth Defects Research, Part B:
Developmental and Reproductive Toxicology, 77(5), 405-412

HERO ID: 630415

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

Confounding /
Variable Control

21. Confounding
Variables in Test
Design and
Procedures

Initial BW not reported;
no statistically significant
changes in BW during
study. Only change in
food consumption was
7% decrease in high-
exposure group from GD
6-8. Respiratory rate not
specifically mentioned,
but no exposure-related
clinical signs reported in

dams, so bradyapnea
unlikely. Downgraded to
medium since PERC is a
respiratory irritant
(HSDB)

Medium

2

2

4

22. Health
Outcomes Unrelated
to Exposure

No mortalities, no
clinical signs. Only
attrition was time-mated
females that were not
pregnant (in all groups)
that were not included in
analysis.

High

1

1

1

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Carney, E. W.,Thorsrud, B. A.,Dugard, P. H.,Zablotny, C. L. (2006). Developmental toxicity studies in Crl:CD (SD)
rats following inhalation exposure to trichloroethylene and perchloroethylene Birth Defects Research, Part B:
Developmental and Reproductive Toxicology, 77(5), 405-412

HERO ID: 630415

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

Data Presentation
and Analysis

23. Statistical
Methods

Litter is statistical unit.
Continuous data were
tested in both studies for
homogeneity of variance
using Bartlett's test. The
raw, log-transformed

and square root-
transformed data were
tested. Based on results,
data were analyzed using

either parametric or
nonparametric tests. If
75% of the data (across

all groups)
were the same value,
then a frequency
analysis was performed.
Treatment groups were

compared using a
Mantel test for a trend in
proportions and also
pairwise Fisher's Exact
tests were used for each
dose group against the
control. Skeletal variants

were analyzed by a
generalized mixed linear
model with a logit link
function and used litter

as a random effect/
Each treated group was
compared to the control
group using a Wald chi-
square test.

High

1

1

1

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Carney, E. W.,Thorsrud, B. A.,Dugard, P. H.,Zablotny, C. L. (2006). Developmental toxicity studies in Crl:CD (SD)
rats following inhalation exposure to trichloroethylene and perchloroethylene Birth Defects Research, Part B:
Developmental and Reproductive Toxicology, 77(5), 405-412

HERO ID: 630415

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e., High, Medium, L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score



24. Reporting of
Data

All reproductive and
developmental findings

were reported
quantitatively in tabular

or graphical format,
maternal body weights
and food consumption
reported in tables.
Mortality and clinical
signs reported
qualitatively (no
exposure-related
findings)

High

1

2

2

High: >=1 and <1.7
Medium: >=1.7 and <2.3
Low: >=2.3 and <=3

Sum of scores:



29

37

Overall Score = Sum of Weighted Scores/Sum
of Metric Weighting Factors:

1.2759

Overall Score:
Nearest *:

1.3

Overall Quality Level:

High

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

2.4. Animal toxicity evaluation results of Nelson et al 1979 for a

neurodevelopmental inhalation study (gd 7-13) study on growth (early life)
and development outcomes

Study reference:

Nelson, B. K.,Taylor, B. J.,Setzer, J. V.,Hornung, R. W. (1979). Behavioral teratology of perchloroethylene in rats
Journal of Environmental Pathology, Toxicology and Oncology, 3(1-2), 233-250

HERO ID: 58224

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

Test Substance

1. Test Substance
Identity

TG-PERC

High

2. Test Substance
Source

TG-PERC obtained from
Fisher Scientific; batch
no. not reported, no
independent analysis

Medium

3. Test Substance
Purity

98.5% pure

High

Test Design

4. Negative and
Vehicle Controls

sham exposed group

High

5. Positive Controls

OECD guideline 426
(developmental
neurotoxicity) states "To
guard against possible
false-negative findings

and the inherent
difficulties in "proving a
negative/' available
positive and historical
control data should be
discussed, especially
when there are no
treatment-related
effects". However,
positive control is not a
requirement - especially
since exposure-related
effects were observed.
Therefore, N/A was
selected.

Not Rated

6. Randomized
Allocation

The study did not report

how animals were
allocated to study groups

Low

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Nelson, B. K.,Taylor, B. J.,Setzer, J. V.,Hornung, R. W. (1979). Behavioral teratology of perchloroethylene in rats
Journal of Environmental Pathology, Toxicology and Oncology, 3(1-2), 233-250

HERO ID: 58224

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

Exposure
Characterization

7. Preparation and
Storage of Test
Substance

Storage not reported.
PERC was vaporized
using heated flask, mixed
with filtered room air
and introduced into
exposure chamber
(airflow change rate
4x/min).

Medium

8. Consistency of

Exposure
Administration

Exposure conditions
were identical for sham-
exposed controls and
exposure group.

High

9. Reporting of
Doses/Concentratio
ns

Only target exposure
levels were reported.
PERC levels in exposure

chambers were
continuously monitored

by a Miran infrared
analyzer and a charcoal
tube sample was taken
from the chamber air
(generally one per day)

and sent to an
independent laboratory
for gas chromatographic
analysis. But results of
analyses were not
reported.

Low

10. Exposure
Frequency and
Duration

GD 7-13; 7 hr/d

High

11. Number of
Exposure Groups
and Dose Spacing

Only exposure group
plus control
(unacceptable based on
PECO statement), but
the use of two separate
exposure durations (GD

7-13, GD 14-20)
mitigates this concern;
exposure level selected
based on dose-finding
study.

Low

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Nelson, B. K.,Taylor, B. J.,Setzer, J. V.,Hornung, R. W. (1979). Behavioral teratology of perchloroethylene in rats
Journal of Environmental Pathology, Toxicology and Oncology, 3(1-2), 233-250

HERO ID: 58224

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

12. Exposure Route
and Method

Whole-body, dynamic
chamber (0.41 cu m). Air
flow 4 changes/min.
Unclear how many
animals per exposure
chamber?

Medium

Test Organism

13. Test Animal
Characteristics

Virgin male and female
SD rats obtained from
Harlan Industries and
mated. Sperm-positive
females used in study.

High

14. Adequacy and

Consistency of
Animal Husbandry
Conditions

Husbandry conditions
were consistent;
pregnant females
housed alone.

High

15. Number per
Group

13-19 dams/group;
litters culled to 4/sex
within 16 hrs of delivery

High

Outcome
Assessment

16. Outcome
Assessment
Methodology

Comprehensive
neurobehavioral testing,
neurochemical analysis,
and neurohistopathology
was conducted on PND
4-46, using 1/sex per
litter; pup body weights
were also monitored.
However, confidence
downgraded to medium
because maternal
toxicity was not
evaluated in this study
(only pilot study).

Medium

17. Consistency of
Outcome
Assessment

Consistent evaluation
between groups.

High

18. Sampling
Adequacy

1/sex per litter in
neurobehavioral testing
(so litter is statistical
unit)

High

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Nelson, B. K.,Taylor, B. J.,Setzer, J. V.,Hornung, R. W. (1979). Behavioral teratology of perchloroethylene in rats
Journal of Environmental Pathology, Toxicology and Oncology, 3(1-2), 233-250

HERO ID: 58224

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

19. Blinding of
Assessors

The study authors did
not indicate whether or
not assessors of
neurobehavior were
blinded. Certain tests

contain subjective
endpoints, which could
have introduced bias.
Pup body weight and
histopathology do not
require blinding.

Low

20. Negative Control
Response

Control data reported.
Study authors noted that

offspring of animals
sham-exposed from 7-13
(this study) and 14-20

(additional study)
differed. Study authors

indicated that this
stressed importance of
appropriate controls;
however, it could also
indicate variation in
control replicates.

Low

Confounding /
Variable Control

21. Confounding
Variables in Test
Design and
Procedures

All females weighed 200-
300 g at study initiation.

Dam BW and food
consumption were not
reported for this study,
but in the pilot study
(which used the same
exposure level), no
significant change in BW

or food consumption
was observed in exposed
dams. Study authors did
not indicate whether
respiratory rate was
measured. Since PERC is

a respiratory irritant,
confidence downgraded
to low.

Low

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Nelson, B. K.,Taylor, B. J.,Setzer, J. V.,Hornung, R. W. (1979). Behavioral teratology of perchloroethylene in rats
Journal of Environmental Pathology, Toxicology and Oncology, 3(1-2), 233-250

HERO ID: 58224

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

22. Health
Outcomes Unrelated
to Exposure

data on attrition and/or

health outcomes
unrelated to exposure
for each study group
were not reported
because only substantial
differences among
groups were noted

Medium

23. Statistical
Methods

Multivariate ANOVA for
most, open field and
ascent tests analyzed
with contingency tables;
neurochemical data
analyzed with 2-tailed
students t-test

High

Data Presentation
and Analysis

24. Reporting of
Data

Graphical presentation
of control and exposure
group data was provided
for some exposure-
related endpoints;
others were reported
qualitatively as
significant findings. Non-
significant findings
reported qualitatively.

Medium

Sum of scores:

High: >=1 and <1.7
Medium: >=1.7 and <2.3

Overall Score = Sum of Weighted Scores/Sum
of Metric Weighting Factors:

Overall Score:
Nearest *:

Low: >=2.3 and <=3

Overall Quality Level:

Low

Study Quality
Comment:

The reviewer downgraded this study's overall quality rating. They noted: Study was downgraded for the following
reasons: 1) lack of blinding in neurobehavioral assessment (which was primary focus of study), 2) variation in
control replicates, 3) lack of evaluation of maternal effects in main study (only pilot study), and 4) only one
exposure level Note: The original calculated score for this study was 1.8. This value is not presented above
because the final rating was changed based on professional judgement.

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

2.5. Animal toxicity evaluation results of Nelson et al 1979 for a neurodevelopmental
inhalation study (gd 14-20) on growth (early life) and development and
neurological/behavior outcomes

Study reference:

Nelson, B. K.,Taylor, B. J.,Setzer, J. V.,Hornung, R. W. (1979). Behavioral teratology of perchloroethylene in rats
Journal of Environmental Pathology, Toxicology and Oncology, 3(1-2), 233-250

HERO ID: 58224

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

Test Substance

1. Test Substance
Identity

Technical Grade-PCE;

High

2. Test Substance
Source

TG-PERC obtained from
Fisher Scientific; batch
no. not reported, no
independent analysis

Medium

3. Test Substance
Purity

98.5% pure

High

Test Design

4. Negative and
Vehicle Controls

sham exposed group

High

5. Positive Controls

OECD guideline 426
(developmental
neurotoxicity) states "To
guard against possible
false-negative findings

Not Rated

6. Randomized
Allocation

The study did not report

how animals were
allocated to study groups

Low

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Nelson, B. K.,Taylor, B. J.,Setzer, J. V.,Hornung, R. W. (1979). Behavioral teratology of perchloroethylene in rats
Journal of Environmental Pathology, Toxicology and Oncology, 3(1-2), 233-250

HERO ID: 58224

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

Exposure
Characterization

7. Preparation and
Storage of Test
Substance

Storage not reported.
PERC was vaporized
using heated flask, mixed
with filtered room air
and introduced into
exposure chamber
(airflow change rate
4x/min).

Medium

8. Consistency of

Exposure
Administration

Exposure conditions
were identical for sham-
exposed controls and
exposure groups.

High

9. Reporting of
Doses/Concentratio
ns

Only target exposure
levels were reported.
PERC levels in exposure

chambers were
continuously monitored

by a Miran infrared
analyzer and a charcoal
tube sample was taken
from the chamber air
(generally one per day)

and sent to an
independent laboratory
for gas chromatographic
analysis. But results of
analyses were not
reported.

Low

10. Exposure
Frequency and
Duration

GD 14-20; 7 hr/d

High

11. Number of
Exposure Groups
and Dose Spacing

2 exposure groups plus
control; exposure levels
selected based on dose-
finding study

High

12. Exposure Route
and Method

Whole-body, dynamic
chamber (0.41 cu m). Air
flow 4 changes/min.
Unclear how many
animals per exposure
chamber?

Medium

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Nelson, B. K.,Taylor, B. J.,Setzer, J. V.,Hornung, R. W. (1979). Behavioral teratology of perchloroethylene in rats
Journal of Environmental Pathology, Toxicology and Oncology, 3(1-2), 233-250

HERO ID: 58224

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

Test Organism

13. Test Animal
Characteristics

Virgin male and female
SD rats obtained from
Harlan Industries and
mated. Sperm-positive
females used in study.

High

14. Adequacy and

Consistency of
Animal Husbandry
Conditions

Husbandry conditions
were consistent;
pregnant females
housed alone.

High

15. Number per
Group

15-21 dams/group;
litters culled to 4/sex
within 16 hrs of delivery

High

Outcome
Assessment

16. Outcome
Assessment
Methodology

Medium

17. Consistency of
Outcome
Assessment

Consistent evaluation
between groups.

High

18. Sampling
Adequacy

1/sex per litter in
neurobehavioral testing
(so litter is statistical
unit)

High

19. Blinding of
Assessors

The study authors did
not indicate whether or
not assessors of
neurobehavior were
blinded. Certain tests

contain subjective
endpoints, which could
have introduced bias.
Pup body weight and
histopathology do not
require blinding.

Low

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Nelson, B. K.,Taylor, B. J.,Setzer, J. V.,Hornung, R. W. (1979). Behavioral teratology of perchloroethylene in rats
Journal of Environmental Pathology, Toxicology and Oncology, 3(1-2), 233-250

HERO ID: 58224

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score



20. Negative Control
Response

Control data reported.
Study authors noted that

offspring of animals
sham-exposed from 7-13
(different study) and 14-
20 (this study) differed.
Study authors indicated
that this stressed
importance of
appropriate controls;
however, it could also
indicate variation in
control replicates.

Low

3

1

3

Confounding /
Variable Control

21. Confounding
Variables in Test
Design and
Procedures

All females weighed 200-
300 g at study initiation.

Dam BW and food
consumption were not
reported for this study,
but in the pilot study
(which used high
exposure level), no
significant change in BW

or food consumption
was observed in exposed
dams. Study authors did
not indicate whether
respiratory rate was
measured. Since PERC is

a respiratory irritant,
confidence downgraded
to low.

Low

3

2

6

22. Health
Outcomes Unrelated
to Exposure

data on attrition and/or

health outcomes
unrelated to exposure
for each study group
were not reported
because only substantial
differences among
groups were noted

Medium

2

1

2

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Nelson, B. K.,Taylor, B. J.,Setzer, J. V.,Hornung, R. W. (1979). Behavioral teratology of perchloroethylene in rats
Journal of Environmental Pathology, Toxicology and Oncology, 3(1-2), 233-250



HERO ID: 58224











Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score



23. Statistical
Methods

Multivariate ANOVA for
most, open field and
ascent tests analyzed
with contingency tables;
neurochemical data
analyzed with 2-tailed
students t-test

High

1

1

1

Data Presentation
and Analysis

24. Reporting of
Data

Control and high-
exposure level data
reported Graphical
presentation of control
and high-exposure level
data was provided for
some exposure-related
endpoints; others were
reported qualitatively as
significant findings. Non-
significant findings
reported qualitatively.
All low-exposure group
data reported
qualitatively (no
exposure-related
findings)

Medium

2

2

4





Sum of scores:



30

52

High: >=1 and <1.7
Medium: >=1.7 and <2.3

Overall Score = Sum of Weighted Scores/Sum
of Metric Weighting Factors:

NA

Overall Score:
Nearest *:

NA

Low: >=2.3 and <=3















Overall Quality Level:



Low



Study Quality
Comment:

The reviewer downgraded this study's overall quality rating. They noted: Study was downgraded for the following

reasons: 1) lack of blinding in neurobehavioral assessment (which was primary focus of study), 2) variation in
control replicates, and 3) lack of evaluation of maternal effects in main study (only pilot study). Note: The original
calculated score for this study was 1.7. This value is not presented above because the final rating was changed

based on professional judgement.

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

2.6. Animal toxicity evaluation results of NTP 1986 for 1-day inhalation studies in rats
and mice on acute toxicity, neurological/behavioral, mortality, nutrition and
metabolic/adult exposure body weight outcomes

Study reference:

Ntp, (1986). Toxicology and carcinogenesis studies of tetrachloroethylene (perchloroethylene) (CAS no. 127-18-
4) in F344/N rats and B6C3F1 mice (inhalation studies)

HERO ID: 632655

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

1. Test Substance
Identity

high-purity
tetrachloroethylene,
Dowper stabilized

High

Test Substance

2. Test Substance
Source

Dow Chemical, lot
TA03116F-01. Purity and
identity analyses
conducted.

High

3. Test Substance
Purity

Confirmed analytically -
approximately 99.9%

High

4. Negative and
Vehicle Controls

Chamber controls were
used.

High

5. Positive Controls

Not needed for study
type.

Not Rated

Test Design

6. Randomized
Allocation

stratified by weight then

assigned to groups
according to a table of

random numbers
(weight is a nonrandom
component)

Medium

Exposure
Characterization

7. Preparation and
Storage of Test
Substance

Tetrachloroethylene was
found to be stable for 2
weeks at 60" C
(Appendix H).
Tetrachloroethylene was

stored at 0" C
Tetrachloroethylene was

vaporized at 100"-
110" C, diluted with air,
and. introduced into the

chambers. Detailed
descriptions in Table 2
and in Appendix 1.

High

8. Consistency of

Exposure
Administration

Concentrations in the
exposure chambers were

monitored 8-12 times
per exposure period by a
Hewlett-Packard 5840A
Gas Chromatograph. No
deviations from protocol
noted.

High

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Ntp, (1986). Toxicology and carcinogenesis studies of tetrachloroethylene (perchloroethylene) (CAS no. 127-18-
4) in F344/N rats and B6C3F1 mice (inhalation studies)

HERO ID: 632655

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

9. Reporting of
Doses/Concentratio
ns

Only target
concentrations reported
for non-chronic studies.,

but actual exposures
expected to be close to
target based on 2-yr
analytical values.

Medium

10. Exposure
Frequency and
Duration

l-d,4 hr

Medium

11. Number of
Exposure Groups
and Dose Spacing

5 dose groups plus
control

High

12. Exposure Route
and Method

Inhalation, dynamic
whole-body chamber.
Flow rate not reported

Low

Test Organism

13. Test Animal
Characteristics

F344/N rats and B6C3F1
mice, Frederick Cancer
Research Center. 5-7 wks
at study initiation. Initial
body weights reported in
Tables 6 and 17.

High

14. Adequacy and

Consistency of
Animal Husbandry
Conditions

Some details of
husbandry in Table 5;
Room conditions not
reported

Medium

15. Number per
Group

5/sex/group

High

Outcome
Assessment

16. Outcome
Assessment
Methodology

Mortality, clinical signs,
body weight, necropsy

High

17. Consistency of
Outcome
Assessment

Consistent evaluation in
all study groups

High

18. Sampling
Adequacy

5/sex/group

High

19. Blinding of
Assessors

Evaluated endpoints did
not require blinding

Not Rated

20. Negative Control
Response

Control responses
reported.

High

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Ntp, (1986). Toxicology and carcinogenesis studies of tetrachloroethylene (perchloroethylene) (CAS no. 127-18-
4) in F344/N rats and B6C3F1 mice (inhalation studies)

HERO ID: 632655

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e., High, Medium, L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

Confounding /
Variable Control

21. Confounding
Variables in Test
Design and
Procedures

There were no reported
differences among the
study groups in initial
body weight. Food and
water intake were not
reported. Respiratory
rate not reported, but
severe clinical signs
included anesthesia
were reported in
exposed animals.
Unclear if bradypnea
was present.

Low

22. Health
Outcomes Unrelated
to Exposure

data on attrition and/or

health outcomes
unrelated to exposure
for each study group
were not reported
because only substantial
differences among
groups were noted

Medium

Data Presentation
and Analysis

23. Statistical
Methods

No statsitics Data for
mortality and terminal
BW were reported
adequately for
independent analysis.
Clinical signs data
inadequate for
independent analysis.

Medium

24. Reporting of
Data

Quantitative mortality
and body weight data.
Exposure-related clinical
signs reported
qualitatively.

Medium

High: >=1 and <1.7
Medium: >=1.7 and <2.3
Low: >=2.3 and <=3

Sum of scores:

Overall Score = Sum of Weighted Scores/Sum
of Metric Weighting Factors:

1.5172

Overall Score:
Nearest *:

1.5

Overall Quality Level:

High

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

2.7. Animal toxicity evaluation results of NTP 1986 for 14-day inhalation studies in rats
and mice on neurological/behavioral, mortality, nutrition and metabolic/adult
exposure body weight outcomes

Study reference:

Ntp, (1986). Toxicology and carcinogenesis studies of tetrachloroethylene (perchloroethylene) (CAS no. 127-18-
4) in F344/N rats and B6C3F1 mice (inhalation studies)

HERO ID: 632655

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

Test Substance

1. Test Substance
Identity

high-purity
tetrachloroethylene,
Dowper stabilized

High

2. Test Substance
Source

Dow Chemical, lot
TA03116F-01. Purity and
identity analyses
conducted.

High

3. Test Substance
Purity

Confirmed analytically -
approximately 99.9%

High

Test Design

4. Negative and
Vehicle Controls

Chamber controls were
used.

High

5. Positive Controls

Not needed for study
type.

Not Rated

6. Randomized
Allocation

stratified by weight then

assigned to groups
according to a table of

random numbers
(weight is a nonrandom
component)

Medium

Exposure
Characterization

7. Preparation and
Storage of Test
Substance

Tetrachloroethylene was
found to be stable for 2
weeks at 60" C
(Appendix H).
Tetrachloroethylene was

stored at 0" C
Tetrachloroethylene was

vaporized at 100"-
110" C, diluted with air,
and. introduced into the

chambers. Detailed
descriptions in Table 2
and in Appendix 1.

High

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Ntp, (1986). Toxicology and carcinogenesis studies of tetrachloroethylene (perchloroethylene) (CAS no. 127-18-
4) in F344/N rats and B6C3F1 mice (inhalation studies)

HERO ID: 632655

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

8. Consistency of

Exposure
Administration

Concentrations in the
exposure chambers were

monitored 8-12 times
per exposure period by a
Hewlett-Packard 5840A
Gas Chromatograph. No
deviations from protocol
noted.

High

9. Reporting of
Doses/Concentratio
ns

Only target
concentrations reported
for non-chronic studies.,

but actual exposures
expected to be close to
target based on 2-yr
analytical values.

Medium

10. Exposure
Frequency and
Duration

14-d, 6 hr/d, 5 d/wk.

High

11. Number of
Exposure Groups
and Dose Spacing

5 dose groups plus
control

High

12. Exposure Route
and Method

Inhalation, dynamic
whole-body chamber.
Flow rate not reported

Low

Test Organism

13. Test Animal
Characteristics

F344/N rats and B6C3F1
mice, Charles River
Breeding. 6-8 wks at
study initiation. Initial
body weights reported in
Tables 7 and 18.

High

14. Adequacy and

Consistency of
Animal Husbandry
Conditions

Some details of
husbandry in Table 5;
room conditions not
reported.

Medium

15. Number per
Group

5/sex/group

High

Outcome
Assessment

16. Outcome
Assessment
Methodology

Mortality, clinical signs,
body weight

High

17. Consistency of
Outcome
Assessment

Consistent evaluation in
all study groups for 14-d
study.

High

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Ntp, (1986). Toxicology and carcinogenesis studies of tetrachloroethylene (perchloroethylene) (CAS no. 127-18-
4) in F344/N rats and B6C3F1 mice (inhalation studies)

HERO ID: 632655

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

18. Sampling
Adequacy

5/sex/group

High

19. Blinding of
Assessors

Evaluated endpoints did
not require blinding

Not Rated

20. Negative Control
Response

Control responses
reported.

High

Confounding /
Variable Control

21. Confounding
Variables in Test
Design and
Procedures

There were no reported
differences among the
study groups in initial
body weight. Food and
water intake were not
reported. Respiratory
rate not reported, but
dyspnea was reported at
highest exposure in both
rats and mice.

Low

22. Health
Outcomes Unrelated
to Exposure

data on attrition and/or

health outcomes
unrelated to exposure
for each study group
were not reported
because only substantial
differences among
groups were noted

Medium

Data Presentation
and Analysis

23. Statistical
Methods

Detailed statistical tests
reported for survival and
tumor analysis of 2-yr
study, unclear if any

statistics were
conducted on shorter-
duration studies.. Data
for mortality and
terminal BW were
reported adequately for
independent analysis.
Clinical signs data
inadequate for
independent analysis.

Medium

24. Reporting of
Data

Quantitative mortality
and body weight data.
Exposure-related clinical
signs reported
qualitatively.

Medium

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Ntp, (1986). Toxicology and carcinogenesis studies of tetrachloroethylene (perchloroethylene) (CAS no. 127-18-
4) in F344/N rats and B6C3F1 mice (inhalation studies)

HERO ID: 632655

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e., High, Medium, L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

High: >=1 and <1.7
Medium: >=1.7 and <2.3
Low: >=2.3 and <=3

Sum of scores:



29

43

Overall Score = Sum of Weighted Scores/Sum
of Metric Weighting Factors:

1.4828

Overall Score:
Nearest *:

1.5

Overall Quality Level:

High

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

2.8. Animal toxicity evaluation results of NTP 1986 for 14-day inhalation studies in rats
and mice (histology) on reproductive, hematological and immune, renal, hepatic,
cardiovascular, endocrine, gastrointestinal, respiratory, skin and connective tissue,
thyroid outcomes

Study reference:

Ntp, (1986). Toxicology and carcinogenesis studies of tetrachloroethylene (perchloroethylene) (CAS no. 127-18-
4) in F344/N rats and B6C3F1 mice (inhalation studies)

HERO ID: 632655

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

Test Substance

1. Test Substance
Identity

high-purity
tetrachloroethylene,
Dowper stabilized

High

2. Test Substance
Source

Dow Chemical, lot
TA03116F-01. Purity and
identity analyses
conducted.

High

3. Test Substance
Purity

Confirmed analytically -
approximately 99.9%

High

Test Design

4. Negative and
Vehicle Controls

Chamber controls were
used.

High

5. Positive Controls

Not needed for study
type.

Not Rated

6. Randomized
Allocation

stratified by weight then

assigned to groups
according to a table of

random numbers
(weight is a nonrandom
component)

Medium

Exposure
Characterization

7. Preparation and
Storage of Test
Substance

Tetrachloroethylene was
found to be stable for 2
weeks at 60" C
(Appendix H).
Tetrachloroethylene was

stored at 0" C
Tetrachloroethylene was

vaporized at 100"-
110" C, diluted with air,
and. introduced into the

chambers. Detailed
descriptions in Table 2
and in Appendix 1.

High

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Ntp, (1986). Toxicology and carcinogenesis studies of tetrachloroethylene (perchloroethylene) (CAS no. 127-18-
4) in F344/N rats and B6C3F1 mice (inhalation studies)

HERO ID: 632655

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

8. Consistency of

Exposure
Administration

Concentrations in the
exposure chambers were

monitored 8-12 times
per exposure period by a
Hewlett-Packard 5840A
Gas Chromatograph. No
deviations from protocol
noted.

High

9. Reporting of
Doses/Concentratio
ns

Only target
concentrations reported
for non-chronic studies.,

but actual exposures
expected to be close to
target based on 2-yr
analytical values.

Medium

10. Exposure
Frequency and
Duration

14-d, 6 hr/d, 5 d/wk.

High

11. Number of
Exposure Groups
and Dose Spacing

5 dose groups plus
control

High

12. Exposure Route
and Method

Inhalation, dynamic
whole-body chamber.
Flow rate not reported

Low

Test Organism

13. Test Animal
Characteristics

F344/N rats and B6C3F1
mice, Charles River
Breeding. 6-8 wks at
study initiation. Initial
body weights reported in
Tables 7 and 18.

High

14. Adequacy and

Consistency of
Animal Husbandry
Conditions

Some details of
husbandry in Table 5;
room conditions not
reported.

Medium

15. Number per
Group

5/sex/group

High

Outcome
Assessment

16. Outcome
Assessment
Methodology

comprehensive
histopathology

High

17. Consistency of
Outcome
Assessment

Consistent evaluation in
all study groups for 14-d
study.

High

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Ntp, (1986). Toxicology and carcinogenesis studies of tetrachloroethylene (perchloroethylene) (CAS no. 127-18-
4) in F344/N rats and B6C3F1 mice (inhalation studies)

HERO ID: 632655

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

18. Sampling
Adequacy

5/sex/group

High

19. Blinding of
Assessors

Evaluated endpoints did
not require blinding

Not Rated

20. Negative Control
Response

Control responses
reported.

High

Confounding /
Variable Control

21. Confounding
Variables in Test
Design and
Procedures

Low

22. Health
Outcomes Unrelated
to Exposure

data on attrition and/or

health outcomes
unrelated to exposure
for each study group
were not reported
because only substantial
differences among
groups were noted

Medium

Data Presentation
and Analysis

23. Statistical
Methods

Detailed statistical tests
reported for survival and
tumor analysis of 2-yr
study, unclear if any

statistics were
conducted on shorter-
duration studies. Histo
data not reported.

Unacceptable

24. Reporting of
Data

Histological results not
reported; no statement
regarding lack of
exposure-related
findings.

Unacceptable

High: >-1 and <1.7
Medium: >=1.7 and <2.3
Low: >=2.3 and <=3

Sum of scores:

Overall Score = Sum of Weighted Scores/Sum
of Metric Weighting Factors:

1.8846

Overall Score:
Nearest *:

1.81

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Ntp, (1986). Toxicology and carcinogenesis studies of tetrachloroethylene (perchloroethylene) (CAS no. 127-18-
4) in F344/N rats and B6C3F1 mice (inhalation studies)

HERO ID: 632655

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score



Overall Quality Level:

Unacceptable1

Study Quality
Comment:

Footnote 1: Consistent with our Application of A Systematic Review in TSCA Risk Evaluations document, if a metric
for a data source receives a score of Unacceptable (score = 4), EPA will determine the study to be unacceptable. In
this case, two of the metrics were rated as unacceptable. As such, the study is considered unacceptable and the

score is presented solely to increase transparency.

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

2.9. Animal toxicity evaluation results of Seo et al 2012

Study reference:

Seo, M.,Kobayashi, R. yo,Okamura, T.,lkeda, K.,Satoh, M.,lnagaki, N.,Nagai, H.,Nagase, H. (2012). Enhancing
effects of trichloroethylene and tetrachloroethylene on type 1 allergic responses in mice Journal of Toxicological
Sciences, 37(2), 439-445



HERO ID: 2128339











Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score



1. Test Substance
Identity

See footnote at end of
page.1

High

1

2

2

Test Substance

2. Test Substance
Source

See footnote at end of
page.1

High

1

1

1



3. Test Substance
Purity

See footnote at end of
page.1

High

1

1

1



4. Negative and
Vehicle Controls

Concurrent control did
not receive vehicle
(DMSO) but author
states that this
concentration of DMSO
did not have effects in
preliminary experiments.

Medium

2

2

4

Test Design

5. Positive Controls

Positive control is not
required.

Not Rated

NA

NA

NA



6. Randomized
Allocation

The study did not report
how animals were
allocated to study
groups. Some
experiments were done
on cells isolated from
animals.

Low

3

1

3



7. Preparation and
Storage of Test
Substance

The storage of
perchloroethylene was
not stated, but it is not
known to be unstable
(Wl).

Medium

2

1

2

Exposure
Characterization

8. Consistency of

Exposure
Administration

The drinking water
dosing was changed
every other day, not
every day. The
concentration was below

the solubility, but the
test compound is slightly
volatile.

Medium

2

1

2

1 Metrics that received a "High" rating met the criteria as discussed in the Applications of Systematic Review for
TSCA Risk Evaluation.

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Seo, M.,Kobayashi, R. yo,Okamura, T.,lkeda, K.,Satoh, M.,lnagaki, N.,Nagai, H.,Nagase, H. (2012). Enhancing
effects of trichloroethylene and tetrachloroethylene on type 1 allergic responses in mice Journal of Toxicological
Sciences, 37(2), 439-445

HERO ID: 2128339

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

9. Reporting of
Doses/Concentratio
ns

Nominal drinking water

concentrations are
provided and doses are
presented as mean ug
ingested per day by each
group of 8 mice (not
adjusted for body
weight). Also, it is
unclear if water intake
varied among treatment
groups. The IP dose
injections and the in
vitro doses were
defined.

Medium

10. Exposure
Frequency and
Duration

The dosing was in
drinking water ad
libitum, but the duration
was defined.

High

11. Number of
Exposure Groups
and Dose Spacing

Dose spacing was 10-100
fold.

High

12. Exposure Route
and Method

Test substance if volatile,
but drinking water was
changed every other
day.

Medium

Test Organism

13. Test Animal
Characteristics

Mouse strains were
identified. Body weight
and health status were
not reported.

Medium

14. Adequacy and

Consistency of
Animal Husbandry
Conditions

Minimal details on
husbandry conditions
were provided. The
dietary mix was not
identified.

Low

15. Number per
Group

The number of animals
per study group was not
reported.

Unacceptable

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Seo, M.,Kobayashi, R. yo,Okamura, T.,lkeda, K.,Satoh, M.,lnagaki, N.,Nagai, H.,Nagase, H. (2012). Enhancing
effects of trichloroethylene and tetrachloroethylene on type 1 allergic responses in mice Journal of Toxicological
Sciences, 37(2), 439-445

HERO ID: 2128339

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

Outcome
Assessment

16. Outcome
Assessment
Methodology

See footnote at end of
page.1

High

1

2

2

17. Consistency of
Outcome
Assessment

The outcomes were
consistent across
experiments.

High

1

1

1

18. Sampling
Adequacy

It is not clear what the
experimental unit was

(i.e., whether the
outcome was measured
separately for each
individual animal).

Low

3

1

3

19. Blinding of
Assessors

Outcome was not
subjective. The
measurements used
analytical devices.

Not Rated

NA

NA

NA

20. Negative Control
Response

See footnote at end of
page.1

High

1

1

1

Confounding /
Variable Control

21. Confounding
Variables in Test
Design and
Procedures

Water intake was not
reported separately for
each dose group, so it is
unclear whether there
were differences in
water intake among
doses. The in vitro study
and the IP study designs
were better controlled.

Low

3

2

6

22. Health
Outcomes Unrelated
to Exposure

Heath outcomes
unrelated to exposure

were not reported;
however, no differences
in health among study
groups were reported.

Medium

2

1

2

Data Presentation
and Analysis

23. Statistical
Methods

Limited details regarding
statistics were provided.
Graphs were plotted for

the results, but the
numerical raw data was
not provided.

Medium

2

1

2

1 Metrics that received a "High" rating met the criteria as discussed in the Applications of Systematic Review for
TSCA Risk Evaluation.

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Seo, M.,Kobayashi, R. yo,Okamura, T.,lkeda, K.,Satoh, M.,lnagaki, N.,Nagai, H.,Nagase, H. (2012). Enhancing
effects of trichloroethylene and tetrachloroethylene on type 1 allergic responses in mice Journal of Toxicological
Sciences, 37(2), 439-445

HERO ID: 2128339

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score



24. Reporting of
Data

See footnote at end of
page.1

High

1

2

2

High: >=1 and <1.7
Medium: >=1.7 and <2.3
Low: >=2.3 and <=3

Sum of scores:



28

53

Overall Score = Sum of Weighted Scores/Sum
of Metric Weighting Factors:

1.8929

Overall Score:
Nearest *:

1.91

Overall Quality Level:

Unacceptable1

Study Quality
Comment:

Footnote 1: Consistent with our Application of A Systematic Review in TSCA Risk Evaluations document, if a metric
for a data source receives a score of Unacceptable (score = 4), EPA will determine the study to be unacceptable. In
this case, one of the metrics were rated as unacceptable. As such, the study is considered unacceptable and the

score is presented solely to increase transparency.

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PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

3. Subchronic Toxicity Studies

3.1. Animal toxicity evaluation results of Buben et al 1985 for a 6 week gavage study of

perc in mice study on hepatic outcomes

Study reference:

Buben, J. A.,0'Flaherty, E. J. (1985). Delineation of the role of metabolism in the hepatotoxicity of
trichloroethylene and perchloroethylene: A dose-effect study Toxicology and Applied Pharmacology, 78(1), 105-
122

HERO ID: 65239

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

Test Substance

1. Test Substance
Identity

Test substance identified
by unambiguous name

High

2. Test Substance
Source

Test substance obtained
commercially

High

3. Test Substance
Purity

Perc reported to have
purity >99%.

High

Test Design

4. Negative and
Vehicle Controls

Sham-treated controls
received corn oil vehicle.

High

5. Positive Controls

Not Rated

6. Randomized
Allocation

Study reports random
allocation to study
groups.

High

Exposure
Characterization

7. Preparation and
Storage of Test
Substance

Preparation method was

reported and
appropriate (prepared
fresh 2-3x/wk); stability

of test material in
vehicle was either not
evaluated or not
reported,, but not
expected to be of
concern given the
frequency of
preparation.

Medium

8. Consistency of

Exposure
Administration

Details of administration
(e.g., time of day) were
not reported; no dosing
errors were noted.

Medium

9. Reporting of
Doses/Concentratio
ns

Dose volumes were
adjusted based on
individual animal body
weights obtained
3x/week.

High

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PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

HERO ID: 65239

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

10. Exposure
Frequency and
Duration

Animals were dosed 5
days/week for 6 weeks.

The duration was
sufficient to induce the
effects of interest
(hepatotoxicity).

High

11. Number of
Exposure Groups
and Dose Spacing

Study used 7 exposure
groups plus control;
overall range of doses
was 100-fold; high dose
was adequate to identify
effect. The lowest Perc
dose of 20 mg/kg may be

a NOAEL, but
histopathology was only
evaluated at 200mg/kg
and 1000 mg/kg (effects

seen at both) so it is
difficult to determine the
NOAEL.

High

12. Exposure Route
and Method

Exposure route and
method were
appropriate for the study
type and test material.

High

Test Organism

13. Test Animal
Characteristics

Test animal source,
strain, sex, and age were
reported. The ages of
mice at study initiation
varied between 3 and 5
months; however, as
mice are adult at these
ages, the age range is
not expected to
influence hepatotoxicity.

Medium

14. Adequacy and

Consistency of
Animal Husbandry
Conditions

Temperature and light-
dark cycle, and housing
conditions were

reported and
appropriate, but
humidity was not
reported.

Medium

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PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

HERO ID: 65239

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

15. Number per
Group

High

Outcome
Assessment

16. Outcome
Assessment
Methodology

Study focused on
hepatotoxicity based on
organ weight, liver G6P
activity and triglycerides,
serum ALT, and
histopathology.

High

17. Consistency of
Outcome
Assessment

Study did not report any
inconsistencies in
execution of outcome
assessments. Histopathy
was only reported in two
dose groups.

Medium

18. Sampling
Adequacy

Incomplete information
was provided on
sampling adequacy
across endpoints.

Histopathology
examinations were
performed on controls,
high dose animals, and
on animals of one
intermediate dose
group.

Medium

19. Blinding of
Assessors

Not Rated

20. Negative Control
Response

Responses of negative
control group were
adequate.

High

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PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

HERO ID: 65239

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

Confounding /
Variable Control

21. Confounding
Variables in Test
Design and
Procedures

Study did not report any

potential differences
among study groups that
might influence the
assessment.

High

22. Health
Outcomes Unrelated
to Exposure

There were no reported
differences among
groups unrelated to
exposure

High

23. Statistical
Methods

Statistical methods were
reported and appeared
to be appropriate.

High

Data Presentation
and Analysis

24. Reporting of
Data

Histopathology results
were reported
semiquantitatively
(incidences not
reported); no statistical
analysis of incidences
was performed, and the
available data are not
adequate to perform
independent statistical

analysis. Data was
quantitatively reported
for all outcomes other
than histopathy at all
dose groups.

Medium

Sum of scores:

High: >=1 and <1.7
Medium: >=1.7 and <2.3

Overall Score = Sum of Weighted Scores/Sum
of Metric Weighting Factors:

Overall Score:
Nearest *:

Low: >=2.3 and <=3

Overall Quality Level:

Medium

Study Quality
Comment:

The reviewer downgraded this study's overall quality rating. They noted: Hlstopathology examinations were
performed in control, 200 and 1000 mg/kg dose groups, and lesions were seen in both exposed groups. Although
there were lower dose groups in which no changes in other parameters were observed, it would be difficult to
identify a NOAEL in the absence of confirmatory histopathology results for the lower dose groups. Note: The
original calculated score for this study was 1.4. This value is not presented above because the final rating was

changed based on professional judgement.

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PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

3.2. Animal toxicity evaluation results of E. I. Dupont De Nemours 1941 for a 10 week
inhalation study in dogs on neurological/behavior, cardiovascular, hematological
and immune outcomes

Study reference:

E. 1. Dupont Denemours,Co, Inc (1941). Initial submission: the toxicity of perchloroethylene with cover letter
dated 10/15/92

HERO ID: 4214432

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

Test Substance

1. Test Substance
Identity

Test substance identified
by unambiguous name
and molecular formula,
but without certification
or validation of identity.

Medium

2. Test Substance
Source

Test substance source
was not reported, and
given the age of the
study, it was probably
not obtained from a
manufacturer.

Low

3. Test Substance
Purity

Test substance
purity/grade not
reported.

Low

Test Design

4. Negative and
Vehicle Controls

A concurrent negative
control group was not
included; animals served
as their own controls.

Unacceptable

5. Positive Controls

positive control not
typical for this study
type.

Not Rated

6. Randomized
Allocation

Animals were not
allocated to groups;
rather, health outcomes
assessed before and
after exposure in all
animals

Unacceptable

Exposure
Characterization

7. Preparation and
Storage of Test
Substance

No information on test
substance preparation or
storage, or methods for
atmosphere generation,
was presented.

Unacceptable

8. Consistency of

Exposure
Administration

There were no details
provided to enable
assessment of
consistency, except that
exposure concentrations
were increased over the
course of the exposure
period.

Unacceptable

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PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

E. 1. Dupont Denemours,Co, Inc (1941). Initial submission: the toxicity of perchloroethylene with cover letter
dated 10/15/92

HERO ID: 4214432

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

9. Reporting of
Doses/Concentratio
ns

Exposure concentrations

were reported
inconsistently within the
study; the methods

section reports
concentrations that
differ from those in the
results sections.. Study

reported exposure
concentrations without
any indication of how
these were estimated or
measured. There is no
indication that exposure
concentrations were
verified analytically.

Unacceptable

10. Exposure
Frequency and
Duration

Dogs were exposed 6
hr/d, 5 d/wk for 10
weeks and Guinea Pigs
were exposed for two
weeks (No exposure
detail reported)

Medium

11. Number of
Exposure Groups
and Dose Spacing

Only one group of
animals was included;
these animals were
exposed to increasing
concentrations over

time, and effects
compared with pre-
exposure conditions.

Unacceptable

12. Exposure Route
and Method

There is no description
of the inhalation
chamber used

Unacceptable

13. Test Animal
Characteristics

Test animal source,
strain, and sex were not
reported.

Low

Test Organism

14. Adequacy and

Consistency of
Animal Husbandry
Conditions

No information on
animal husbandry was
provided.

Low

15. Number per
Group

Four animals were
exposed, and served as
their own controls.

Low

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PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

E. 1. Dupont Denemours,Co, Inc (1941). Initial submission: the toxicity of perchloroethylene with cover letter
dated 10/15/92

HERO ID: 4214432

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

Outcome
Assessment

16. Outcome
Assessment
Methodology

The outcome assessment
methodologies were not

reported, and the
outcomes assessed were
not sensitive (oxygen

content of blood,
electrocardiography,

some hematology
endpoints, and gross
pathology)

Unacceptable

17. Consistency of
Outcome
Assessment

Outcome assessments
were not adequately
reported for meaningful
interpretation of results.

Unacceptable

18. Sampling
Adequacy

Information was not
adequate to evaluate
sampling adequacy, but

it appears that all
animals were evaluated
for all endpoints.

Low

19. Blinding of
Assessors

Most outcomes were not
subjective.

Not Rated

20. Negative Control
Response

There was no control
group; dogs served as
their own controls.

Unacceptable

Confounding /
Variable Control

21. Confounding
Variables in Test
Design and
Procedures

No information on
potential confounding
factors was reported.
Initial body weight and
food and water intake
were not reported.

Low

22. Health
Outcomes Unrelated
to Exposure

Data on attrition or
health outcomes
unrelated to exposure
were not reported.

Low

Data Presentation
and Analysis

23. Statistical
Methods

Statistical analysis was

not performed, and
reported data were not

adequate to enable
independent statistical
analysis.

Unacceptable

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

E. 1. Dupont Denemours,Co, Inc (1941). Initial submission: the toxicity of perchloroethylene with cover letter
dated 10/15/92

HERO ID: 4214432

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score



24. Reporting of
Data

Most data were reported
qualitatively and without
clear reference to the
pre-exposure response.

Unacceptable

4

2

8

High: >=1 and <1.7
Medium: >=1.7 and <2.3
Low: >=2.3 and <=3

Sum of scores:



29

100

Overall Score = Sum of Weighted Scores/Sum
of Metric Weighting Factors:

3.4483

Overall Score:
Nearest *:

3.41

Overall Quality Level:

Unacceptable1

Study Quality
Comment:

Footnote 1: Consistent with our Application of A Systematic Review in TSCA Risk Evaluations document, if a metric
for a data source receives a score of Unacceptable (score = 4), EPA will determine the study to be unacceptable. In
this case, twelve of the metrics were rated as unacceptable. As such, the study is considered unacceptable and

the score is presented solely to increase transparency.

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

3.3. Animal toxicity evaluation results of Natl Institute of Health 1977 for a 6-week oral
(rats and mice) study on mortality and metabolic/adult exposure body weight
outcomes

Study reference:

Natl Inst Of, Health (1977). Bioassay of tetrachloroethylene for possible carcinogenicity
HERO ID: 4214470

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

Test Substance

1. Test Substance
Identity

The test substance was
identified definitively.

High

1

2

2

2. Test Substance
Source

The source of the test
substance was reported,
including manufacturer.
A lot/batch number was
not reported.

Medium

2

1

2

3. Test Substance
Purity

The purity was reported
by the manufacturer (at
least 99%). The study
report also stated that
gas-liquid
chromatography showed

the major component
consisting of over 99% of
the total peak area, with

a minor impurity
present, which was not
identified.

Medium

2

1

2

Test Design

4. Negative and
Vehicle Controls

The study authors
reported using an
appropriate concurrent
control group (vehicle
control administered
corn oil only).

High

1

2

2

5. Positive Controls

Positive control is not
indicated for the study
type.

Not Rated

NA

NA

NA

6. Randomized
Allocation

The study did not report
how animals were
allocated to study
groups.

Low

3

1

3

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Natl Inst Of, Health (1977). Bioassay of tetrachloroethylene for possible carcinogenicity
HERO ID: 4214470

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

Exposure
Characterization

7. Preparation and
Storage of Test
Substance

The test substance
preparation and storage

conditions were
reported but there were
minor limitations in the
test substance
preparation. The test
substance was prepared

weekly, sealed, and
stored at 34 degrees F,
which the study authors
noted were considered
conditions that would
allow test substance to
remain stable for 10
days. However, no
report of stability in the
vehicle (corn oil), or of
PERC in the prepared
solutions, was reported.

Medium

2

1

2

8. Consistency of

Exposure
Administration

Details of exposure
administration were not
fully reported (volume
administered by gavage
was not reported).
However, reported
information indicated
that exposures were
administered
consistently across study
groups.

Medium

2

1

2

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PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Natl Inst Of, Health (1977). Bioassay of tetrachloroethylene for possible carcinogenicity
HERO ID: 4214470

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score



9. Reporting of
Doses/Concentratio
ns

Initial administered
doses were reported;
however, dose levels
were raised and/or
lowered during the study
in both rats and mice
based on clinical signs

and there is some
ambiguity in the actual
dose levels after
adjustment and the
exact days during the
study when doses were
raised and/or lowered
(only reported in weeks).
For example, for rats, the
study authors stated that

the low doses were
adjusted accordingly, so
that they consistently
remained one-half of the
high dose but actual
adjusted dose levels
were not reported.

Medium

2

2

4

10. Exposure
Frequency and
Duration

Exposure frequency (5
consecutive d/wk) was
reported and acceptable.
However, the exposure
duration was shorter
than studies of similar
type (i.e., 2 years for
carcinogenicity studies is
typical for rodents) and
was not justified by the
study authors. In this
study, animals were
dosed for 78 weeks
followed by an
observation period of 32
weeks in rats and 12
weeks in mice.

Medium

2

1

2

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PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Natl Inst Of, Health (1977). Bioassay of tetrachloroethylene for possible carcinogenicity
HERO ID: 4214470

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score



11. Number of
Exposure Groups
and Dose Spacing

The number of exposure
groups and spacing were
considered adequate to
address the purpose of
the study. However, the
highest doses produced
a high rate of early
mortality in both rats
and mice, which the
study authors noted may
indicate that the
optimum dose was
exceeded in both
species.

Medium

2

1

2

12. Exposure Route
and Method

The route and method of
exposure were reported
and were suited to the
test substance.

High

1

1

1

Test Organism

13. Test Animal
Characteristics

The test animal source,
species, strain, sex, age,
and starting body weight
were reported. The test
animal (species, strain,
sex, life-stage, source)
was appropriate for the
evaluation of the specific
outcome(s) of interest.

Medium

2

2

4

14. Adequacy and

Consistency of
Animal Husbandry
Conditions

Due to starting the
vehicle control rats and
mice earlier than animals
of other groups, and
housing of vehicle
control rats and a
different room than
other rats, there may
have been some
differences in husbandry
/ exposure conditions.

Low

3

1

3

15. Number per
Group

The number per group

was acceptable
(5/sex/group) for the 6-
week, range-finding
study

High

1

1

1

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PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Natl Inst Of, Health (1977). Bioassay of tetrachloroethylene for possible carcinogenicity
HERO ID: 4214470

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

Outcome
Assessment

16. Outcome
Assessment
Methodology

The outcome assessment
methodology was only
briefly reported. For
example, it was not
reported how often body

weights were
determined during the 6-
week dosing period and

2-week observation
period. Additionally, the
only endpoints evaluated
were grossly observable
endpoints, including
clinical signs and
mortality.

Low

3

2

6

17. Consistency of
Outcome
Assessment

Details of the outcome
assessment protocol
were not reported and
these deficiencies are

likely to have a
substantial impact on
results.

Low

3

1

3

18. Sampling
Adequacy

Details regarding
sampling of outcomes
were not reported and
this deficiency is likely to
have a substantial
impact on results.

Low

3

1

3

19. Blinding of
Assessors

No subjective outcomes
were reported.

Not Rated

NA

NA

NA

20. Negative Control
Response

The biological responses
of the negative control
group were adequate.

High

1

1

1

Confounding /
Variable Control

21. Confounding
Variables in Test
Design and
Procedures

No confounding
variables in test design
or procedures were
reported.

High

1

2

2

22. Health
Outcomes Unrelated
to Exposure

Data on attrition and/or

health outcomes
unrelated to exposure
for each study group
were not reported
because only substantial
differences among
groups were noted.

Medium

2

1

2

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PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Natl Inst Of, Health (1977). Bioassay of tetrachloroethylene for possible carcinogenicity
HERO ID: 4214470

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

Data Presentation
and Analysis

23. Statistical
Methods

The statistical methods
were clearly described
by the study authors and
were appropriate for
datasets.

High

1

1

1

24. Reporting of
Data

Data were reported
incompletely. Body
weights were reported in
figures and changes in
body weight gain were
reported in percentages
in the text.

Low

3

2

6

High: >=1 and <1.7
Medium: >=1.7 and <2.3
Low: >=2.3 and <=3

Sum of scores:



29

56

Overall Score = Sum of Weighted Scores/Sum
of Metric Weighting Factors:

NA

Overall Score:
Nearest *:

NA

Overall Quality Level:

Low

Study Quality
Comment:

The reviewer downgraded this study's overall quality rating based on limited reporting of outcome assessment
methodology and protocol and limited reporting of data. Note: The original calculated score for this study was
1.9. This value is not presented above because the final rating was changed based on professional judgement.

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

4. Chronic Toxicity Studies

4.1. Animal toxicity evaluation results of Dow et al 1978 for a 12 month inhalation
study in rats, with lifetime observation on renal, hepatic, nutrition and
metabolic/adult exposure body weight, hematological and immune outcomes

Study reference:

Dow Chem, Co (1978). Results of a long-term inhalation toxicity study on rats of a perchloroethylene
(tetrachloroethylene) formulation #journal#, #volume#(#issue#), #Pages#

HERO ID: 4214237

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

Test Substance

1. Test Substance
Identity

Test substance identified
by name and CASRN

High

2. Test Substance
Source

Test substance was
identified by lot number
and verified analytically,
with results presented.

High

3. Test Substance
Purity

Purity was not reported
explicitly, but based on
GC results and reported
percentages of
contaminants, test
substance was >99%
(vol%) perc (impurities
comprised 63 ppm vol %)

Medium

Test Design

4. Negative and
Vehicle Controls

Negative controls were
not sham-exposed, but
rather held in the room
where exposed animals
were housed when not
in exposure chambers.

Low

5. Positive Controls

Positive controls not
typical for this study type

Not Rated

6. Randomized
Allocation

Study reported random
allocation

High

Exposure
Characterization

7. Preparation and
Storage of Test
Substance

Method of vapor
generation was
described in detail and
appropriate (dynamic
airflow); however, there
was no diagram of the
chamber, so it is unclear
whether vertical mixing
was adequate (Perc
vapor is much heavier
than air) and/or whether
analytical measurements
were in the animals'
breathing zones.

Medium

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Dow Chem, Co (1978). Results of a long-term inhalation toxicity study on rats of a perchloroethylene
(tetrachloroethylene) formulation #journal#, #volume#(#issue#), #Pages#

HERO ID: 4214237

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score



8. Consistency of

Exposure
Administration

Control animals were not
sham-exposed. Authors

report that exposures
during first 5 months ran
at the same time in both
exposed groups, but
thereafter they ran at
different times of day
(low dose in morning
and high dose in
evening) using the same
exposure chamber.
Finally, the high dose
group was accidentally

exposed to
concentrations of 1500
ppm for 3 days during
the first week.

Low

3

1

3

9. Reporting of
Doses/Concentratio
ns

Concentrations were
measured using infrared
spectrophotometry and
analytical results were

reported. Mean
analytical values were
within 10% of nominal.
Analytical method was
less than ideal, and it is

unclear whether the
measurements were in
the animals' breathing
zones. Time to achieve
desired exposure
concentration in the
chambers was not
reported,.

Low

3

2

6

10. Exposure
Frequency and
Duration

Frequency (6 hr/d, 5
d/wk) and duration (12
mo) of exposure were
reported and
appropriate for
noncancer endpoints.

High

1

1

1

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Dow Chem, Co (1978). Results of a long-term inhalation toxicity study on rats of a perchloroethylene
(tetrachloroethylene) formulation #journal#, #volume#(#issue#), #Pages#

HERO ID: 4214237

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score



11. Number of
Exposure Groups
and Dose Spacing

Two exposure
concentrations differing
2-fold were tested; these
were selected based on

multiples of the
maximum permissible
excursion concentration
fromACGIH. Little to no
toxicity was reported,
suggesting that the high
concentration may not
have been high enough.

Low

3

1

3

12. Exposure Route
and Method

Route and method were
reported and
appropriate (dynamic
whole body chamber
was used for vapor that
may condense.)

Medium

2

1

2

Test Organism

13. Test Animal
Characteristics

Test animal species,
strain, sex, age, source,
and body weight were

reported; however,
authors did not report
acclimation or pathogen

testing/health status
prior to study initiation.

Medium

2

2

4

14. Adequacy and

Consistency of
Animal Husbandry
Conditions

Animal husbandry
conditions (temperature,

humidity, light-dark
cycle, housing) were not
reported.

Low

3

1

3

15. Number per
Group

Exposed groups
consisted of 96/sex and
controls consisted of
192/sex.

High

1

1

1

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PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Dow Chem, Co (1978). Results of a long-term inhalation toxicity study on rats of a perchloroethylene
(tetrachloroethylene) formulation #journal#, #volume#(#issue#), #Pages#

HERO ID: 4214237

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

Outcome
Assessment

16. Outcome
Assessment
Methodology

Nearly all evaluations
took place 12 to 19
months after the end of
exposure. Hematology
(with the exception of a
small number of animals
evaluated earlier),
clinical chemistry, and
urinalysis evaluations
were performed 12
months after exposure
ended or at terminal
necropsy up to 19
months after the end of
exposure. Except for
groups of 3
rats/sex/exposure, organ

weight and pathology
assessments occurred at
death/moribund
sacrifice or at study
termination 19 months
after exposure ended.
Hematology and clinical
chemistry methods were
not reported.

Unacceptable

4

2

8

17. Consistency of
Outcome
Assessment

Outcome assessment
was performed
consistently across
groups. Apart from the
unexplained loss of a few
rats per group, which
was evaluated under

health outcomes
unrelated to exposure,
no inconsistencies in the
execution were noted.

Medium

2

1

2

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Dow Chem, Co (1978). Results of a long-term inhalation toxicity study on rats of a perchloroethylene
(tetrachloroethylene) formulation #journal#, #volume#(#issue#), #Pages#

HERO ID: 4214237

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score



18. Sampling
Adequacy

Sampling of endpoints at
the end of exposure was
not adequate; only
3/sex/group were
sacrificed for organ

weights and
histopathology at the
end of the 12 month
exposure. This number
is too small to discern
subtle differences.

Unacceptable

4

1

4

19. Blinding of
Assessors

Blinding was not
reported for subjective
outcomes consisting of
cageside observations.
Other endpoints were
not subjective and/or
blinding is not typical.

Not Rated

NA

NA

NA

20. Negative Control
Response

Control responses were
reported and appeared
to be adequate and
without excessive
variability.

High

1

1

1

Confounding /
Variable Control

21. Confounding
Variables in Test
Design and
Procedures

No information on
respiratory rates or
indications of reflex
bradypnea was reported.
Food and water intake
during the study were
not reported.

Low

3

2

6

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Dow Chem, Co (1978). Results of a long-term inhalation toxicity study on rats of a perchloroethylene
(tetrachloroethylene) formulation #journal#, #volume#(#issue#), #Pages#

HERO ID: 4214237

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

22. Health
Outcomes Unrelated
to Exposure

Study authors reported

unexplained
discrepancies between
initial animal numbers

and final animal
numbers (instead of
96/sex/exposure group
and 192/sex controls, 91
to 94/sex/exposure
group and 189/sex
controls were accounted

for). However, the
remaining numbers were
sufficient to observe an
effect and the attrition

appeared to be
essentially consistent
across groups so this
discrepancy was not
considered
unacceptable.

Low

Data Presentation
and Analysis

23. Statistical
Methods

Statistical analyses were
performed and
described, and
appropriate to the
endpoints.

High

24. Reporting of
Data

All data were reported

with measures of
variability and numbers
evaluated.

High

High: >=1 and <1.7
Medium: >=1.7 and <2.3
Low: >=2.3 and <=3

Sum of scores:

Overall Score = Sum of Weighted Scores/Sum
of Metric Weighting Factors:

2.4138

Overall Score:
Nearest *:

2.41

Overall Quality Level:

Unacceptable1

Study Quality
Comment:

Footnote 1: Consistent with our Application of A Systematic Review in TSCA Risk Evaluations document, if a metric
for a data source receives a score of Unacceptable (score = 4), EPA will determine the study to be unacceptable. In
this case, two of the metrics were rated as unacceptable. As such, the study is considered unacceptable and the

score is presented solely to increase transparency.

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PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

4.2. Animal toxicity evaluation results of Halogenated Solvents, Indust for a multigen
inhalation study in rats on reproductive, renal, hepatic, growth (early life) and
development, neurological/behavior, nutrition and metabolic/adult exposure
body weight outcomes

Study reference:

Halogenated Solvents, Indus (1995). Perchloroethylene: multigeneration inhalation study in the rat, with cover
letter dated 07/06/95 #journal#, #volume#(#issue#), #Pages#

HERO ID: 4214380

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

Test Substance

1. Test Substance
Identity

Test substance identified
by unambiguous name

High

2. Test Substance
Source

Test substance source
and lot number was
identified and certificate
of analysis provided.

High

3. Test Substance
Purity

Test substance purity
reported to be 99.9%
(w/w).

High

Test Design

4. Negative and
Vehicle Controls

Study does not explicitly
state that controls were

sham-treated, but
descriptions of exposure
imply sham-treatment:

"the females in the
control, 300, and 1000
ppm groups were
exposed"

Medium

5. Positive Controls

Positive controls not
typical for this study type

Not Rated

6. Randomized
Allocation

Study reports allocation
method, which was semi
random while preventing
sibling matings.

Medium

Exposure
Characterization

7. Preparation and
Storage of Test
Substance

Preparation and storage

conditions were
reported, and stability
was satisfactory.
Methods for test
atmosphere generation

were reported and
appropriate. Air changes

per hour were
appropriate (>10 based
on chamber volume of
3400 L and air flow rate
of 700 L/min).

High

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PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Halogenated Solvents, Indus (1995). Perchloroethylene: multigeneration inhalation study in the rat, with cover
letter dated 07/06/95 #journal#, #volume#(#issue#), #Pages#

HERO ID: 4214380

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

8. Consistency of

Exposure
Administration

Animals were exposed in
cages arranged vertically
in the exposure
chamber, which could
allow for some
inconsistencies in
breathing zone
concentrations if vertical
mixing was inadequate
(Perc is much more
dense than air). In
addition, the exposure

frequency varied
between 5 and 7 days
per week at different
phases of the study, but
the frequencies were the
same across different
exposure groups.

Medium

9. Reporting of
Doses/Concentratio
ns

Analytical concentrations
were reported and mean
values were within 10%
of nominal at all phases..

High

10. Exposure
Frequency and
Duration

Exposure frequency and
duration were typical for
this study type

High

11. Number of
Exposure Groups
and Dose Spacing

Three nonzero exposure
groups were used, with
half log spacing.
Exposure range was
sufficient to enable
identification of effect
levels.

High

12. Exposure Route
and Method

Inhalation study,
adequately described

High

Test Organism

13. Test Animal
Characteristics

Species, strain, sex,
health status, age, body
weight, and source were
reported and
appropriate.

High

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Halogenated Solvents, Indus (1995). Perchloroethylene: multigeneration inhalation study in the rat, with cover
letter dated 07/06/95 #journal#, #volume#(#issue#), #Pages#

HERO ID: 4214380

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score



14. Adequacy and

Consistency of
Animal Husbandry
Conditions

Authors noted that
faulty light switches
altered the light cycle for
F0 parents and this
alteration may have
been responsible for
reduced pre-coital
interval in exposed
groups.

Low

3

1

3

15. Number per
Group

All groups consisted of
24/sex. EPA guidelines
call for group size
yielding 20 pregnant
females so group size
was appropriate.

High

1

1

1

Outcome
Assessment

16. Outcome
Assessment
Methodology

Outcome assessment
methodology was
reported. Neither sperm
parameters nor estrus
cyclicity was evaluated;
water intake was not
measured. In addition,
only testes, kidneys, and

liver weights were
obtained (EPAguidelines
recommend several
other organ weights),
and histopathology did

not include organs
typically assessed in this
study type (e.g., pituitary
and adrenal glands).

Ages at vaginal
opening/preputial
separation were not
evaluated in F1
offspring.

Medium

2

2

4

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PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Halogenated Solvents, Indus (1995). Perchloroethylene: multigeneration inhalation study in the rat, with cover
letter dated 07/06/95 #journal#, #volume#(#issue#), #Pages#

HERO ID: 4214380

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

17. Consistency of
Outcome
Assessment

Histopathology
examinations were not

consistent across
animals. Histopathology
examinations were
initially limited to liver
and kidney of control
and high dose animals,
and reproductive organs
of suspected infertile
animals. Additional
groups were evaluated

for liver and kidney
histopathology but the
assessment was not
consistent across groups.
Histologic examination
of testes was extended
to fertile F1 males,
necessitating re-
examination of infertile
males for consistency.

Medium

18. Sampling
Adequacy

Sampling was reported

and appropriate;
endpoints evaluated in
all exposed animals.

High

19. Blinding of
Assessors

Study did not report
blinding for clinical
observations, but the
main outcomes assessed
were not subjective.

Not Rated

20. Negative Control
Response

Control responses were
reported and appeared
to be appropriate.

High

Confounding /
Variable Control

21. Confounding
Variables in Test
Design and
Procedures

No confounding factors
apart from the lighting
malfunction in the first
generation were noted.
Respiratory rate was not
reported.

Medium

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PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Halogenated Solvents, Indus (1995). Perchloroethylene: multigeneration inhalation study in the rat, with cover
letter dated 07/06/95 #journal#, #volume#(#issue#), #Pages#

HERO ID: 4214380

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score



22. Health
Outcomes Unrelated
to Exposure

Authors noted that there

was no evidence of
disease or infection that
might have affected
outcomes.

High

1

1

1

Data Presentation
and Analysis

23. Statistical
Methods

Statistical analysis was
performed, described,
and appropriate to the
outcomes.

High

1

1

1

24. Reporting of
Data

All data were presented
graphically or in tabular
form, with measures of
variability.

High

1

2

2

High: >=1 and <1.7
Medium: >=1.7 and <2.3
Low: >=2.3 and <=3

Sum of scores:



29

40

Overall Score = Sum of Weighted Scores/Sum
of Metric Weighting Factors:

NA

Overall Score:
Nearest *:

NA

Overall Quality Level:

Medium

Study Quality
Comment:

The reviewer downgraded this study's overall quality rating. They noted: Study was generally well conducted but
evaluations were limited and performed inconsistently Note: The original calculated score for this study was 1.3.
This value is not presented above because the final rating was changed based on professional judgement.

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PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

4.3. Animal toxicity evaluation results of NTP 1986 for 13-week inhalation studies in
rats and mice on reproductive, hematological and immune, neurological/behavior,
renal, hepatic, cardiovascular, endocrine, gastrointestinal, mortality, nutrition and
metabolic/adult exposure body weight, respiratory, skin and connective tissue,
and thyroid outcomes

Study reference:

Ntp, (1986). Toxicology and carcinogenesis studies of tetrachloroethylene (perchloroethylene) (CAS no. 127-18-
4) in F344/N rats and B6C3F1 mice (inhalation studies)

HERO ID: 632655

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

1. Test Substance
Identity

high-purity
tetrachloroethylene,
Dowper stabilized

High

Test Substance

2. Test Substance
Source

Dow Chemical, lot
TA03116F-01. Purity and
identity analyses
conducted.

High

3. Test Substance
Purity

Confirmed analytically -
approximately 99.9%

High

4. Negative and
Vehicle Controls

Chamber controls were
used.

High

Test Design

5. Positive Controls

Not needed for study
type.

Not Rated

6. Randomized
Allocation

computer generated
tables of random
numbers

High

Exposure
Characterization

7. Preparation and
Storage of Test
Substance

Tetrachloroethylene was
found to be stable for 2
weeks at 60" C
(Appendix H).
Tetrachloroethylene was

stored at 0" C
Tetrachloroethylene was

vaporized at 100"-
110" C, diluted with air,
and. introduced into the

chambers. Detailed
descriptions in Table 2
and in Appendix 1.

High

8. Consistency of

Exposure
Administration

Concentrations in the
exposure chambers were

monitored 8-12 times
per exposure period by a
Hewlett-Packard 5840A
Gas Chromatograph. No
deviations from protocol
noted.

High

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PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Ntp, (1986). Toxicology and carcinogenesis studies of tetrachloroethylene (perchloroethylene) (CAS no. 127-18-
4) in F344/N rats and B6C3F1 mice (inhalation studies)

HERO ID: 632655

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

9. Reporting of
Doses/Concentratio
ns

Only target
concentrations reported
for non-chronic studies.,

but actual exposures
expected to be close to
target based on 2-yr
analytical values.

Medium

10. Exposure
Frequency and
Duration

13-wk, 6 hr/d, 5 d/wk.

High

11. Number of
Exposure Groups
and Dose Spacing

5 dose groups plus
control

High

12. Exposure Route
and Method

Inhalation, dynamic
whole-body chamber.
Flow rate not reported

Low

Test Organism

13. Test Animal
Characteristics

F344/N rats and B6C3F1
mice, Charles River
Breeding. 7-9 wks at
study initiation. Initial
body weights reported in
Tables 8, and 19.

High

14. Adequacy and

Consistency of
Animal Husbandry
Conditions

Details of husbandry in
Table 5

High

15. Number per
Group

10/sex/group

High

Outcome
Assessment

16. Outcome
Assessment
Methodology

Mortality, clinical signs,
body weight,
comprehensive
histopathology

High

17. Consistency of
Outcome
Assessment

The majority of
organs/tissues were only
evaluated in control and

high-dose groups.
Organs with exposure-
related findings were
evaluated in lower-dose
groups as needed.

High

18. Sampling
Adequacy

10/sex/group

High

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PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Ntp, (1986). Toxicology and carcinogenesis studies of tetrachloroethylene (perchloroethylene) (CAS no. 127-18-
4) in F344/N rats and B6C3F1 mice (inhalation studies)

HERO ID: 632655

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

19. Blinding of
Assessors

Evaluated endpoints did
not require blinding

Not Rated

20. Negative Control
Response

Control responses
reported.

High

Confounding /
Variable Control

21. Confounding
Variables in Test
Design and
Procedures

There were no reported
differences among the
study groups in initial
body weight. Food and
water intake were not
reported. Respiratory
rate was not specifically

mentioned, but no
exposure-related clinical
signs were reported.
While there is no
evidence of bradypnea.

Animal temperature
should be measured to
rule out bradypnea.

Medium

22. Health
Outcomes Unrelated
to Exposure

data on attrition and/or

health outcomes
unrelated to exposure
for each study group
were not reported
because only substantial
differences among
groups were noted

Medium

Data Presentation
and Analysis

23. Statistical
Methods

Detailed statistical tests
reported for survival and
tumor analysis of 2-yr
study, unclear if any

statistics were
conducted on shorter-
duration studies.. Data
for mortality, terminal
BW, liver and lung histo
findings (rat) and liver
and kidney findings
(mouse) were
adequately reported for
independent analysis.

Medium

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PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Ntp, (1986). Toxicology and carcinogenesis studies of tetrachloroethylene (perchloroethylene) (CAS no. 127-18-
4) in F344/N rats and B6C3F1 mice (inhalation studies)

HERO ID: 632655

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e., High, Medium, L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score



24. Reporting of
Data

Quantitative mortality,
body weight, and
exposure-related
nonneoplastic findings
(lung and liver in rats,
liver and kidney in mice).
Histological results from

other organs not
reported; assumed to be
no exposure-related
findings.. Exposure-
related clinical signs
reported qualitatively in
mice.

Low

3

2

6

High: >=1 and <1.7
Medium: >=1.7 and <2.3
Low: >=2.3 and <=3

Sum of scores:



29

41

Overall Score = Sum of Weighted Scores/Sum
of Metric Weighting Factors:

1.4138

Overall Score:
Nearest *:

1.4

Overall Quality Level:

High

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PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

4.4. Animal toxicity evaluation results of Tinston et al 1994 for a multigeneration
inhalation study on reproductive, growth (early life) and development, and renal
outcomes

Study reference:

Tinston, D. J. (1994). Perchloroethylene: A multigeneration inhalation study in the rat
HERO ID: 631041

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

Test Substance

1. Test Substance
Identity

Idenitified by chemical
name.

High

1

2

2

2. Test Substance
Source

Manufacturer and lot no.
were given.

High

1

1

1

3. Test Substance
Purity

99.9% pure

High

1

1

1

Test Design

4. Negative and
Vehicle Controls

filtered air

High

1

2

2

5. Positive Controls

Positive controls are not
used for multigeneration
studies.

Not Rated

NA

NA

NA

6. Randomized
Allocation

The F0 parents were
distributed amongst the
four experimental
groups after ensuring

that any litters
containing unhealthy
individuals and litters at
the extreme of the
weight range were
excluded from the
randomization
procedure. Allocation
from within the litters
was also at random. The
Fl, F1A and F2A litters
and normal pups from
each litter were
randomly selected.

High

1

1

1

Exposure
Characterization

7. Preparation and
Storage of Test
Substance

Preparation and storage

were well described;
analysis determined that
stability was satisfactory.

High

1

1

1

8. Consistency of

Exposure
Administration

Same exposure
frequency, chamber
design and animals per
chamber.

High

1

1

1

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PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Tinston, D. J. (1994). Perchloroethylene: A multigeneration inhalation study in the rat
HERO ID: 631041

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

9. Reporting of
Doses/Concentratio
ns

The authors report that
the daily mean analyzed

concentrations of
Perchloroethylene were
close to target.

High

10. Exposure
Frequency and
Duration

6h/day 5 day per week,
except during mating
and gestation (6h/day, 7
days/week)/

High

11. Number of
Exposure Groups
and Dose Spacing

3 exposure groups plus a
control, not justified by
study suthors, but dose
response relationships
were apparent.

Medium

12. Exposure Route
and Method

Whole body chamber;
unclear whether vapor
would condense; 12
exchanges/hour were
calculated from data
provided.

Medium

Test Organism

13. Test Animal
Characteristics

Species and source were
reported.

High

14. Adequacy and

Consistency of
Animal Husbandry
Conditions

All husbandry conditions
were reported.

High

15. Number per
Group

~25/sex/group

High

Outcome
Assessment

16. Outcome
Assessment
Methodology

The outcome assessment
methodology reported.

High

17. Consistency of
Outcome
Assessment

See footnote at end of
page.1

High

18. Sampling
Adequacy

F2C litter inlcuded
control and high dose
group only.

Medium

19. Blinding of
Assessors

Blinding not reported;
however outcomes were
objective.

Not Rated

1 Metrics that received a "High" rating met the criteria as discussed in the Applications of Systematic Review for
TSCA Risk Evaluation.

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Tinston, D. J. (1994). Perchloroethylene: A multigeneration inhalation study in the rat
HERO ID: 631041

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e., High, Medium, L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score



20. Negative Control
Response

Some clinical signs and
histopath. lesions in
controls.

Medium

2

1

2



21. Confounding
Variables in Test
Design and
Procedures

Increased breathing rate
was observed at 300
ppm; breathing
irregulaties occurred at
1000 ppm;

Low

3

2

6

Confounding /
Variable Control

22. Health
Outcomes Unrelated
to Exposure

Problems with the
lighting in the early part
of the mating period;
changes in pre-coital
interval resulted from
alterations in the
photoperiod.

Low

3

1

3

Data Presentation
and Analysis

23. Statistical
Methods

Statistical methods were
clearly described.

High

1

1

1

24. Reporting of
Data

Data tables were
provided for all
outcomes.

High

1

2

2





Sum of scores:



29

39

High: >=1 and <1.7
Medium: >=1.7 and <2.3

Overall Score = Sum of Weighted Scores/Sum
of Metric Weighting Factors:

1.3448

Overall Score:
Nearest *:

1.3

Low: >=2.3 and <=3















Overall Quality Level:



High

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PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

5. Cancer Studies

5.1. Animal toxicity evaluation results of Dow et al 1978 for a 12 month inhalation
study in rats, with lifetime observation (cancer) on cancer outcomes

Study reference:

Dow Chem, Co (1978). Results of a long-term inhalation toxicity study on rats of a perchloroethylene
(tetrachloroethylene) formulation

HERO ID: 4214237

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

Test Substance

1. Test Substance
Identity

Test substance identified
by name and CASRN

High

2. Test Substance
Source

Test substance was
identified by lot number
and verified analytically,
with results presented.

High

3. Test Substance
Purity

Purity was not reported
explicitly, but based on
GC results and reported
percentages of
contaminants, test
substance was >99%
(vol%) perc (impurities
comprised 63 ppm vol %)

Medium

Test Design

4. Negative and
Vehicle Controls

Negative controls were
not sham-exposed, but
rather held in the room
where exposed animals
were housed when not
in exposure chambers.

Low

5. Positive Controls

Positive controls not
typical for this study type

Not Rated

6. Randomized
Allocation

Study reported random
allocation

High

Exposure
Characterization

7. Preparation and
Storage of Test
Substance

Medium

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PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Dow Chem, Co (1978). Results of a long-term inhalation toxicity study on rats of a perchloroethylene
(tetrachloroethylene) formulation

HERO ID: 4214237

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score



8. Consistency of

Exposure
Administration

Control animals were not
sham-exposed. Authors

report that exposures
during first 5 months ran
at the same time in both
exposed groups, but
thereafter they ran at
different times of day
(low dose in morning
and high dose in
evening) using the same
exposure chamber.
Finally, the high dose
group was accidentally

exposed to
concentrations of 1500
ppm for 3 days during
the first week.

Low

3

1

3

9. Reporting of
Doses/Concentratio
ns

Concentrations were
measured using infrared
spectrophotometry and
analytical results were

reported. Mean
analytical values were
within 10% of nominal.
Analytical method was
less than ideal, and it is

unclear whether the
measurements were in
the animals' breathing
zones. Time to achieve
desired exposure
concentration in the
chambers was not
reported,.

Low

3

2

6

10. Exposure
Frequency and
Duration

Duration (12 mo) of
exposure is not
considered adequate for
cancer endpoints.

Low

3

1

3

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Dow Chem, Co (1978). Results of a long-term inhalation toxicity study on rats of a perchloroethylene
(tetrachloroethylene) formulation

HERO ID: 4214237

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score



11. Number of
Exposure Groups
and Dose Spacing

Two exposure
concentrations differing
2-fold were tested; these
were selected based on

multiples of the
maximum permissible
excursion concentration
fromACGIH. Little to no
toxicity was reported,
suggesting that the high
concentration may not
have been high enough.

Low

3

1

3

12. Exposure Route
and Method

Route and method were
reported and
appropriate (dynamic
whole body chamber
was used for vapor that
may condense.)

Medium

2

1

2

Test Organism

13. Test Animal
Characteristics

Test animal species,
strain, sex, age, source,
and body weight were

reported; however,
authors did not report
acclimation or pathogen

testing/health status
prior to study initiation.

Medium

2

2

4

14. Adequacy and

Consistency of
Animal Husbandry
Conditions

Animal husbandry
conditions (temperature,

humidity, light-dark
cycle, housing) were not
reported.

Low

3

1

3

15. Number per
Group

Exposed groups
consisted of 96/sex and
controls consisted of
192/sex.

High

1

1

1

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PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Dow Chem, Co (1978). Results of a long-term inhalation toxicity study on rats of a perchloroethylene
(tetrachloroethylene) formulation

HERO ID: 4214237

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

Outcome
Assessment

16. Outcome
Assessment
Methodology

Except for groups of 3
rats/sex/exposure,
histopathology
assessments occurred at
death/moribund
sacrifice or at study
termination 19 months
after exposure ended.
This very long
postexposure
observation period may
have resulted in tumor
regression.

Unacceptable

4

2

8

17. Consistency of
Outcome
Assessment

Outcome assessment
was performed
consistently across
groups. Apart from the
unexplained loss of a few
rats per group, which
was evaluated under

health outcomes
unrelated to exposure,
no inconsistencies in the
execution were noted.

Medium

2

1

2

18. Sampling
Adequacy

Sampling of endpoints at
the end of exposure was
not adequate; only
3/sex/group were
sacrificed for
histopathology at the
end of the 12 month
exposure. This number
is too small to discern
differences in tumor
incidences.

Unacceptable

4

1

4

19. Blinding of
Assessors

Blinding is not typical for
initial histopathology
review.

High

1

1

1

20. Negative Control
Response

Control responses were
reported and appeared
to be adequate and
without excessive
variability.

High

1

1

1

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Dow Chem, Co (1978). Results of a long-term inhalation toxicity study on rats of a perchloroethylene
(tetrachloroethylene) formulation

HERO ID: 4214237

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

21. Confounding
Variables in Test
Design and
Procedures

No information on
respiratory rates or
indications of reflex
bradypnea was reported.
Food and water intake
during the study were
not reported.

Low

Confounding /
Variable Control

22. Health
Outcomes Unrelated
to Exposure

Study authors reported

unexplained
discrepancies between
initial animal numbers

and final animal
numbers (instead of
96/sex/exposure group
and 192/sex controls, 91
to 94/sex/exposure
group and 189/sex
controls were accounted

for). However, the
remaining numbers were
sufficient to observe an
effect and the attrition

appeared to be
essentially consistent
across groups so this
discrepancy was not
considered
unacceptable.

Low

Data Presentation

23. Statistical
Methods

Statistical analyses were
performed and
described, and
appropriate to the
endpoints.

High

and Analysis

24. Reporting of
Data

Tumor incidences were
reported with numbers
of animals evaluated for
each organ and
timepoint..

High

High: >-1 and <1.7
Medium: >=1.7 and <2.3
Low: >=2.3 and <=3

Sum of scores:

Overall Score = Sum of Weighted Scores/Sum
of Metric Weighting Factors:

2.2333

Overall Score:
Nearest *:

2.21

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Dow Chem, Co (1978). Results of a long-term inhalation toxicity study on rats of a perchloroethylene
(tetrachloroethylene) formulation

HERO ID: 4214237

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score



Overall Quality Level:

Unacceptable1

Study Quality
Comment:

Footnote 1: Consistent with our Application of A Systematic Review in TSCA Risk Evaluations document, if a metric
for a data source receives a score of Unacceptable (score = 4), EPA will determine the study to be unacceptable. In
this case, two of the metrics were rated as unacceptable. As such, the study is considered unacceptable and the

score is presented solely to increase transparency.

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PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

5.2. Animal toxicity evaluation results of Jisa et al 1993 for a cancer bioassay study on

cancer; nutrition and metabolic/adult exposure body weight outcomes

Study reference:

Jisa, (1993). Carcinogenicity study of tetrachloroethylene by inhalation in rats and mice
HERO ID: 630653

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score



1. Test Substance
Identity

Structural formula,
CASRN, physiochemical
properties were
provided

High

1

2

2

Test Substance

2. Test Substance
Source

Source and lot numbers
provided; identity
verified by mass spec
and infrared absorption
spectrum of each lot

High

1

1

1



3. Test Substance
Purity

Purity such that effects
likely due to test
subsstance

High

1

1

1



4. Negative and
Vehicle Controls

Concurrent negative
controls were included

High

1

2

2

Test Design

5. Positive Controls

Positive control animals
were not required for
this study

Not Rated

NA

NA

NA

6. Randomized
Allocation

Animals assigned to each
treatment group by
grouping method
(optimal stratification
system).

Medium

2

1

2



7. Preparation and
Storage of Test
Substance

Method of generating
vapor and storage was
described in detail and
appropriate

High

1

1

1



8. Consistency of

Exposure
Administration

Exposures were
administered
consistently

High

1

1

1

Exposure
Characterization

9. Reporting of
Doses/Concentratio
ns

Nominal and analytical
concentrations were

reported,
tetrachloroethylene
concentration inside the
inhalation chamber was
determined before
exposure started and
then every 15 minutes
until exposure was
completed using GC.

High

1

2

2

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PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Jisa, (1993). Carcinogenicity study of tetrachloroethylene by inhalation in rats and mice
HERO ID: 630653

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score



10. Exposure
Frequency and
Duration

The frequency and
duration were reported
and appropriate

High

1

1

1



11. Number of
Exposure Groups
and Dose Spacing

The rationale for the
exposure concentrations
and number of groups
were reported.

High

1

1

1



12. Exposure Route
and Method

The route and method of
exposure were
adequate.

High

1

1

1



13. Test Animal
Characteristics

Species, age, health, sex,
starting body weight
provided for both rats
and mice

High

1

2

2

Test Organism

14. Adequacy and

Consistency of
Animal Husbandry
Conditions

Conditions were
reported and the same
across groups.

High

1

1

1



15. Number per
Group

The number was
reported and
appropriate.
50/sex/group

High

1

1

1



16. Outcome
Assessment
Methodology

The outcome assessment
methodology addressed
the intended outcomes
of interest

High

1

2

2

Outcome

17. Consistency of
Outcome
Assessment

Outcomes assess
consistently across
groups

High

1

1

1

Assessment

18. Sampling
Adequacy

Sampling was adequate
for the outcomes

High

1

1

1



19. Blinding of
Assessors

Blinding not required

Not Rated

NA

NA

NA



20. Negative Control
Response

Negative responses were
adequate

High

1

1

1

Confounding /
Variable Control

21. Confounding
Variables in Test
Design and
Procedures

No confounding variable
reported

High

1

2

2

22. Health
Outcomes Unrelated
to Exposure

No confounding
variables reported

High

1

1

1

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PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Jisa, (1993). Carcinogenicity study of tetrachloroethylene by inhalation in rats and mice
HERO ID: 630653

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

Data Presentation
and Analysis

23. Statistical
Methods

Statistical methods were
appropriate

High

1

1

1

24. Reporting of
Data

Data for non-cancer
endpoints summarized in
text, but specific details
not provided.

Medium

2

2

4

High: >=1 and <1.7
Medium: >=1.7 and <2.3
Low: >=2.3 and <=3

Sum of scores:



29

32

Overall Score = Sum of Weighted Scores/Sum
of Metric Weighting Factors:

1.1034

Overall Score:
Nearest *:

1.1

Overall Quality Level:

High

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PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

5.3. Animal toxicity evaluation results of Natl Institute of Health 1977 for a 78-week
cancer bioassay (rats and mice) study on cancer, mortality, respiratory, hepatic,
renal, thyroid, cardiovascular, neurological/behavior, nutrition and
metabolic/adult exposure body weight, hematological and immune, skin and
connective tissue, and gastrointestinal outcomes	

Study reference:

Natl Inst Of, Health (1977). Bioassay of tetrachloroethylene for possible carcinogenicity
HERO ID: 4214470

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

Test Substance

1. Test Substance
Identity

The test substance was
identified definitively.

High

1

2

2

2. Test Substance
Source

The source of the test
substance was reported,
including manufacturer.
A lot/batch number was
not reported.

Medium

2

1

2

3. Test Substance
Purity

The purity was reported
by the manufacturer (at
least 99%). The study
report also stated that
gas-liquid
chromatography showed

the major component
consisting of over 99% of
the total peak area, with

a minor impurity
present, which was not
identified.

Medium

2

1

2

Test Design

4. Negative and
Vehicle Controls

The study authors
reported using an
appropriate concurrent
control group (vehicle
control and untreated
control groups.)

High

1

2

2

5. Positive Controls

Positive control is not
indicated for the study
type.

Not Rated

NA

NA

NA

6. Randomized
Allocation

The study did not report
how animals were
allocated to study
groups.

Low

3

1

3

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Natl Inst Of, Health (1977). Bioassay of tetrachloroethylene for possible carcinogenicity
HERO ID: 4214470

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

Exposure
Characterization

7. Preparation and
Storage of Test
Substance

The test substance
preparation and storage

conditions were
reported but there were
minor limitations in the
test substance
preparation. The test
substance was prepared

weekly, sealed, and
stored at 34 degrees F,
which the study authors
noted were considered
conditions that would
allow test substance to
remain stable for 10
days. However, no
report of stability in the
vehicle (corn oil), or of
PERC in the prepared
solutions, was reported.

Medium

2

1

2

8. Consistency of

Exposure
Administration

Details of exposure
administration were not
fully reported (volume
administered by gavage
was not reported).

Low

3

1

3

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Natl Inst Of, Health (1977). Bioassay of tetrachloroethylene for possible carcinogenicity
HERO ID: 4214470

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score



9. Reporting of
Doses/Concentratio
ns

Initial administered
doses were reported;
however, dose levels
were raised and/or
lowered during the study
in both rats and mice
based on clinical signs

and there is some
ambiguity in the actual
dose levels after
adjustment and the
exact days during the
study when doses were
raised and/or lowered
(only reported in weeks).
For example, for rats, the
study authors stated that

the low doses were
adjusted accordingly, so
that they consistently
remained one-half of the
high dose but actual
adjusted dose levels
were not reported (p. 11
of the study report).

Low

3

2

6

10. Exposure
Frequency and
Duration

Exposure frequency (5
consecutive d/wk) was
reported and acceptable.
However, the exposure
duration was shorter
than studies of similar
type (i.e., 2 years for
carcinogenicity studies is
typical for rodents) and
was not justified by the
study authors. In this
study, animals were
dosed for 78 weeks
followed by an
observation period of 32
weeks in rats and 12
weeks in mice.

Medium

2

1

2

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Natl Inst Of, Health (1977). Bioassay of tetrachloroethylene for possible carcinogenicity
HERO ID: 4214470

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score



11. Number of
Exposure Groups
and Dose Spacing

The number of exposure
groups was considered

adequate for the
purpose of the study.
However, the highest
doses produced a high
rate of early mortality in

both rats and mice,
which the study authors
noted may indicate that
the optimum dose was
exceeded in both
species.

Medium

2

1

2

12. Exposure Route
and Method

The route and method of
exposure were reported
and were suited to the
test substance.

High

1

1

1

Test Organism

13. Test Animal
Characteristics

The test animal source,
species, strain, sex, age,
and starting body weight
were reported. However,
health status at the
beginning of the study
was not reported.

Medium

2

2

4

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PEER REVIEW DRAFT. DO NOT CITE OR QUOTE



14. Adequacy and

Consistency of
Animal Husbandry
Conditions

The study authors stated
that housing rooms were

maintained in a
temperature range of 20
to 24 deg C, a relative
humidity of 45 to 55%,
with a 12-hour light cycle

and 12 complete
changes of room air per
hour. However, some
differences between
PERC-treated /
untreated control
animals and the vehicle
control animals were
reported, which included
that PERC-treated /
untreated control rats
were housed in one
room while the vehicle
control rats were housed
in another room. The
study authors also
reported that the vehicle

control rats were
approximately 4 weeks
older than rats in the
PERC-treated and
untreated control groups
and, therefore, were
started on the test 4
weeks earlier. Similarly,
vehicle control mice
were approximately 2
weeks older than mice in
the other groups and,
therefore, were started
on the test earlier. Due
to starting the vehicle
control rats and mice
earlier than animals of
other groups, and
housing of vehicle
control rats and a
different room than
other rats, there may
have been some
differences in husbandry
/ exposure conditions.

Low

3

1

3

15. Number per
Group

The number of animals

in the PERC-treated
groups (50/sex/group)
was reported,
appropriate for the study

type and outcome
analysis, and consistent

Medium

2

1

2

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Natl Inst Of, Health (1977). Bioassay of tetrachloroethylene for possible carcinogenicity
HERO ID: 4214470

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score





with studies of the same
or similar type; however,
the number of animals in
each of the two control
groups (vehicle and
untreated each had
20/sex/group) was lower
than the typical number
used in studies of the
same or similar type.











16. Outcome
Assessment
Methodology

The outcome assessment
methodology addressed
or reported the intended
outcomes of interest and
was sensitive for the
outcomes of interest.

High

1

2

2



17. Consistency of
Outcome
Assessment

Details of the outcome
assessment protocol
were reported and
outcomes were assessed
consistently across study
groups.

High

1

1

1

Outcome
Assessment

18. Sampling
Adequacy

Details regarding
sampling for the
outcomes of interest
were reported and the
study used adequate

sampling for the
outcomes of interest.

High

1

1

1



19. Blinding of
Assessors

No subjective outcomes
were reported and
histopathology
examinations were not
described as a re-
evaluation

Not Rated

NA

NA

NA



20. Negative Control
Response

The biological responses
of the negative control
groups were adequate.

High

1

1

1

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Natl Inst Of, Health (1977). Bioassay of tetrachloroethylene for possible carcinogenicity
HERO ID: 4214470

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

Confounding /
Variable Control

21. Confounding
Variables in Test
Design and
Procedures

There were minor
uncertainties regarding
biological responses of
the negative control. For
example, in mice, while
no appreciable
differences in body
weight gain were
observed between PERe-
treated and untreated
mice, PERC-treated male
mice gained less than
vehicle control animals
after the first three
months and PERC-
treated female mice
gained less than vehicle
control animals during
the second year of the

bioassay. These
differences are unlikely
to have a substantial
impact on results.

Medium

2

2

4

22. Health
Outcomes Unrelated
to Exposure

Data on attrition and/or

health outcomes
unrelated to exposure
for each study group
were not reported
because only substantial
differences among
groups were noted.

Medium

2

1

2

Data Presentation
and Analysis

23. Statistical
Methods

The statistical methods
were clearly described
by the study authors and
were appropriate for
datasets.

High

1

1

1

24. Reporting of
Data

Some data are reported

incompletely. For
example, incidences for
reported clinical signs
were not reported.
Severity scores were not
reported for non-
neoplastic data.

Low

3

2

6



Sum of scores:



29

54

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

Natl Inst Of, Health (1977). Bioassay of tetrachloroethylene for possible carcinogenicity
HERO ID: 4214470

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e., High, Medium, L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

High: >=1 and <1.7
Medium: >-1.7 and <2.3
Low: >=2.3 and <=3

Overall Score = Sum of Weighted Scores/Sum
of Metric Weighting Factors:

1.8621

Overall Score:
Nearest *:

1.9

Overall Quality Level:

Medium

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

5.4. Animal toxicity evaluation results of NTP 1986 for 2-year cancer biossay, inhalation
studies in rats and mice on cancer, reproductive, hematological and immune,
neurological/behavior, renal, hepatic, cardiovascular, endocrine, gastrointestinal,
mortality, nutrition and metabolic/adult exposure body weight, respiratory, skin
and connective tissues, thyroid outcomes

Study reference:

NTP (1986). Toxicology and carcinogenesis studies of tetrachloroethylene (perchloroethylene) (CAS no. 127-18-
4) in F344/N rats and B6C3F1 mice (inhalation studies)

HERO ID: 632655

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

Test Substance

1. Test Substance
Identity

high-purity
tetrachloroethylene,
Dowper stabilized

High

2. Test Substance
Source

Dow Chemical, lots
TA03116F-01 and
TA08190D. Purity and
identity analyses
conducted.

High

3. Test Substance
Purity

Confirmed analytically

for both lots -
approximately 99.9%

High

Test Design

4. Negative and
Vehicle Controls

Chamber controls were
used.

High

5. Positive Controls

Not needed for study
type.

Not Rated

6. Randomized
Allocation

computer generated
tables of random
numbers.

High

Exposure
Characterization

7. Preparation and
Storage of Test
Substance

Tetrachloroethylene was
found to be stable for 2
weeks at 60" C
(Appendix H).
Tetrachloroethylene was

stored at 0" C
Tetrachloroethylene was

vaporized at 100"-
110" C, diluted with air,
and. introduced into the

chambers. Detailed
descriptions in Table 2
and in Appendix 1.

High

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

NTP (1986). Toxicology and carcinogenesis studies of tetrachloroethylene (perchloroethylene) (CAS no. 127-18-
4) in F344/N rats and B6C3F1 mice (inhalation studies)

HERO ID: 632655

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score



8. Consistency of

Exposure
Administration

Concentrations in the
exposure chambers were

monitored 8-12 times
per exposure period by a
Hewlett-Packard 5840A
Gas Chromatograph. On

one occasion
(September 13,1982) in
the 2-year studies, the
concentration in the
400-

ppm chamber was 800
ppm for 12 minutes and

2,400 ppm for 48
minutes. Animals were
therefore not exposed at
all on September 14,
1982

Medium

2

1

2

9. Reporting of
Doses/Concentratio
ns

Target and analytical
exposure levels reported
for 2 yr study in rats and

mice only. Mean
analytical concentrations

(99.5, 201, 403 ppm)
very close to target (100,
200, 400 ppm).

High

1

2

2

10. Exposure
Frequency and
Duration

2-yr, 6 hr/d, 5 d/wk.

High

1

1

1

11. Number of
Exposure Groups
and Dose Spacing

2 dose groups plus
control

High

1

1

1

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

NTP (1986). Toxicology and carcinogenesis studies of tetrachloroethylene (perchloroethylene) (CAS no. 127-18-
4) in F344/N rats and B6C3F1 mice (inhalation studies)

HERO ID: 632655

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

Inhalation, dynamic
whole-body chamber.
Flow rate not reported

12. Exposure Route
and Method

For the chemistry data,
all of the available
records concerning
receipt, initial analysis,
and stability testing by
Midwest Research
Instiitute (MRI) were
examined. In addition,
records pertaining to
receipt, bulk chemical
analysis, generation of
chamber concentrations,
exposure chamber
monitoring, and gas
chromatographic
calibration by the study
laboratory were
examined.

Low

Test Organism

13. Test Animal
Characteristics

F344/N rats and B6C3F1
mice, Charles River
Breeding. 8-9 wks at
study initiation. Initial
BW reported in Tables
10 and 21, respectively.

High

14. Adequacy and

Consistency of
Animal Husbandry
Conditions

Details of husbandry in
Table 5

High

15. Number per
Group

49-50/sex/group per
species

High

Outcome
Assessment

16. Outcome
Assessment
Methodology

Mortality, clinical signs,
body weight,
comprehensive
histopathology

High

17. Consistency of
Outcome
Assessment

Consistent evaluation in
all study groups.

High

18. Sampling
Adequacy

49-50/sex/group

High

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

NTP (1986). Toxicology and carcinogenesis studies of tetrachloroethylene (perchloroethylene) (CAS no. 127-18-
4) in F344/N rats and B6C3F1 mice (inhalation studies)

HERO ID: 632655

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e.,High,Medium,L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

19. Blinding of
Assessors

For histo - Slides/tissues
are generally not
evaluated in a blind
fashion (i.e., without
knowledge of dose
group) unless the lesions
in question are subtle or

unless there is an
inconsistent diagnosis of
lesions by the laboratory

pathologist and
pathology work group.
Evaluated endpoints did
not require blinding.

Not Rated

20. Negative Control
Response

Control responses
reported. Historical
incidences of tumors in
control animals also
reported.

High

Confounding /
Variable Control

21. Confounding
Variables in Test
Design and
Procedures

There were no reported
differences among the
study groups in initial
body weight. Food and
water intake were not
reported. Respiratory
rate was not specifically

mentioned, but no
exposure-related clinical
signs were reported.
While there is no
evidence of bradypnea,

animal temperature
should be measured to
rule out bradypnea.

Medium

22. Health
Outcomes Unrelated
to Exposure

data on attrition and/or

health outcomes
unrelated to exposure
for each study group
were not reported
because only substantial
differences among
groups were noted

Medium

-------
PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Study reference:

NTP (1986). Toxicology and carcinogenesis studies of tetrachloroethylene (perchloroethylene) (CAS no. 127-18-
4) in F344/N rats and B6C3F1 mice (inhalation studies)

HERO ID: 632655

Domain

Metric

Eval Comment

Qualitative
Determination
[i.e., High, Medium, L
ow,Unacceptable,
or Not rated]

Metric
Score

Metric Weighting
Factor

Weighted
Score

Data Presentation
and Analysis

23. Statistical
Methods

Detailed statistical tests
reported for survival and
tumor analysis.

Appendices C and D
contain nonneoplastic
data reporting sufficient
for statistical analysis.
Body weight data not
adequate for
independent analysis (no
variance data)

Medium

2

1

2

24. Reporting of
Data

quantitative mortality,
body weight,
nonneoplastic, and
neoplastic data. Clinical
signs data not reported.

Medium

2

2

4

High: >=1 and <1.7
Medium: >=1.7 and <2.3
Low: >=2.3 and <=3

Sum of scores:



29

38

Overall Score = Sum of Weighted Scores/Sum
of Metric Weighting Factors:

1.3103

Overall Score:
Nearest *:

1.3

Overall Quality Level:

High

-------