Draft Risk Evaluation for Carbon Tetrachloride, Systematic Review Supplemental File: Data Quality Evaluation of Human Health Hazard Studies Animal and Invitro Studies


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vvEPA
United States	Office of Chemical Safety and
Environmental Protection Agency	Pollution Prevention
Risk Evaluation for
Carbon Tetrachloride
Systematic Review Supplemental File:
Data Quality Evaluation of Human Health Hazard Studies
Animal and In Vitro Studies
CASRN: 56-23-5
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January 2020
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Table of Contents
1.	Acute Toxicity Studies	4
1.1.	Animal toxicity evaluation results of Adams et al 1952 for an acute inhalation
toxicity study in rats on mortality outcomes	4
1.2.	Animal toxicity evaluation results of Adams et al 1952 for an acute inhalation
toxicity study in rats on neurological/behavior outcomes	9
1.3.	Animal toxicity evaluation results of Bruckner et al 1986 for a study on renal and
hepatic outcomes	14
1.4.	Animal toxicity evaluation results of Hayes et al 1986 for an acute oral lethality
study on mortality outcomes	22
1.5.	Animal toxicity evaluation results of Kronevi et al 1979 for an acute dermal study on
liver toxicity, kidney toxicity, and skin morphology outcomes	25
1.6.	Animal toxicity evaluation results of Roudabush et al 1965 for an acute dermal
toxicity and dermal irritation study on acute toxicity/poisoning and irritation outcomes....29
1.7.	Animal toxicity evaluation results of Wahlberg et al 1979 for an acute percutaneous
toxicity in guinea pig study on mortality and nutrition and metabolic/adult exposure body
weight outcomes	35
2.	Short - Term Toxicity Studies	40
2.1.	Animal toxicity evaluation results of Civo et al 1985 for a 4-week inhalation-liver
toxicity study on hepatic outcomes	40
2.2.	Animal toxicity evaluation results of Hayes et al 1986 for an 14 day oral toxicity test
in mice study on mortality, clinical chemistry /biochemical, renal, hepatic, respiratory,
hematological and immune, neurological/behavior, and reproductive outcomes	43
2.3.	Animal toxicity evaluation results of Sun et al 2014 for a study on
genomics/metabolomics outcomes	49
2.4.	Animal toxicity evaluation results of Sun et al 2014 for a study on hepatic outcomes
52
3.	Subchronic Toxicity Studies	55
3.1.	Animal toxicity evaluation results of Adams et al 1952 for a subchronic inhalation
exposures (46 to 94 days) in rats study on renal, hepatic, nutrition and metabolic/adult
exposure body weight, and cardiovascular outcomes	55
3.2.	Animal toxicity evaluation results of Allis et al 1990 for a 12-week oral study on
hepatic, nutrition and metabolic/adult exposure body weight, clinical
chemistry /biochemical outcomes	60
3.3.	Animal toxicity evaluation results of Benson et al 1999 for inhalation and drinking
water ingestion studies (1, 4 and 12 weeks) on hepatic outcomes	67
3.4.	Animal toxicity evaluation results of Condie et al 1986 for a 90-day oral study on
mortality, metabolic/adult exposure body weight, hepatic, and clinical
chemistry /biochemical outcomes	70
3.5.	Animal toxicity evaluation results of Hayes et al 1986 for a 90-day oral toxicity test
in mice study on reproductive, hematological and immune, neurological, renal, hepatic,
clinical chemistry /biochemical, mortality, nutrition and metabolic/adult exposure body
weight, and respiratory outcomes	75
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3.6. Animal toxicity evaluation results of Nagano et al 2007 for a 13-week inhalation
study in rats and mice study on renal, hepatic, hematological and immune, clinical
chemistry/biochemical, and body weight outcomes	80
4.	Chronic Toxicity Studies	84
4.1.	Animal toxicity evaluation results of Adams et al 1952 for a 6-month inhalation
exposures in rats, guinea pigs, rabbits, and monkeys study on renal, hepatic, respiratory,
cardiovascular, hematological and immune, nutrition and nutrition and metabolic/adult
exposure body weight outcomes	84
4.2.	Animal toxicity evaluation results of DuPont et al 2001 for cancer inhalation-rats
(liver), mice (liver, adrenal gland) study on cancer outcomes	89
4.3.	Animal toxicity evaluation results of Nagano et al 2007 for a 2-year bioassay study
on cancer, mortality, hepatic, renal, respiratory, endocrine, clinical chemistry/biochemical,
and nutrition and metabolic/adult exposure body weight outcomes	93
5.	Reproductive/Developmental Toxicity Studies	100
5.1.	Animal toxicity evaluation results of Schwetz et al 1974 for inhalation
developmental toxicity study in rats study on growth (early life) and development outcomes
100
5.2.	Animal toxicity evaluation results of Narotsky et al 1997	104
6.	In Vitro Studies	107
6.1.	In vitro evaluation results of Araki et al 2004	107
6.2.	In vitro evaluation results of Garb erg etall988	Ill
6.3.	In vitro evaluation results of Imperial et al 1976 for a genotoxicity-bacterial reverse
mutation study	114
6.4.	In vitro evaluation results of Cummings et al 2000	118
7.	References	121
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1. Acute Toxicity Studies
1.1. Animal toxicity evaluation results of Adams et al 1952 for an acute inhalation toxicity
study in rats on mortality outcomes
Study reference:
Adams, E. M., Spencer, H. C., Rowe, V. K., McCollister, D. D., Irish, D. D. (1952). Vapor toxicity of
carbon tetrachloride determined by experiments on laboratory animals. Archives of Environmental
and Occupational Health, 6(1), 50-66

HERO ID: 62373

Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

1. Test Substance
Identity
Test substance
identified by
unambiguous name
and contaminants
identified.
High
1
2
2
Test Substance
2. Test Substance
Source
Test substance was
reportedly a
commercial product
but specific source was
not reported. Infrared
absorption
spectroscopy used to
verify identity and
identify contaminants.
Medium
2
1
2

4. Negative and
Vehicle Controls
Negative controls not
required for acute
lethality test
Not Rated
NA
NA
NA
Test Design
5. Positive
Controls
Positive controls not
typical for acute
lethality test
Not Rated
NA
NA
NA

6. Randomized
Allocation
Study did not describe
method of animal
allocation
Low
3
1
3
4

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Study reference:
Adams, E. M., Spencer, H. C., Rowe, V. K., McCollister, D. D., Irish, D. D. (1952). Vapor toxicity of
carbon tetrachloride determined by experiments on laboratory animals. Archives of Environmental
and Occupational Health, 6(1), 50-66

HERO ID: 62373





Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

7. Preparation and
Storage of Test
Substance
Method of vapor
generation was
incompletely reported
(equipment not
specified; temperature
used to achieve
vaporization was not
reported) but there is
no reason to believe
there would be an
impact on animal
exposure, as vapor
concentrations were
reportedly analyzed
regularly and within
10% of nominal.
Medium
2
1
2
Exposure
Characterization
8. Consistency of
Exposure
Administration
Exposures at different
concentrations were
administered for
different durations,
making it difficult to
discern effects of
changing duration
from effects of
changing
concentration.
Low
3
1
3

9. Reporting of
Doses/Concentrati
ons
Air concentrations
were reported, but it is
not clear whether these
were nominal or actual
concentrations.
Analysis of chamber
concentrations was by
combustion analysis,
which is likely an
insensitive method.
Low
3
2
6
5

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Study reference:
Adams, E. M., Spencer, H. C., Rowe, V. K., McCollister, D. D., Irish, D. D. (1952). Vapor toxicity of
carbon tetrachloride determined by experiments on laboratory animals. Archives of Environmental
and Occupational Health, 6(1), 50-66

HERO ID: 62373

Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

10. Exposure
Frequency and
Duration
Exposure durations
ranged between 0.1
and 12 hours. Acute
inhalation lethality
tests are typically 4
hours in duration.
Medium
2
1
2

11. Number of
Exposure Groups
and Dose Spacing
6 exposure groups
ranging more than 6-
fold (high to low) were
used, but the durations
of exposure varied by
exposure.
Medium
2
1
2

12. Exposure
Route and Method
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, and source (in-
house colony) were
reported. Study
reports using both
sexes but does not
indicate which sex was
used for each exposure
level and duration.
Initial health status,
age, and body weight
were not reported.
Low
3
2
6
14. Adequacy and
Consistency of
Animal Husbandry
Conditions
Animal husbandry
conditions other than
the exposure chamber
were not reported.
Low
3
1
3

15. Number per
Group
Between 5 and 20
animals were used for
each combination of
concentration and
duration. This is more
than required for an
acute lethality study
High
1
1
1
6

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Study reference:
Adams, E. M., Spencer, H. C., Rowe, V. K., McCollister, D. D., Irish, D. D. (1952). Vapor toxicity of
carbon tetrachloride determined by experiments on laboratory animals. Archives of Environmental
and Occupational Health, 6(1), 50-66

HERO ID: 62373





Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

16. Outcome
Assessment
Methodology
Outcome assessment
methodology and
outcomes assessed
were typical for acute
lethality study.
High
1
2
2
Outcome
Assessment
17. Consistency of
Outcome
Assessment
Study reports
observing survivors for
2-3 weeks or until full
recovery was
established. This
could lead to
inconsistencies in
mortality assessment if
there are late deaths.
Low
3
1
3

18. Sampling
Adequacy
See footnote at end of
page.1
High
1
1
1

19. Blinding of
Assessors
Mortality is not
subjective outcome.
Not Rated
NA
1
NA

20. Negative
Control Response
Negative controls not
required for acute
lethality study.
Not Rated
NA
NA
NA
Confounding /
21. Confounding
Variables in Test
Design and
Procedures
Initial body weight,
food/water intake, and
respiratory rate were
not reported.
Low
3
2
6
Variable Control
22. Health
Outcomes
Unrelated to
Exposure
See footnote at end of
page. 1
High
1
1
1
Data
Presentation and
Analysis
23. Statistical
Methods
Statistical analysis was
not conducted, and an
LC50 was not
identified. Mortality
data enabling
independent statistical
analysis were reported.
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:
Adams, E. M., Spencer, H. C., Rowe, V. K., McCollister, D. D., Irish, D. D. (1952). Vapor toxicity of
carbon tetrachloride determined by experiments on laboratory animals. Archives of Environmental
and Occupational Health, 6(1), 50-66
HERO ID: 62373
Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

24. Reporting of
Data
Mortality data are
reported, but without
time to death and not
by sex.
Low
3
2
6
High: >=1 and <1.7
Medium: >=1.7 and <2.3
Low: >=2.3 and <=3
Sum of scores:

27
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. They noted: Varying numbers of
animals were exposed to different concentrations for different durations and with varying
postexposure observation times. The original calculated score for this study was 2.1. This value is not
presented above because the final rating was changed based on professional judgement.
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1.2. Animal toxicity evaluation results of Adams et al 1952 for an acute inhalation toxicity
study in rats on neurological/behavior outcomes
Study reference:
Adams, E. M., Spencer, H. C., Rowe, V. K., McCollister, D. D., Irish, D. D. (1952). VaDor toxicity of
carbon tetrachloride determined by experiments on laboratory animals. Archives of Environmental
and Occupational Health, 6(1), 50-66

HERO ID: 62373

Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

3. Test Substance
Purity
Test substance purity
not reported, but paper
reports purification of
commercial product by
redistillation and
confirmation of
identity by infrared
absorption
spectroscopy. Minor
contaminants were
identified at low (?
0.05%) concentrations.
Medium
2
1
2
Test Design
4. Negative and
Vehicle Controls
Negative controls not
required for acute
lethality test, but
neurotoxicity cannot
be assessed without
negative controls.
Unacceptable
4
2
8
5. Positive
Controls
Positive controls not
typical for acute
lethality test
Not Rated
NA
NA
NA

6. Randomized
Allocation
Study did not describe
method of animal
allocation
Low
3
1
3
9

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Study reference:
Adams, E. M., Spencer, H. C., Rowe, V. K., McCollister, D. D., Irish, D. D. (1952). Vapor toxicity of
carbon tetrachloride determined by experiments on laboratory animals. Archives of Environmental
and Occupational Health, 6(1), 50-66

HERO ID: 62373





Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

7. Preparation and
Storage of Test
Substance
Method of vapor
generation was
incompletely reported
(equipment not
specified; temperature
used to achieve
vaporization was not
reported) but there is
no reason to believe
there would be an
impact on animal
exposure, as vapor
concentrations were
reportedly analyzed
regularly and within
10% of nominal.
Medium
2
1
2
Exposure
Characterization
8. Consistency of
Exposure
Administration
Exposures at different
concentrations were
administered for
different durations,
making it difficult to
discern effects of
changing duration
from effects of
changing
concentration.
Low
3
1
3

9. Reporting of
Doses/Concentrati
ons
Air concentrations
were reported, but it is
not clear whether these
were nominal or actual
concentrations.
Analysis of chamber
concentrations was by
combustion analysis,
which is likely an
insensitive method.
Low
3
2
6

10. Exposure
Frequency and
Duration
Exposure durations
ranged between 0.1
and 12 hours.
High
1
1
1
10

HERO ID: 62373

Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

11. Number of
Exposure Groups
and Dose Spacing
6 exposure groups
ranging more than 6-
fold (high to low) were
used, but the durations
of exposure varied by
exposure.
Medium
2
1
2

15. Number per
Group
Between 5 and 20
animals were used for
each combination of
concentration and
duration. This should
be adequate for acute
toxicity
High
1
1
1
Outcome
Assessment
16. Outcome
Assessment
Methodology
Frequency and timing
of observation for
clinical signs of
neurotoxicity was not
described.
Low
3
2
6
11

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Study reference:
Adams, E. M., Spencer, H. C., Rowe, V. K., McCollister, D. D., Irish, D. D. (1952). Vapor toxicity of
carbon tetrachloride determined by experiments on laboratory animals. Archives of Environmental
and Occupational Health, 6(1), 50-66

HERO ID: 62373





Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

17. Consistency of
Outcome
Assessment
No information on
consistency of clinical
observations was
provided.
Low
3
1
3

18. Sampling
Adequacy
See footnote at end of
page.1
High
1
1
1

19. Blinding of
Assessors
Observations for
clinical signs may be
subjective and blinding
was not reported.
Unacceptable
4
1
4

20. Negative
Control Response
Negative controls were
not used.
Not Rated
NA
NA
NA
Confounding /
21. Confounding
Variables in Test
Design and
Procedures
Initial body weight,
food/water intake, and
respiratory rate were
not reported.
Low
3
2
6
Variable Control
22. Health
Outcomes
Unrelated to
Exposure
See footnote at end of
page.2
High
1
1
1
Data
Presentation and
Analysis
23. Statistical
Methods
Statistical analysis was
not conducted, and
data enabling
independent statistical
analysis were not
reported.
Unacceptable
4
1
4

24. Reporting of
Data
Incidences of clinical
signs of neurotoxicity
were not reported
Unacceptable
4
2
8
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 *:
2.62
1	Metrics that received a "High" rating met the criteria as discussed in the Applications of Systematic Review for
TSCA Risk Evaluation.
2	Metrics that received a "High" rating met the criteria as discussed in the Applications of Systematic Review for
TSCA Risk Evaluation.
12

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Study reference:
Adams, E. M., Spencer, H. C., Rowe, V. K., McCollister, D. D., Irish, D. D. (1952). Vapor toxicity of
carbon tetrachloride determined by experiments on laboratory animals. Archives of Environmental
and Occupational Health, 6(1), 50-66

HERO ID: 62373





Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

Overall Quality Level:
Unacceptable2
Study Quality
Comment:
Footnote 2: Consistent with our Application of A Systematic Review in TSCARisk
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 Bruckner et al 1986 for a study on renal and
hepatic outcomes
Study reference:
Bruckner, J. V., Mackenzie, W. F., Muralidhara, S., Luthra, R., Kvle, G. M., Acosta, D. (1986). Oral
toxicity of carbon tetrachloride: Acute, subacute, and subchronic studies in rats. Fundamental and
Applied Toxicology, 6(1), 16-34

HERO ID: 62379

Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

1. Test Substance
Identity
The test substance was
clearly identified by
name (CASRN not
provided).
High
1
2
2

2. Test Substance
Source
The source of the test
substance (analytical
grade CC14) was
reported.
High
1
1
1
Test Substance
3. Test Substance
Purity
The grade, but not the
purity of the test
substance was
reported. Since the test
substance was
obtained from a
manufacturer, it is
unlikely that impurities
would have a
substantial impact on
the results.
Medium
2
1
2

4. Negative and
Vehicle Controls
Appropriate control
groups were used.
Treated animals were
administered CC14 in
corn oil via gavage.
Control animals were
treated with corn oil
only.
High
1
2
2
Test Design
5. Positive
Controls
A positive control
group is not indicated
by study type (acute,
subacute, and
subchronic-duration
animal toxicity
studies).
Not Rated
NA
NA
NA

6. Randomized
Allocation
The study indicated
that rats were
randomly divided into
groups.
High
1
1
1
14

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Study reference:
Bruckner, J. V., Mackenzie, W. F., Muralidhara, S., Luthra, R., Kvle, G. M., Acosta, D. (1986). Oral
toxicity of carbon tetrachloride: Acute, subacute, and subchronic studies in rats. Fundamental and
Applied Toxicology, 6(1), 16-34

HERO ID: 62379





Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score
Exposure
7. Preparation and
Storage of Test
Substance
The study indicated
that CC14 was mixed
with corn oil and
administered via
gavage in a total
volume of 1
mL/animal. Test
substance
stability/storage
conditions were not
reported, but are not
likely to substantially
impact the results.
Medium
2
1
2
Characterization
8. Consistency of
Exposure
Administration
Details of exposure
administration were
reported and exposures
were administered
consistently across
groups (same
frequency, same time
of day, consistent
gavage volumes).
High
1
1
1

9. Reporting of
Doses/Concentrati
ons
Administered doses
were reported without
ambiguity.
High
1
2
2
15

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PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Study reference:
Bruckner, J. V., Mackenzie, W. F., Muralidhara, S., Luthra, R., Kvle, G. M., Acosta, D. (1986). Oral
toxicity of carbon tetrachloride: Acute, subacute, and subchronic studies in rats. Fundamental and
Applied Toxicology, 6(1), 16-34

HERO ID: 62379





Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

10. Exposure
Frequency and
Duration
The exposure
frequency and duration
were clearly reported.
However, minor
limitations in the
frequency/duration of
treatment were
identified (acute,
subacute, and
subchronic durations
were not "standard").
Animals treated a
single time by gavage
were sacrificed 24
hours after exposure
(not followed for up to
14 days); animals
treated sub-acutely
were administered
CC14 on a cycle of 5
days on, 2 days off, 4
days on (with sacrifice
after 4 or 11 days), and
animals treated for a
subchronic duration
were administered
CC14 for 12 weeks
(less than 90 days).
Medium
2
1
2

11. Number of
Exposure Groups
and Dose Spacing
The number of dose
groups and dose
spacing were justified
by the authors and
considered adequate to
address the purpose of
the study (identifying
NOAEL and LOAEL
levels, with a focus on
liver effects).
High
1
1
1
16

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PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Study reference:
Bruckner, J. V., Mackenzie, W. F., Muralidhara, S., Luthra, R., Kvle, G. M., Acosta, D. (1986). Oral
toxicity of carbon tetrachloride: Acute, subacute, and subchronic studies in rats. Fundamental and
Applied Toxicology, 6(1), 16-34

HERO ID: 62379





Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

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
species, strain, sex,
and starting body
weights (within a
range) were reported.;
the species and strain
were appropriate.
Animals were obtained
from a commercial
laboratory. Rats were
described as adults
(specific age not
reported). Health status
of the rats was not
explicitly specified.
These minor
limitations are unlikely
to substantially impact
the study results.
Medium
2
2
4
17

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PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Study reference:
Bruckner, J. V., Mackenzie, W. F., Muralidhara, S., Luthra, R., Kvle, G. M., Acosta, D. (1986). Oral
toxicity of carbon tetrachloride: Acute, subacute, and subchronic studies in rats. Fundamental and
Applied Toxicology, 6(1), 16-34

HERO ID: 62379





Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

14. Adequacy and
Consistency of
Animal Husbandry
Conditions
Some husbandry
conditions were
specified (i.e. reverse
light/dark conditions
were reported) . The
lack of information on
other conditions (i.e.
temperature, humidity)
are considered minor
uncertainties that are
unlikely to have a
substantial impact on
the results (no
indication that
conditions were
different among
treated rats and
controls).
Medium
2
1
2

15. Number per
Group
The number of animals
per study group was
reported.. However,
only male rats were
used; the number of
animals used were 5
for acute and sub-acute
studies, and 15-16 for
the subchronic-
duration study
(compared to
10/sex/group used for
standard 2 8-day and
90-day repeated-dose
studies).
Medium
2
1
2
18

-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Study reference:
Bruckner, J. V., Mackenzie, W. F., Muralidhara, S., Luthra, R., Kvle, G. M., Acosta, D. (1986). Oral
toxicity of carbon tetrachloride: Acute, subacute, and subchronic studies in rats. Fundamental and
Applied Toxicology, 6(1), 16-34

HERO ID: 62379





Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score
Outcome
Assessment
16. Outcome
Assessment
Methodology
The outcome
assessment partially
addressed the intended
outcomes of interest.
Liver and kidney
effects were evaluated
by examining limited
clinical chemistry
parameters, organ
weights, and/or
histopathological
effects. Other common
clinical chemistry
parameters associated
with liver and kidney
function were not
measured.
Medium
2
2
4

17. Consistency of
Outcome
Assessment
Outcome assessment
protocols were
described, and
outcomes were
assessed consistently
across groups.Data for
liver lesions were
presented
quantitatively as
means (+/-SD) based
on severity scores
ranging from 0 to 8.
High
1
1
1
19

-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Study reference:
Bruckner, J. V., Mackenzie, W. F., Muralidhara, S., Luthra, R., Kvle, G. M., Acosta, D. (1986). Oral
toxicity of carbon tetrachloride: Acute, subacute, and subchronic studies in rats. Fundamental and
Applied Toxicology, 6(1), 16-34

HERO ID: 62379





Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

18. Sampling
Adequacy
Details regarding
sampling for the
outcomes of interest
were reported, with
minor limitations (e.g.
number of histology
slides evaluated not
reported). Numbers of
animals evaluated for
specific endpoints
were generally limited
(5-9 males/group, even
for the subchronic-
duration study).
Medium
2
1
2

19. Blinding of
Assessors
Histopathology slides
were coded and
examined in a single
blind fashion.
High
1
1
1

20. Negative
Control Response
The biological
responses of the
control group were
reported for most
endpoints; however,
liver histopathology
data for control
animals subjected to
acute and sub-acute
treatment were not
shown (no effects were
reported). Liver weight
data were provided in
the text for the control
and high-dose groups
only.
Medium
2
1
2
Confounding /
Variable Control
21. Confounding
Variables in Test
Design and
Procedures
There were no reported
differences in initial
body weights among
study groups.
High
1
2
2
20

-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Study reference:
Bruckner, J. V., Mackenzie, W. F., Muralidhara, S., Luthra, R., Kvle, G. M., Acosta, D. (1986). Oral
toxicity of carbon tetrachloride: Acute, subacute, and subchronic studies in rats. Fundamental and
Applied Toxicology, 6(1), 16-34
HERO ID: 62379
Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

22. Health
Outcomes
Unrelated to
Exposure
See footnote at end of
page.1
High
1
1
1
Data
Presentation and
Analysis
23. Statistical
Methods

Medium
2
1
2
24. Reporting of
Data
Data were presented
by exposure group for
most endpoints. Liver
histopathology data for
the negative control
group (acute and
subacute studies) are
not shown in the data
tables. Liver weight
data are provided for
the control and high-
dose groups only.
Medium
2
2
4
High: >=1 and <1.7
Medium: >=1.7 and <2.3
Low: >=2.3 and <=3
Sum of scores:

30
44
Overall Score = Sum of Weighted
Scores/Sum of Metric Weighting Factors:
1.4667
Overall Score:
Nearest *:
1.5
Overall Quality Level:
High
1 Metrics that received a "High" rating met the criteria as discussed in the Applications of Systematic Review for
TSCA Risk Evaluation.
21

-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
1.4. Animal toxicity evaluation results of Hayes et al 1986 for an acute oral lethality study on
mortality outcomes
Study reference:
Haves, J. R., Condie, L. W., Borzelleca, J. F. (1986). Acute, 14-dav repeated dosins, and 90-dav
subchronic toxicity studies of carbon tetrachloride in CD-I mice. Fundamental and Applied
Toxicology, 7(3), 454-463

HERO ID: 194400

Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

1. Test Substance
Identity
Test substance
identified by
unambiguous name
High
1
2
2
Test Substance
2. Test Substance
Source
Test substance source
and lot number
reported, but
certification/analytical
verification of identity
was not.
Medium
2
1
2

3. Test Substance
Purity
Test substance
reported to be HPLC
grade and >99% pure.
High
1
1
1

4. Negative and
Vehicle Controls
Negative control not
required for acute
lethality study.
Not Rated
NA
NA
NA
Test Design
5. Positive
Controls
Positive controls not
typical for this study
type.
Not Rated
NA
NA
NA

6. Randomized
Allocation
Study reports
randomizing the mice
but is not clear
regarding the
allocation.
Medium
2
1
2

9. Reporting of
Doses/Concentrati
ons
Dose reported in
mg/kg bw; body
weight not reported.
Medium
2
2
4
22

-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Study reference:
Haves, J. R., Condie, L. W., Borzelleca, J. F. (1986). Acute, 14-dav repeated dosins, and 90-dav
subchronic toxicity studies of carbon tetrachloride in CD-I mice. Fundamental and Applied
Toxicology, 7(3), 454-463

HERO ID: 194400





Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

10. Exposure
Frequency and
Duration
See footnote at end of
page.1
High
1
1
1

11. Number of
Exposure Groups
and Dose Spacing
Single exposure group
is not sufficient to
determine LD50
Unacceptable
4
1
4

12. Exposure
Route and Method
See footnote at end of
page.2
High
1
1
1
Test Organism
13. Test Animal
Characteristics
Test animal species,
strain, sex, lifestage,
and source were
reported and
appropriate. Initial
body weights were not
reported.
Medium
2
2
4
14. Adequacy and
Consistency of
Animal Husbandry
Conditions
All husbandry
conditions were
described and
appropriate.
High
1
1
1

15. Number per
Group
10/sex were tested; this
is more than adequate
for acute lethality
High
1
1
1

16. Outcome
Assessment
Methodology
Duration of post-
exposure observation
was not reported.
Unacceptable
4
2
8
Outcome
Assessment
17. Consistency of
Outcome
Assessment
Only one group tested.
Not Rated
NA
NA
NA

18. Sampling
Adequacy
Mortality assessed in
all exposed animals.
High
1
1
1

19. Blinding of
Assessors
Mortality is not
subjective
Not Rated
NA
NA
NA
1	Metrics that received a "High" rating met the criteria as discussed in the Applications of Systematic Review for
TSCA Risk Evaluation.
2	Metrics that received a "High" rating met the criteria as discussed in the Applications of Systematic Review for
TSCA Risk Evaluation.
23

-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Study reference:
Haves, J. R., Condie, L. W., Borzelleca, J. F. (1986). Acute, 14-dav repeated dosins, and 90-dav
subchronic toxicity studies of carbon tetrachloride in CD-I mice. Fundamental and Applied
Toxicology, 7(3), 454-463
HERO ID: 194400
Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

20. Negative
Control Response
No negative control
was used
Not Rated
NA
NA
NA
Confounding /
Variable Control
21. Confounding
Variables in Test
Design and
Procedures
Only one group tested
Not Rated
NA
NA
NA
22. Health
Outcomes
Unrelated to
Exposure
acute lethality test; no
other outcomes
assessed
Not Rated
NA
NA
NA
Data
Presentation and
Analysis
23. Statistical
Methods
Statistical analysis not
possible on single
group
Not Rated
NA
NA
NA
24. Reporting of
Data
Mortality data were
not reported
Unacceptable
4
2
8
High: >=1 and <1.7
Medium: >=1.7 and <2.3
Low: >=2.3 and <=3
Sum of scores:

24
47
Overall Score = Sum of Weighted
Scores/Sum of Metric Weighting Factors:
1.9583
Overall Score:
Nearest *:
2.01
Overall Quality Level:
Unacceptable1
Study Quality
Comment:
Footnote 1: Consistent with our Application of A Systematic Review in TSCARisk
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.
24

-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
1.5. Animal toxicity evaluation results of Kronevi et al 1979 for an acute dermal study on
liver toxicity, kidney toxicity, and skin morphology outcomes
Study reference:
T. Kronevi, J. Wahlbere, B. Holmbers (1979). HistoDatholoev of skin, liver, and kidnev after
epicutaneous administration of five industrial solvents to guinea pigs. Environmental Research,
19(1,1), 56-69

HERO ID: 3684159

Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

1. Test Substance
Identity
Test substance
identified as carbon
tetrachloride (p.a.).
High
1
2
2
Test Substance
2. Test Substance
Source
Obtained from E.
Merck, Darmstadt,
Germany. No batch/lot
number.
Medium
2
1
2

3. Test Substance
Purity
Not specified, but
reported "p.a.", which
indicates analytical
grade
High
1
1
1
Test Design
4. Negative and
Vehicle Controls
No control animals
were used. Study
authors note that skin
morphology in
exposed area was
compared to skin
morphology from
unexposed area in the
same animal. No
comparator for liver or
kidney histology.
Unacceptable
4
2
8

5. Positive
Controls

Not Rated
4
4
4

6. Randomized
Allocation
Study authors did not
report animal
allocation methods.
Low
3
1
3
Exposure
Characterization
7. Preparation and
Storage of Test
Substance
Pure solvent was
applied, so no
preparation was
required.
Not Rated
NA
NA
NA
8. Consistency of
Exposure
Administration
All animals similarly
exposed
High
1
1
1
25

-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Study reference:
T. Kronevi, J. Wahlbere, B. Holmbers (1979). Histopatholoev of skin, liver, and kidnev after
epicutaneous administration of five industrial solvents to guinea pigs. Environmental Research,
19(1,1), 56-69

HERO ID: 3684159




Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

9. Reporting of
Doses/Concentrati
ons
1 mL of pure solvent
applied within a glass
ring with an inside
diameter of 20 mm
(area 3.1 cm2). At a
density of 1.59 g/cm3
= 1.59 g/mL, the
administered dose was
1.59 g. Glass ring
was covered with glass
(occluded conditions).
High
1
2
2

10. Exposure
Frequency and
Duration
Exposure was for 15
minutes, 1 hr, 4 hr, or
16 hr
High
1
1
1

11. Number of
Exposure Groups
and Dose Spacing
Only one dose group
(pure solvent), but for
4 durations.
Low
3
1
3

12. Exposure
Route and Method
Dermal exposure using
a covered glass ring to
prevent volatilization
or exposure via
inhalation or oral
routes.
High
1
1
1

13. Test Animal
Characteristics
Albino guinea pigs
weighting between 440
and 570 g. Source and
sex of animals not
reported.
Low
3
2
6
Test Organism
14. Adequacy and
Consistency of
Animal Husbandry
Conditions
No husbandry
conditions were
reported, but since this
is an acute study this is
not likely to have a
major impact on study.
Medium
2
1
2
26

-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Study reference:
T. Kronevi, J. Wahlbere, B. Holmbers (1979). Histopatholoev of skin, liver, and kidnev after
epicutaneous administration of five industrial solvents to guinea pigs. Environmental Research,
19(1,1), 56-69

HERO ID: 3684159




Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

15. Number per
Group
The number of animals
per group were not
explicitly reported.
Overall number of
animals was 20. There
were 5 compounds
tested, with each
compound evaluated
for 4 time-points. This
implies that only one
animal was used per
compound per
duration.
Unacceptable
4
1
4

16. Outcome
Assessment
Methodology
Skin biopsy was
performed on exposed
area and neighboring
unexposed animal.
Liver and kidney
histology were
assessed for evaluation
of liver and kidney
histology.
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
Only one animal per
group and no controls,
so sampling adequacy
is N/A
Not Rated
NA
NA
NA

19. Blinding of
Assessors
Blinding is not
required for initial
histopathological
review.
Not Rated
NA
NA
NA
1 Metrics that received a "High" rating met the criteria as discussed in the Applications of Systematic Review for
TSCA Risk Evaluation.
27

-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Study reference:
T. Kronevi, J. Wahlbere, B. Holmbers (1979). Histopatholoev of skin, liver, and kidnev after
epicutaneous administration of five industrial solvents to guinea pigs. Environmental Research,
19(1,1), 56-69
HERO ID: 3684159
Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

20. Negative
Control Response
Skin biopsy results
from untreated skin
were not reported. No
control specimens for
liver or kidney
histology.
Unacceptable
4
1
4
Confounding /
Variable Control
21. Confounding
Variables in Test
Design and
Procedures
Little concern with
confounding in acute
study design
High
1
2
2
22. Health
Outcomes
Unrelated to
Exposure
Attrition/infection N/A
due to acute study
design
Not Rated
NA
NA
NA
Data
Presentation and
Analysis
23. Statistical
Methods
No statistical methods.
Only one animal per
group, so data
insufficient for
statistical analysis.
Unacceptable
4
1
4
24. Reporting of
Data
Results reported
qualitatively.
Medium
2
2
4
High: >=1 and <1.7
Medium: >=1.7 and <2.3
Low: >=2.3 and <=3
Sum of scores:

30
57
Overall Score = Sum of Weighted
Scores/Sum of Metric Weighting Factors:
1.900
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, three of the metrics were rated as unacceptable.
As such, the study is considered unacceptable and the score is presented solely to increase
transparency.
28

-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
1.6. Animal toxicity evaluation results of Roudabush et al 1965 for an acute dermal toxicity
and dermal irritation study on acute toxicity/poisoning and irritation outcomes
Study reference:
Roudabush, R. L., Terhaar, C. J., Fassett, D. W., Dziuba, S. P. (1965). Comparative acute effects of
some chemicals on the skin of rabbits and guinea pigs. Toxicology and Applied Pharmacology, 7(4),
559-565

HERO ID: 79743

Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

1. Test Substance
Identity
Test substance was
clearly identified.
High
1
2
2
Test Substance
2. Test Substance
Source
The manufacturer was
reported. The batch lot
number for materials
was not reported;
however, this omission
is unlikely to have a
substantial impact on
result.
Medium
2
1
2

3. Test Substance
Purity
Purity or chemical
grade was not
reported.; however
given other
information, purity
was not expected to be
of concern.
Medium
2
1
2
Test Design
4. Negative and
Vehicle Controls
The use of controls
were not discussed in
the methodology
sections of the report;
however, the results
table of the dermal
irritation tests reported
results for distilled
water. The standard
test guidelines (e.g.,
OECD) do not require
negative controls for
acute toxicity studies.
High
1
2
2

5. Positive
Controls
Not applicable for this
study type.
Not Rated
NA
NA
NA

6. Randomized
Allocation
The study did not
report how animals
were allocated to study
groups for either the
acute toxicity nor the
irritation studies.
Low
3
1
3
29

-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Study reference:
Roudabush, R. L., Terhaar, C. J., Fassett, D. W., Dziuba, S. P. (1965). Comparative acute effects of
some chemicals on the skin of rabbits and guinea pigs. Toxicology and Applied Pharmacology, 7(4),
559-565

HERO ID: 79743





Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

7. Preparation and
Storage of Test
Substance
Test materials were
noted to be undiluted.
Storage conditions
were not reported;
however, omission of
these details are
unlikely to have a
substantial impact on
results.
Medium
2
1
2

8. Consistency of
Exposure
Administration
Exposure
administration was
reported for both
studies and were
administered
consistently across
study groups for both
species.
High
1
1
1
Exposure
Characterization
9. Reporting of
Doses/Concentrati
ons
Study report does not
specify the
administered dermal
doses for the acute
toxicity study or the
irritation study for
either species. The
report only states "a
minimum of 3 dosages
was employed" for the
acute dermal toxicity
test..
Unacceptable
4
2
8

10. Exposure
Frequency and
Duration
The report notes that
the procedure followed
the protocols described
in the Regulations (21
CFR 191.10), which
includes details on
exposure duration for
both the acute dermal
toxicity test (24 hours)
and the primary
irritation test (24 hours
and 72 hours).
High
1
1
1
30

-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Study reference:
Roudabush, R. L., Terhaar, C. J., Fassett, D. W., Dziuba, S. P. (1965). Comparative acute effects of
some chemicals on the skin of rabbits and guinea pigs. Toxicology and Applied Pharmacology, 7(4),
559-565

HERO ID: 79743





Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
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
stated as "a minimum
of 3 dosages" for the
acute dermal toxicity
study; the actual
number of dose groups
and spacing is not
reported. The dosing
of the irritation study
is also not reported.
Unacceptable
4
1
4

12. Exposure
Route and Method
The route and method
of exposure was
reported and
appropriate for the
study types
High
1
1
1
Test Organism
13. Test Animal
Characteristics
There are deficiencies
in the reporting of the
test animal
characteristics. The
strain of guinea pigs
and rabbits, sex used
for each study, and the
starting body weight
ranges were reported.
There is some
uncertainty in the
source of white rabbits
(reported to be from a
"local supplier").
These uncertainties are
unlikely to have a
substantial impact on
results.
Medium
2
2
4
31

-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Study reference:
Roudabush, R. L., Terhaar, C. J., Fassett, D. W., Dziuba, S. P. (1965). Comparative acute effects of
some chemicals on the skin of rabbits and guinea pigs. Toxicology and Applied Pharmacology, 7(4),
559-565

HERO ID: 79743





Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

14. Adequacy and
Consistency of
Animal Husbandry
Conditions
Animal husbandry
conditions were not
reported, to evaluate if
husbandry was
adequate and if
differences occurred
between control and
exposed groups..
Low
3
1
3

15. Number per
Group
The reported number
of animals per study
group for the acute
toxicity test was
unclear (reported to be
"usually" 4
animals/dose group).
Medium
2
1
2

16. Outcome
Assessment
Methodology
The outcome
assessment
methodology
addressed or reported
the intended
outcome(s) of interest.
High
1
2
2
Outcome
Assessment
17. Consistency of
Outcome
Assessment
There was incomplete
reporting of minor
details of outcome
assessment protocol
execution, but these
uncertainties or
limitations are unlikely
to have substantial
impact on results.
Medium
2
1
2

18. Sampling
Adequacy
Details on outcome
assessments sampling
were not reported, but
is likely that all tested
animals were sampled.
Medium
2
1
2

19. Blinding of
Assessors
The study types do not
require blinding of
assessors.
Not Rated
NA
NA
NA
32

HERO ID: 79743

Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

20. Negative
Control Response
The biological
response of the
negative control group
(distilled water) was
adequate for the
dermal irritation study.
There was no reported
control used in the
acute toxicity test.
High
1
1
1
Confounding /
Variable Control
21. Confounding
Variables in Test
Design and
Procedures
There were no
reporting for any
possible differences
among the study
groups that could
influence the outcome
assessment.; however,
the lack of reporting is
not likely to have a
significant impact on
results.
Medium
2
2
4

22. Health
Outcomes
Unrelated to
Exposure
Data for outcomes
unrelated to exposure
for each study group
were not reported, but
the lack of reporting is
unlikely to influence
the study results.
Medium
2
1
2
Data
Presentation and
Analysis
23. Statistical
Methods
Statistical analysis was
not well described but
would unlikely have a
substantial impact on
results. The acute
toxicity test reported
calculating the LD50
using the method of
Finney (1952), while
the calculation of the
primary irritation score
were made according
to the Regulations (21
CFR 191.11).
Medium
2
1
2
33

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PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Study reference:
Roudabush, R. L., Terhaar, C. J., Fassett, D. W., Dziuba, S. P. (1965). Comparative acute effects of
some chemicals on the skin of rabbits and guinea pigs. Toxicology and Applied Pharmacology, 7(4),
559-565
HERO ID: 79743
Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

24. Reporting of
Data
Data for exposure-
related findings were
reported for most, but
not all, outcomes by
exposure group. Data
was reported for
guinea pigs (male
only) but was not
reported by sex for
rabbits, rather the data
reported was for males
and females combined.
There was not
presentation of
mortality incidence for
the acute toxicity study
and no description of
severity scores for the
irritation study (only
the primary irritation
score was reported).
These uncertainties in
outcome reporting are
unlikely to have
substantial impact on
results.
Medium
2
2
4
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:
1.9310
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.
34

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PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
1.7. Animal toxicity evaluation results of Wahlberg et al 1979 for an acute
percutaneous toxicity in guinea pig study on mortality and nutrition and
metabolic/adult exposure body weight outcomes
Study reference:
J. E. Wahlbers, A. Boman (1979). Comparative percutaneous toxicity of ten industrial solvents in
the guinea pig. Scandinavian Journal of Work, Environment and Health, 5(4,4), 345-351
HERO ID: 61688
Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score
Test Substance
1. Test Substance
Identity
The test substances
were identified;
however, the test
substances were
lacking
characterization
details; unlikely to
have a substantial
impact on results.
Medium
2
2
4
2. Test Substance
Source
The source of the test
substances were
identified; did not
include batch/lot
numbers; unlikely to
have a substantial
impact on results.
Medium
2
1
2
3. Test Substance
Purity
purity or grade of test
substances were not
reported; possible
impurities were not
reported.
Low
3
1
3
Test Design
4. Negative and
Vehicle Controls
Distilled water was
used as a concurrent
control
High
1
2
2
5. Positive
Controls
This metric is not
rated/applicable;
positive control was
not indicated by 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
Exposure
Characterization
7. Preparation and
Storage of Test
Substance
There were no details
of test substance
preparation and/or
storage conditions
reported.
Low
3
1
3
35

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PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Study reference:
J. E. Wahlbers, A. Boman (1979). Comparative percutaneous toxicity of ten industrial solvents in
the guinea pig. Scandinavian Journal of Work, Environment and Health, 5(4,4), 345-351
HERO ID: 61688
Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

8. Consistency of
Exposure
Administration
Single application to
skin depot (31 cm2)
and covered
CK: Not 31 cm2. The
solvents was
administered to a skin
depot area 3.1 cm2
High
1
1
1
9. Reporting of
Doses/Concentrati
ons
applied concentrations
were reported in ml;
mean body weight was
reported to estimate an
administered dose.
Medium
2
2
4
10. Exposure
Frequency and
Duration
single application,
covered, and observed
for 35 d
High
1
1
1
11. Number of
Exposure Groups
and Dose Spacing
The number of
exposure groups for
CC14 = 2 and TCE=1;
number of exposure
groups and spacing
were not justified by
the author; Doses
were considered
adequate to address the
purpose of the study
for changes in body
weight for both CC14
and TCE; however for
TCE, it is unclear if
the exposure level was
adequate to show
results relevant to
mortality as there were
no effects at the single
concentration tested.
Medium
2
1
2
12. Exposure
Route and Method
The route and method
of exposure were
reported and were
suited to the test
substances
High
1
1
1
36

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PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Study reference:
J. E. Wahlbers, A. Boman (1979). Comparative percutaneous toxicity of ten industrial solvents in
the guinea pig. Scandinavian Journal of Work, Environment and Health, 5(4,4), 345-351

HERO ID: 61688





Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

13. Test Animal
Characteristics
The source, strain, or
sex of the test guinea
pigs were not reported.
Low
3
2
6
Test Organism
14. Adequacy and
Consistency of
Animal Husbandry
Conditions
Husbandry conditions
were not sufficiently
reported to evaluate if
husbandry was
adequate
Low
3
1
3

15. Number per
Group
20 animals per series
High
1
1
1

16. Outcome
Assessment
Methodology
The outcome
assessment
methodology
addressed or reported
the intended outcomes
of interest and was
sensitive for the
outcomes of interest;
mortality was
monitored and body
weight was recorded
High
1
2
2
Outcome
Assessment
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

18. Sampling
Adequacy
Mortality observations
and weight
measurements were
made for all animals
daily except weekends
High
1
1
1

19. Blinding of
Assessors
this metric is not
rated/applicable
because no subjective
outcomes were
assessed.
Not Rated
NA
NA
NA
37

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PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Study reference:
J. E. Wahlbers, A. Boman (1979). Comparative percutaneous toxicity of ten industrial solvents in
the guinea pig. Scandinavian Journal of Work, Environment and Health, 5(4,4), 345-351

HERO ID: 61688

Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

20. Negative
Control Response
The biological
responses of the
negative control
group(s) were
adequate
High
1
1
1
Confounding /
Variable Control
21. Confounding
Variables in Test
Design and
Procedures
Initial body weights
were reported; there
was no reporting of
food/water intake;
unlikely to have a
significant 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
Medium
2
1
2
Data
Presentation and
Analysis
23. Statistical
Methods
Noted that an analysis
of variance was
applied in the
statistical calculations,
though statistical tests
were not specified. P-
values (unspecified
significance test) were
reported for body
weight changes. No
statistical significance
values were reported
for mortality
Low
3
1
3

24. Reporting of
Data
Incidence of mortality
was reported for both
CC14 and TCE. Body
weight changes was
reported for TCE, but
not CC14
Medium
2
2
4
High: >-1 and <1.7
Medium: >=1.7 and <2.3
Low: >=2.3 and <=3
Sum of scores:

29
54
Overall Score = Sum of Weighted
Scores/Sum of Metric Weighting Factors:
1.862
Overall Score:
Nearest *:
1.9
38

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PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Study reference:
J. E. Wahlbers, A. Boman (1979). Comparative percutaneous toxicity of ten industrial solvents in
the guinea pig. Scandinavian Journal of Work, Environment and Health, 5(4,4), 345-351
HERO ID: 61688
Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

Overall Quality Level:
Medium
39

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PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
2. Short - Term Toxicity Studies
2.1. Animal toxicity evaluation results of Civo et al 1985 for a 4-week inhalation-liver
toxicity study on hepatic outcomes
Study reference:
Civo Institute, Tno (1985). Fixed Versus Variable Levels of Exposure in Inhalation Toxicitv Testing
with Reference to the Workplace Studies with Acetaldehyde and Carbon Tetrachloride.

HERO ID: 4215798 (same as 4215910)

Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

1. Test Substance
Identity
Test substance
identified by name.
High
1
2
2
Test Substance
2. Test Substance
Source
Source was reported
incompletely, but the
omitted details are
unlikely to have a
substantial impact on
results
Medium
2
1
2

3. Test Substance
Purity
Purity such that effects
likely due to test
substance.
High
1
1
1

4. Negative and
Vehicle Controls
Concurrent negative
controls were used.
High
1
2
2
Test Design
5. Positive
Controls
Positive controls not
required.
Not Rated
NA
NA
NA

6. Randomized
Allocation
Computer
randomization used for
allocation.
High
1
1
1

7. Preparation and
Storage of Test
Substance
Method and equipment
of generation was
reported.
High
1
1
1

8. Consistency of
Exposure
Administration
Exposures were
administered
consistently.
High
1
1
1
Exposure
Characterization
9. Reporting of
Doses/Concentrati
ons
Concentrations were
reported.
High
1
2
2

10. Exposure
Frequency and
Duration
Frequency and
duration were reported.
High
1
1
1

11. Number of
Exposure Groups
and Dose Spacing
the number of groups
and concentration
spacing were reported
and justified.
High
1
1
1
40

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PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Study reference:
Civo Institute, Tno (1985). Fixed Versus Variable Levels of Exposure in Inhalation Toxicity Testing
with Reference to the Workplace Studies with Acetaldehyde and Carbon Tetrachloride.
HERO ID: 4215798 (same as 4215910)
Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

12. Exposure
Route and Method
Exposure route and
method were reported
and appropriate.
High
1
1
1
Test Organism
13. Test Animal
Characteristics
The source, species,
strain, sex, and initial
body weight were
reported. Health status
and age were not
reported.
Medium
2
2
4
14. Adequacy and
Consistency of
Animal Husbandry
Conditions
Husbandry details
were reported.
High
1
1
1
15. Number per
Group
The number of animals
per group was
appropriate.
High
1
1
1
Outcome
Assessment
16. Outcome
Assessment
Methodology
Outcome assessment
methodology was
reported and
appropriate.
High
1
2
2
17. Consistency of
Outcome
Assessment
Outcomes were
assessed consistently.
High
1
1
1
18. Sampling
Adequacy
Sampling was
adequate for outcomes
of interest.
High
1
1
1
19. Blinding of
Assessors
Blinding not required.
Not Rated
NA
NA
NA
20. Negative
Control Response
Negative control
responses were
appropriate.
High
1
1
1
Confounding /
Variable Control
21. Confounding
Variables in Test
Design and
Procedures
Respiratory rate was
not reported but is not
likely to have
significant impact on
results.
Medium
2
2
4
41

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PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Study reference:
Civo Institute, Tno (1985). Fixed Versus Variable Levels of Exposure in Inhalation Toxicity Testing
with Reference to the Workplace Studies with Acetaldehyde and Carbon Tetrachloride.
HERO ID: 4215798 (same as 4215910)
Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

22. Health
Outcomes
Unrelated to
Exposure
No health outcomes
unrelated to exposure
were reported.
High
1
1
1
Data
Presentation and
Analysis
23. Statistical
Methods
Statistical methods
were reported and
appropriate.
High
1
1
1
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:

29
34
Overall Score = Sum of Weighted
Scores/Sum of Metric Weighting Factors:
1.172
Overall Score:
Nearest *:
1.2
Overall Quality Level:
High
1 Metrics that received a "High" rating met the criteria as discussed in the Applications of Systematic Review for
TSCA Risk Evaluation.
42

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PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
2.2. Animal toxicity evaluation results of Hayes et al 1986 for an 14 day oral toxicity test in
mice study on mortality, clinical chemistry/biochemical, renal, hepatic, respiratory,
hematological and immune, neurological/behavior, and reproductive outcomes
Study reference:
Haves, J. R., Condie, L. W., Borzelleca, J. F. (1986). Acute, 14-dav repeated dosins, and 90-dav
subchronic toxicity studies of carbon tetrachloride in CD-I mice. Fundamental and Applied
Toxicology, 7(3), 454-463

HERO ID: 194400

Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

3. Test Substance
Purity
Test substance
reported to be HPLC
grade and >99% pure.
High
1
1
1

4. Negative and
Vehicle Controls
Both naive and sham-
treated control groups
were used. Sham-
treated controls
received vehicle.
High
1
2
2
Test Design
5. Positive
Controls
Positive controls not
typical for this study
type.
Not Rated
4
4
4

6. Randomized
Allocation
Study reports
randomizing the mice
but does not discuss
the allocation to
groups
Medium
2
1
2

7. Preparation and
Storage of Test
Substance
Study reports daily
preparation of solution,
but does not report
storage.
Low
3
1
3
Exposure
Characterization
8. Consistency of
Exposure
Administration
Administration details
are provided, including
gavage volume and
time of day of
administration. No
inconsistencies in
exposures across
groups were noted.
High
1
1
1
43

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PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Study reference:
Haves, J. R., Condie, L. W., Borzelleca, J. F. (1986). Acute, 14-dav repeated dosins, and 90-dav
subchronic toxicity studies of carbon tetrachloride in CD-I mice. Fundamental and Applied
Toxicology, 7(3), 454-463

HERO ID: 194400





Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

9. Reporting of
Doses/Concentrati
ons
Dose reported in
mg/kg bw; body
weight not reported.
Medium
2
2
4

10. Exposure
Frequency and
Duration
Animals gavaged daily
for 14 days
High
1
1
1

11. Number of
Exposure Groups
and Dose Spacing
3 nonzero doses
ranging 4-fold were
used. Effects were
seen at all doses, so it
is not clear that the
lowest dose was low
enough.
Medium
2
1
2

12. Exposure
Route and Method
See footnote at end of
page.1
High
1
1
1
Test Organism
13. Test Animal
Characteristics
Test animal species,
strain, sex, lifestage,
and source were
reported and
appropriate. Initial
body weights were not
reported.
Medium
2
2
4
14. Adequacy and
Consistency of
Animal Husbandry
Conditions
All husbandry
conditions were
described and
appropriate.
High
1
1
1

15. Number per
Group
20/sex/dose were
tested; this is more
than adequate.
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.
44

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PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Study reference:
Haves, J. R., Condie, L. W., Borzelleca, J. F. (1986). Acute, 14-dav repeated dosing, and 90-dav
subchronic toxicity studies of carbon tetrachloride in CD-I mice. Fundamental and Applied
Toxicology, 7(3), 454-463

HERO ID: 194400





Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

16. Outcome
Assessment
Methodology
Outcome assessment
methodology was
described in detail and
appropriate.
Histopathology was
not evaluated, but
organ weights, serum
chemistry, and
hematology were.
Food and water intake
were not reported. The
only neurological and
reproductive endpoints
assessed were brain
and testes weights,
respectively.
Medium
2
2
4
Outcome
Assessment
17. Consistency of
Outcome
Assessment
No inconsistencies in
outcome assessment
were noted by the
authors apart from one
gavage death in high
dose females.
High
1
1
1

18. Sampling
Adequacy
Mortality, organ
weights evaluated in
all animals;
hematology and serum
chemistry evaluated in
5/sex/dose each.
Medium
2
1
2

19. Blinding of
Assessors
No subjective
outcomes were
evaluated
Not Rated
4
NA
NA

20. Negative
Control Response
Responses of both
naive and vehicle
controls were reported
for all endpoints other
than hematology.
Responses appeared to
be as expected and
without excessive
variability.
High
1
1
1
45

HERO ID: 194400

Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

21. Confounding
Variables in Test
Design and
Procedures
Initial body weight and
food and water intake
were not reported.
Low
3
2
6
Confounding /
Variable Control
22. Health
Outcomes
Unrelated to
Exposure
The study reports that
20 animals/sex/dose
were tested, and that
organ weights were
evaluated in all
animals; however,
results are reported for
only 10
animals/sex/dose. The
study authors do not
explain this
discrepancy.
Low
3
1
3

23. Statistical
Methods
Statistical methods
were reported and
appropriate to the data.
High
1
1
1
Data
Presentation and
Analysis
24. Reporting of
Data
Mortality, organ
weights, and
significant clinical
chemistry findings
were reported; body
weight, hematology
results, and non-
significant clinical
chemistry findings
were not. The lack of
body weight data is
problematic for
interpretation of
relative organ weight
changes.
Low
3
2
6
High: >-1 and <1.7
Medium: >=1.7 and <2.3
Low: >=2.3 and <=3
Sum of scores:

23
55
Overall Score = Sum of Weighted
Scores/Sum of Metric Weighting Factors:
1.667
Overall Score:
Nearest *:
1.7
46

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PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Study reference:
Haves, J. R., Condie, L. W., Borzelleca, J. F. (1986). Acute, 14-dav repeated dosing, and 90-dav
subchronic toxicity studies of carbon tetrachloride in CD-I mice. Fundamental and Applied
Toxicology, 7(3), 454-463
HERO ID: 194400
Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

Overall Quality Level:
Medium
47

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PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
48

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PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
2.3. Animal toxicity evaluation results of Sun et al 2014 for a study on
genomics/metabolomics outcomes
Study reference:
Sun, J., Schmitt, T., Schnackenberg, L. K., Pence, L., Ando, Y., Greenhaw, J., Yang, X. i, Slavov, S.,
Davis, K., Salminen, W. F., Mendrick, D. L., Beser, R. D. (2014). Comprehensive analysis of
alterations in lipid and bile acid metabolism by carbon tetrachloride using integrated
transcriptomics and metabolomics. Metabolomics, 10(6), 1293-1304

HERO ID: 3487830




Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
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
Commercial source
was identified.
High
1
1
1

3. Test Substance
Purity
Purity not reported.
Low
3
1
3

4. Negative and
Vehicle Controls
Vehicle (corn oil)
controls were used.
High
1
2
2
Test Design
5. Positive
Controls
Positive controls were
not used for
genomic/metabolomics
alterations.
Not Rated
NA
NA
NA

6. Randomized
Allocation
Animals were
randomly assigned to
each dose group.
High
1
1
1
Exposure
Characterization
7. Preparation and
Storage of Test
Substance
Preparation and
storage were not
described; however,
omission of these
details are unlikely to
have a substantial
impact on results
(acute exposure).
Medium
2
1
2
8. Consistency of
Exposure
Administration
Gavage volume was
not excessive.
High
1
1
1

9. Reporting of
Doses/Concentrati
ons
See footnote at end of
page.1
High
1
2
2
1 Metrics that received a "High" rating met the criteria as discussed in the Applications of Systematic Review for
TSCA Risk Evaluation.
49

-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Study reference:
Sun, J., Schmitt, T., Schnackenberg, L. K., Pence, L., Ando, Y., Greenhaw, J., Yang, X. i, Slavov, S.,
Davis, K., Salminen, W. F., Mendrick, D. L., Beser, R. D. (2014). Comprehensive analvsis of
alterations in lipid and bile acid metabolism by carbon tetrachloride using integrated
transcriptomics and metabolomics. Metabolomics, 10(6), 1293-1304

HERO ID: 3487830




Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

10. Exposure
Frequency and
Duration
Genomic/metabolic
data provide
mechanistic
understanding for liver
effects which occur
after acute exposure.
High
1
1
1

11. Number of
Exposure Groups
and Dose Spacing
Adequate number of
dose groups. Dose
spacing justified by
previous research.
High
1
1
1

12. Exposure
Route and Method
See footnote at end of
page.1
High
1
1
1

13. Test Animal
Characteristics
FDA colony; species,
strain and starting age
reported.
High
1
2
2
Test Organism
14. Adequacy and
Consistency of
Animal Husbandry
Conditions
See footnote at end of
page.1
High
1
1
1

15. Number per
Group
15/group
High
1
1
1

16. Outcome
Assessment
Methodology
Mechanistic changes
related to liver toxicity
High
1
2
2
Outcome
17. Consistency of
Outcome
Assessment
See footnote at end of
page.1
High
1
1
1
Assessment
18. Sampling
Adequacy
Summary data for
metabolomics and
genomics is provided
for the high dose group
only. Supplemental
data tables are
available for purchase.
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.
50

-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Study reference:
Sun, J., Schmitt, T., Schnackenberg, L. K., Pence, L., Ando, Y., Greenhaw, J., Yang, X. i, Slavov, S.,
Davis, K., Salminen, W. F., Mendrick, D. L., Beser, R. D. (2014). Comprehensive analvsis of
alterations in lipid and bile acid metabolism by carbon tetrachloride using integrated
transcriptomics and metabolomics. Metabolomics, 10(6), 1293-1304

HERO ID: 3487830




Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

19. Blinding of
Assessors
Blinding was not
reported; however,
lack of blinding is not
expected to have a
substantial impact on
results.
Medium
2
1
2

20. Negative
Control Response
Metabolomics changes
were reported relative
to control.
High
1
1
1
Confounding /
Variable Control
21. Confounding
Variables in Test
Design and
Procedures
Lack of reporting of
initial body weights
and food/water intake
is not likely to have a
significant impact on
results.
Medium
2
2
4

22. Health
Outcomes
Unrelated to
Exposure
See footnote at end of
page.11
High
1
1
1

23. Statistical
Methods
See footnote at end of
page.1
High
1
1
1
Data
Presentation and
Analysis
24. Reporting of
Data
Summary data is
reported in the paper;
supplemental data
table are available for
purchase.
Medium
2
2
4


Sum of scores:

30
39
High: >=
Medium: >=
1 and <1.7
=1.7 and <2.3
Overall Score = Sum of Weighted
Scores/Sum of Metric Weighting Factors:
1.3
Overall Score:
Nearest *:
1.3
Low: >=2.3 and <=3







Overall Quality Level:

High

1 Metrics that received a "High" rating met the criteria as discussed in the Applications of Systematic Review for
TSCA Risk Evaluation.
51

-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
2.4. Animal toxicity evaluation results of Sun et al 2014 for a study on hepatic outcomes
Study reference:
Sun, J., Schmitt, T., Schnackenberg, L. K., Pence, L., Ando, Y., Greenhaw, J., Yang, X. i, Slavov, S.,
Davis, K., Salminen, W. F., Mendrick, D. L., Beser, R. D. (2014). Comprehensive analysis of
alterations in lipid and bile acid metabolism by carbon tetrachloride using integrated
transcriptomics and metabolomics. Metabolomics, 10(6), 1293-1304

HERO ID: 3487830




Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
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
Commercial source
was identified.
High
1
1
1

3. Test Substance
Purity
Purity not reported.
Low
3
1
3

4. Negative and
Vehicle Controls
Vehicle (corn oil)
controls were used.
High
1
2
2
Test Design
5. Positive
Controls
Positive controls not
used for liver toxicity.
Not Rated
NA
NA
NA

6. Randomized
Allocation
Animals were
randomly assigned to
each dose group.
High
1
1
1

7. Preparation and
Storage of Test
Substance
Preparation and
storage were not
described; however,
omission of these
details are unlikely to
have a substantial
impact on results
(acute exposure).
Medium
2
1
2
Exposure
Characterization
8. Consistency of
Exposure
Administration
Gavage volume was
not excessive.
High
1
1
1

9. Reporting of
Doses/Concentrati
ons
See footnote at end of
page.1
High
1
2
2

10. Exposure
Frequency and
Duration
Acute studies are
included; liver effects
occur after acute
exposure.
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.
52

-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Study reference:
Sun, J., Schmitt, T., Schnackenberg, L. K., Pence, L., Ando, Y., Greenhaw, J., Yang, X. i, Slavov, S.,
Davis, K., Salminen, W. F., Mendrick, D. L., Beser, R. D. (2014). Comprehensive analvsis of
alterations in lipid and bile acid metabolism by carbon tetrachloride using integrated
transcriptomics and metabolomics. Metabolomics, 10(6), 1293-1304

HERO ID: 3487830




Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

11. Number of
Exposure Groups
and Dose Spacing
Two dose groups plus
control. High dose
chosen to induce mild
to moderate adverse
effects based on range-
finding study. 30
animals received
single dose and an
additional 15 animals
received a total of 3
once daily doses,
which should be
sufficient for the main
purpose of this study
(e.g., metabolomics).
High
1
1
1

12. Exposure
Route and Method
See footnote at end of
page.1
High
1
1
1

13. Test Animal
Characteristics
FDA colony; species,
strain and starting age
reported.
High
1
2
2
Test Organism
14. Adequacy and
Consistency of
Animal Husbandry
Conditions
See footnote at end of
page.1
High
1
1
1

15. Number per
Group
30 animals received
single dose and an
additional 15 animals
received a total of 3
once daily doses
High
1
1
1
Outcome
16. Outcome
Assessment
Methodology
Clinical chemistry and
liver histopathology.
High
1
2
2
Assessment
17. Consistency of
Outcome
Assessment
See footnote at end of
page.1
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.
53

-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Study reference:
Sun, J., Schmitt, T., Schnackenberg, L. K., Pence, L., Ando, Y., Greenhaw, J., Yang, X. i, Slavov, S.,
Davis, K., Salminen, W. F., Mendrick, D. L., Beser, R. D. (2014). Comprehensive analvsis of
alterations in lipid and bile acid metabolism by carbon tetrachloride using integrated
transcriptomics and metabolomics. Metabolomics, 10(6), 1293-1304

HERO ID: 3487830




Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

18. Sampling
Adequacy
5/group used for
clinical chemistry and
histopathology.
Medium
2
1
2

19. Blinding of
Assessors
Blinding was not
reported; however,
lack of blinding is not
expected to have a
substantial impact on
results.
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
Lack of reporting of
initial body weights
and food/water intake
is not likely to have a
significant impact on
results.
Medium
2
2
4

22. Health
Outcomes
Unrelated to
Exposure
See footnote at end of
page.1
High
1
1
1
Data
Presentation and
Analysis
23. Statistical
Methods
Statistical methods
were well-described.
High
1
1
1
24. Reporting of
Data
See footnote at end of
page.1
High
1
2
2


Sum of scores:

30
37
High: >=
Medium: >=
1 and <1.7
=1.7 and <2.3
Overall Score = Sum of Weighted
Scores/Sum of Metric Weighting Factors:
1.233
Overall Score:
Nearest *:
1.2
Low: >=2.3 and <=3







Overall Quality Level:

High

1 Metrics that received a "High" rating met the criteria as discussed in the Applications of Systematic Review for
TSCA Risk Evaluation.
54

-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
3. Subchronic Toxicity Studies
3.1. Animal toxicity evaluation results of Adams et al 1952 for a subchronic inhalation
exposures (46 to 94 days) in rats study on renal, hepatic, nutrition and metabolic/adult
exposure body weight, and cardiovascular outcomes
Study reference:
Adams, E. M., Spencer, H. C., Rowe, V. K., McCollister, D. D., Irish, D. D. (1952). Vapor toxicitv of
carbon tetrachloride determined by experiments on laboratory animals. Archives of Environmental
and Occupational Health, 6(1), 50-66

HERO ID: 62373

Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

4. Negative and
Vehicle Controls
Both untreated and
sham-treated control
groups were used.
High
1
2
2
Test Design
5. Positive
Controls
Positive controls not
typical for this study
type
Not Rated
NA
NA
NA

6. Randomized
Allocation
Study did not describe
method of animal
allocation
Low
3
1
3
55

-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Study reference:
Adams, E. M., Spencer, H. C., Rowe, V. K., McCollister, D. D., Irish, D. D. (1952). Vapor toxicity of
carbon tetrachloride determined by experiments on laboratory animals. Archives of Environmental
and Occupational Health, 6(1), 50-66

HERO ID: 62373





Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

7. Preparation and
Storage of Test
Substance
Method of vapor
generation was
incompletely reported
(equipment not
specified; temperature
used to achieve
vaporization was not
reported) but there is
no reason to believe
there would be an
impact on animal
exposure, as vapor
concentrations were
reportedly analyzed
regularly and within
10% of nominal.
Medium
2
1
2
Exposure
Characterization
8. Consistency of
Exposure
Administration
Exposures at different
concentrations were
administered for
different durations,
making it difficult to
discern effects of
changing duration
from effects of
changing
concentration.
Low
3
1
3

9. Reporting of
Doses/Concentrati
ons
Air concentrations
were reported, but it is
not clear whether these
were nominal or actual
concentrations.
Analysis of chamber
concentrations was by
combustion analysis,
which is likely an
insensitive method.
Low
3
2
6
56

-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Study reference:
Adams, E. M., Spencer, H. C., Rowe, V. K., McCollister, D. D., Irish, D. D. (1952). Vapor toxicity of
carbon tetrachloride determined by experiments on laboratory animals. Archives of Environmental
and Occupational Health, 6(1), 50-66

HERO ID: 62373





Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

10. Exposure
Frequency and
Duration
Exposure frequencies
ranged between 0.05
and 1 hour per day.
This well below the
daily duration typically
used for subchronic
toxicity evaluation.
Unacceptable
4
1
4

11. Number of
Exposure Groups
and Dose Spacing
2 exposure
concentrations were
tested; the low
concentration was
tested at four different
daily exposure
durations (0.05 to 1
hr/day)
Medium
2
1
2

12. Exposure
Route and Method
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, and source
(in-house colony) were
reported. Study
reports choosing
animals for the study
based on health during
pre-exposure
observation period.
Age and initial body
weight were not
reported.
Medium
2
2
4

14. Adequacy and
Consistency of
Animal Husbandry
Conditions
Animal husbandry
conditions other than
the exposure chamber
were not reported.
Low
3
1
3
57

HERO ID: 62373

Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

15. Number per
Group
Group sizes were 5 or
6/sex/group. This is
consistent with
recommendations for
28 day studies but less
than recommended for
subchronic studies.
Medium
2
1
2

16. Outcome
Assessment
Methodology
Outcome assessment
methodology was
described, and
outcomes included
body weight and
weights and
histopathology of liver,
kidney, lung, and
heart.
High
1
2
2
Outcome
Assessment
17. Consistency of
Outcome
Assessment
No inconsistencies in
assessment of these
endpoints were
reported.
High
1
1
1

18. Sampling
Adequacy
All animals were
evaluated for these
endpoints.
High
1
1
1

19. Blinding of
Assessors
No subjective
outcomes were
evaluated.
Not Rated
NA
NA
NA

20. Negative
Control Response
Control responses
were not reported.
Unacceptable
4
1
4
Confounding /
21. Confounding
Variables in Test
Design and
Procedures
Initial body weight,
food/water intake, and
respiratory rate were
not reported.
Low
3
2
6
Variable Control
22. Health
Outcomes
Unrelated to
Exposure
Health outcomes
unrelated to exposure
were not reported.
High
1
1
1
58

-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Study reference:
Adams, E. M., Spencer, H. C., Rowe, V. K., McCollister, D. D., Irish, D. D. (1952). Vapor toxicity of
carbon tetrachloride determined by experiments on laboratory animals. Archives of Environmental
and Occupational Health, 6(1), 50-66
HERO ID: 62373
Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score
Data
Presentation and
Analysis
23. Statistical
Methods
Statistical analysis was
conducted and
methodology
described; the method
did not account for
multiple comparisons.
Medium
2
1
2
24. Reporting of
Data
All data were reported
qualitatively without
indication of which
control group(s) was
compared for
statistical analysis.
Low
3
2
6
High: >=1 and <1.7
Medium: >=1.7 and <2.3
Low: >=2.3 and <=3
Sum of scores:

32
62
Overall Score = Sum of Weighted
Scores/Sum of Metric Weighting Factors:
1.938
Overall Score:
Nearest *:
1.91
Overall Quality Level:
Unacceptable1
Study Quality
Comment:
Footnote 1: Consistent with our Application of A Systematic Review in TSCARisk
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.
59

-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
3.2. Animal toxicity evaluation results of Allis et al 1990 for a 12-week oral study on hepatic,
nutrition and metabolic/adult exposure body weight, clinical chemistry/biochemical
outcomes
Study reference:
Allis, J. W., Ward, T. R., Seelv. J. C., Simmons, J. E. (1990). Assessment of hepatic indicators of
subchronic carbon tetrachloride injury and recovery in rats. Fundamental and Applied Toxicology,
15(3), 558-570

HERO ID: 194565

Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

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
High
1
1
1
Test Substance
3. Test Substance
Purity
Test substance purity
and grade were not
reported and there was
no analysis conducted
for measurement of
impurities, if present.
Low
3
1
3

4. Negative and
Vehicle Controls
A concurrent negative
control group was used
and was appropriate.
High
1
2
2
Test Design
5. Positive
Controls
Positive control is not
indicated by the study
type.
Not Rated
NA
NA
NA

6. Randomized
Allocation
The study authors did
not report how animals
were allocated to study
groups.
Low
3
1
3
Exposure
Characterization
7. Preparation and
Storage of Test
Substance
The study authors
stated that new gavage
solutions were used
daily and were
prepared weekly;
however, the
procedures for
preparing the solutions
in vehicle (corn oil)
were incompletely
reported and storage
conditions were not
reported. Deficiencies
in reporting may have
a substantial impact on
results.
Low
3
1
3
60

-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Study reference:
Allis, J. W., Ward, T. R., Seelv. J. C., Simmons, J. E. (1990). Assessment of hepatic indicators of
subchronic carbon tetrachloride injury and recovery in rats. Fundamental and Applied Toxicology,
15(3), 558-570

HERO ID: 194565





Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

8. Consistency of
Exposure
Administration
Details on exposure
administration were
reported, including
consistent dosing
volumes, and
exposures were
administered
consistently across
study groups in a
scientifically sound
manner (dose volume
of 2 mL/kg was
acceptable).
High
1
1
1

9. Reporting of
Doses/Concentrati
ons
The administered
doses were reported
without ambiguity.
High
1
2
2

10. Exposure
Frequency and
Duration
The exposure
frequency and duration
were reported and
were appropriate for
the study type and
outcomes of interest.
In this subchronic
study, animals were
gavaged 5 days per
week for 12 weeks.
High
1
1
1
61

-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Study reference:
Allis, J. W., Ward, T. R., Seelv. J. C., Simmons, J. E. (1990). Assessment of hepatic indicators of
subchronic carbon tetrachloride injury and recovery in rats. Fundamental and Applied Toxicology,
15(3), 558-570

HERO ID: 194565





Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

11. Number of
Exposure Groups
and Dose Spacing
Although two
quantitative dose
groups (20 and 40
mg/kg/day) were used,
there were deficiencies
in the dose spacing.
Adverse effects,
including liver
histopathology,
clinical chemistry, and
reduced body weight
gain, were observed at
both doses and, in
some cases, there were
few differences
between the two dose
groups (e.g.,
histopathology
incidence).
Low
3
1
3

12. Exposure
Route and Method
The route and method
of exposure were
reported (gavage) and
suited to the test
substance.
High
1
1
1
Test Organism
13. Test Animal
Characteristics
Test animal
characteristics were
reported (source,
species, strain, sex,
age, starting body
weight); however,
health status at the
start of the study was
not reported.
Medium
2
2
4

14. Adequacy and
Consistency of
Animal Husbandry
Conditions
Most husbandry
conditions were
reported and were
adequate and similar
for all groups.
Medium
2
1
2
62

-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Study reference:
Allis, J. W., Ward, T. R., Seelv. J. C., Simmons, J. E. (1990). Assessment of hepatic indicators of
subchronic carbon tetrachloride injury and recovery in rats. Fundamental and Applied Toxicology,
15(3), 558-570

HERO ID: 194565





Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

15. Number per
Group
Groups were
subdivided for some
evaluations, resulting
in a lower number of
animals per group than
is typical. For
example, from the 24
animals/dose level, 6
animals each were
terminated on
respective days 1, 8,
15, and 22 post-
exposure for
evaluation of hepatic
cytochrome P450,
serum chemistry, and
light microscope
histopathology,
resulting in only 6
animals/dose group
evaluated for these
endpoints.
Medium
2
1
2

16. Outcome
The outcome
assessment
methodology
addressed or reported
the intended outcomes
of interest and was
sensitive for the
outcomes of interest,
which were primarily
effects on the liver.




Outcome
Assessment
Assessment
Methodology
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
63

-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Study reference:
Allis, J. W., Ward, T. R., Seelv. J. C., Simmons, J. E. (1990). Assessment of hepatic indicators of
subchronic carbon tetrachloride injury and recovery in rats. Fundamental and Applied Toxicology,
15(3), 558-570

HERO ID: 194565





Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

18. Sampling
Adequacy
Details regarding
sampling for the
outcomes of interest
were reported and
were adequate.
Medium
2
1
2

19. Blinding of
Assessors
No subjective
outcomes were
reported. Blood
samples were assayed
commercially and
histopathology was not
described as a re-
evaluation so I scored
this metric as not
applicable.
Not Rated
NA
NA
NA

20. Negative
Control Response
The negative control
response was adequate.
High
1
1
1

21. Confounding
Variables in Test
Design and
Procedures
There were no reported
differences among the
study groups in initial
body weight or food or
water intake that could
influence the outcome
assessment.
High
1
2
2
Confounding /
Variable Control
22. Health
Outcomes
Unrelated to
Exposure
Data on attrition and
health outcomes
unrelated to exposure
for each study group
were not reported
because only
substantial differences
among groups were
noted.
Medium
2
1
2
64

-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Study reference:
Allis, J. W., Ward, T. R., Seelv. J. C., Simmons, J. E. (1990). Assessment of hepatic indicators of
subchronic carbon tetrachloride injury and recovery in rats. Fundamental and Applied Toxicology,
15(3), 558-570
HERO ID: 194565
Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score
Data
Presentation and
Analysis
23. Statistical
Methods
Statistical analyses that
were conducted were
not described clearly
for each endpoint
evaluated. Statistical
analyses/results were
not reported for the
hepatic histopathology
data (Table 2 of the
study report); however,
sufficient data were
provided to allow an
independent analysis.
Statistical analysis
results were not shown
for body weights.
Although body weight
gain data were
provided in a figure
(Figure 6), the data
were provided without
mean values and error
bars.
Medium
2
1
2
24. Reporting of
Data
Data for exposure-
related findings were
presented by exposure
group, with quantal
and/or continuous
presentation, as well as
severity scores.
Negative findings were
reported in the text.
High
1
2
2
High: >=1 and <1.7
Medium: >=1.7 and <2.3
Low: >=2.3 and <=3
Sum of scores:

29
44
Overall Score = Sum of Weighted
Scores/Sum of Metric Weighting Factors:
1.517
Overall Score:
Nearest *:
1.5
Overall Quality Level:
Medium
65

-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Study reference:
Allis, J. W., Ward, T. R., Seelv. J. C., Simmons, J. E. (1990). Assessment of hepatic indicators of
subchronic carbon tetrachloride injury and recovery in rats. Fundamental and Applied Toxicology,
15(3), 558-570
HERO ID: 194565
Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score
Study Quality
Comment:
The reviewer downgraded this study's overall quality rating. They noted: I would downgrade the
study to medium for the follow reasons: lack of details on test substance purity/grade and lack of
details on preparation of test substance and storage, both in the absence of reported measurement of
test solutions demonstrating stability of test substance in the prepared solutions during the one week
storage period and under the conditions of storage, given potential volatility of CC14. Note: The
original calculated score for this study was 1.5. This value is not presented above because the final
rating was changed based on professional judgement.
66

-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
3.3. Animal toxicity evaluation results of Benson et al 1999 for inhalation and drinking
water ingestion studies (1, 4 and 12 weeks) on hepatic outcomes
Study reference:
Benson, J. M., Springer, D. L. (1999). Improved risk estimates for carbon tetrachloride. Final report
HERO ID: 195107
Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score
Test Substance
1. Test Substance
Identity
Identified by chemical
name.
High
1
2
2
2. Test Substance
Source
No details were
provided on them
source of the test
substance.
Low
3
1
3
3. Test Substance
Purity
Purity was not
reported.
Low
3
1
3
Test Design
4. Negative and
Vehicle Controls
Negative air and dw
controls.
High
1
2
2
5. Positive
Controls
Positive controls are
not generally included
in studies of liver
toxicity.
Not Rated
NA
NA
NA
6. Randomized
Allocation
The study did not
report how animals
were allocated to study
groups.
Low
3
1
3
Exposure
Characterization
7. Preparation and
Storage of Test
Substance
Inhalation exposure
details were provided
in the ADME study
description (method of
vapor generation was
described and
appropriate).
High
1
1
1
8. Consistency of
Exposure
Administration
See footnote at end of
page.1
High
1
1
1
9. Reporting of
Doses/Concentrati
ons
Actual concentrations
were not reported.
Low
3
2
6
10. Exposure
Frequency and
Duration
Continuous exposure
for dw; 6hour/day 5
days/week, for 1, 4 or
12 weeks.
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.
67

-------
Carbon tetrachloride
Study reference:
Benson, J. M., Springer, D. L. (1999). Improved risk estimates for carbon tetrachloride. Final report
HERO ID: 195107
Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

11. Number of
Exposure Groups
and Dose Spacing
2-3 groups plus
control; doses were not
justified, but dose
response relationships
were apparent.
Medium
2
1
2

12. Exposure
Route and Method
Dynamic whole-body
chambers.
High
1
1
1

13. Test Animal
Characteristics
Rat, mouse and
hamster species, strain
and age were reported
in the ADME study,
Obtained from
commercial source.
High
1
2
2
Test Organism
14. Adequacy and
Consistency of
Animal Husbandry
Conditions
Adequate husbandry
conditions as described
in ADME studies.
High
1
1
1

15. Number per
Group
5-6/group for most
endpoints (10/group
for serum chemistry at
12 weeks); adequate
for statistics.
Medium
2
1
2

16. Outcome
Assessment
Methodology
Outcome methods
were sensitive for
hepatotoxicity (serum
chemistry, histopath.
and hepatocellular
replication).
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; however,
outcomes were
objective.
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.
68

-------
Carbon tetrachloride
Study reference:
Benson, J. M., Springer, D. L. (1999). Improved risk estimates for carbon tetrachloride. Final report
HERO ID: 195107
Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

20. Negative
Control Response
No incidence of
hepatocellular necrosis
in controls.
High
1
1
1
Confounding /
Variable Control
21. Confounding
Variables in Test
Design and
Procedures
Respiratory rate was
not measured; CC14 is
anticipated to be a
respiratory irritant.
Low
3
2
6
22. Health
Outcomes
Unrelated to
Exposure
Data on attrition and/or
health outcomes
unrelated to exposure
were not reported for
each study group.
Low
3
1
3
Data
Presentation and
Analysis
23. Statistical
Methods
See footnote at end of
page.1
High
1
1
1
24. Reporting of
Data
Data were reported for
all time points and
exposure groups.
High
1
2
2
High: >=1 and <1.7
Medium: >=1.7 and <2.3
Low: >=2.3 and <=3
Sum of scores:

30
49
Overall Score = Sum of Weighted
Scores/Sum of Metric Weighting Factors:
1.633
Overall Score:
Nearest *:
1.6
Overall Quality Level:
High
1 Metrics that received a "High" rating met the criteria as discussed in the Applications of Systematic
Review for TSCA Risk Evaluation.
69

-------
Carbon tetrachloride
3.4. Animal toxicity evaluation results of Condie et al 1986 for a 90-day oral study on
mortality, metabolic/adult exposure body weight, hepatic, and clinical
chemistry/biochemical outcomes
Study reference:
Condie, L. W., Laurie, R. D., Mills, T., Robinson. M., Bercz, J. P. (1986). Effect of savase vehicle on
hepatotoxicity of carbon tetrachloride in CD-I mice: corn oil versus Tween-60 aqueous emulsion.
Toxicological Sciences, 7(2), 199-206

HERO ID: 60712

Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

1. Test Substance
Identity
The test substance was
identified definitively.
High
1
2
2
Test Substance
2. Test Substance
Source
The source of the test
substance, including
manufacturer and lot
number, was reported.
High
1
1
1

3. Test Substance
Purity
The purity was
reported (98.2%) and
impurities
(chloroform, 1.8%)
were identified.
High
1
1
1

4. Negative and
Vehicle Controls
The study authors
reported using
appropriate concurrent
negative control
groups (corn oil and
Tween-60).
High
1
2
2
Test Design
5. Positive
Controls
Positive control is not
indicated for the study
type.
Not Rated
NA
NA
NA

6. Randomized
Allocation
The study authors did
not report how animals
were allocated to study
groups.
Low
3
1
3
Exposure
Characterization
7. Preparation and
Storage of Test
Substance
The study authors did
not report preparation
and storage conditions,
including how often
test substance was
prepared and under
what conditions the
test substance was
stored. Deficiencies in
reporting may have a
substantial impact on
results.
Low
3
1
3
70

-------
Carbon tetrachloride
Study reference:
Condie, L. W., Laurie, R. D., Mills, T., Robinson. M., Bercz, J. P. (1986). Effect of savase vehicle on
hepatotoxicity of carbon tetrachloride in CD-I mice: corn oil versus Tween-60 aqueous emulsion.
Toxicological Sciences, 7(2), 199-206

HERO ID: 60712





Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

8. Consistency of
Exposure
Administration
Details of exposure
administration were
reported and exposures
were administered
consistently across
study groups.
High
1
1
1

9. Reporting of
Doses/Concentrati
ons
Administered doses
were reported without
ambiguity.
High
1
2
2

10. Exposure
Frequency and
Duration
The exposure
frequency and duration
of exposure were
reported and
appropriate for the
study type and
outcomes of interest.
High
1
1
1

11. Number of
Exposure Groups
and Dose Spacing
The number of
exposure groups and
spacing were reported
and considered
adequate for the
purpose of the study.
Selected
concentrations were
not justified by the
study authors but the
selected doses appear
acceptable.
High
1
1
1

12. Exposure
Route and Method
The route and method
of exposure were
reported and these
were suited to the test
substance.
High
1
1
1
71

-------
Carbon tetrachloride
Study reference:
Condie, L. W., Laurie, R. D., Mills, T., Robinson. M., Bercz, J. P. (1986). Effect of savase vehicle on
hepatotoxicity of carbon tetrachloride in CD-I mice: corn oil versus Tween-60 aqueous emulsion.
Toxicological Sciences, 7(2), 199-206

HERO ID: 60712





Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score
Test Organism
13. Test Animal
Characteristics
The animal species,
strain, and sex were
reported; however,
age, starting body
weight, and health
status were not
reported. The test
species was obtained
from a commercial
source and was an
appropriate model for
evaluation of the
outcomes of interest.
The reporting
deficiencies are
unlikely to have a
substantial impact on
results.
Medium
2
2
4

14. Adequacy and
Consistency of
Animal Husbandry
Conditions
All husbandry
conditions were
reported (e.g.,
temperature, humidity,
light- dark cycle) and
were adequate and the
same for control and
exposed populations.
High
1
1
1

15. Number per
Group
The number of animals
per study group was
reported and
appropriate for the
study type.
High
1
1
1
Outcome
Assessment
16. Outcome
Assessment
Methodology
The outcome
assessment
methodology
addressed the intended
outcomes of interest
and was sensitive for
the outcomes of
interest.
High
1
2
2
72

-------
Carbon tetrachloride
Study reference:
Condie, L. W., Laurie, R. D., Mills, T., Robinson. M., Bercz, J. P. (1986). Effect of savase vehicle on
hepatotoxicity of carbon tetrachloride in CD-I mice: corn oil versus Tween-60 aqueous emulsion.
Toxicological Sciences, 7(2), 199-206

HERO ID: 60712





Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

17. Consistency of
Outcome
Assessment
The outcome
assessment protocol
was reported; however,
the descriptions of
sampling of blood for
serum enzymes do not
clearly indicate when
blood was collected
from the animals.
Medium
2
1
2

18. Sampling
Adequacy
Details regarding
sampling for the
outcomes of interest
were reported by the
study authors and the
study used adequate
sampling for the
outcomes of interest
(e.g., adequate number
of animals from each
group).
High
1
1
1

19. Blinding of
Assessors
The study did not
report evaluation of
subjective outcomes
except histopathology.
According to the
criteria, however, this
metric is not
rated/applicable for
initial histopathology
review.
Not Rated
NA
NA
NA

20. Negative
Control Response
The negative control
response was adequate.
High
1
1
1
Confounding /
Variable Control
21. Confounding
Variables in Test
Design and
Procedures
There were no
confounding variables
among the study
groups that could
influence the outcome
assessment.
High
1
2
2
73

-------
Carbon tetrachloride
Study reference:
Condie, L. W., Laurie, R. D., Mills, T., Robinson. M., Bercz, J. P. (1986). Effect of savase vehicle on
hepatotoxicity of carbon tetrachloride in CD-I mice: corn oil versus Tween-60 aqueous emulsion.
Toxicological Sciences, 7(2), 199-206
HERO ID: 60712
Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

22. Health
Outcomes
Unrelated to
Exposure
Data on attrition or
health outcomes
unrelated to exposure
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
and appropriate for the
data set.
High
1
1
1
24. Reporting of
Data
Data for exposure-
related findings were
presented for all
outcomes by exposure
group and sex with
quantal and/or
continuous
presentation and
description of severity
scores.
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:
1.279
Overall Score:
Nearest *:
1.3
Overall Quality Level:
High
74

-------
Carbon tetrachloride
3.5. Animal toxicity evaluation results of Hayes et al 1986 for a 90-day oral toxicity test in
mice study on reproductive, hematological and immune, neurological, renal, hepatic,
clinical chemistry/biochemical, mortality, nutrition and metabolic/adult exposure body
Study reference:
Haves, J. R., Condie, L. W., Borzelleca, J. F. (1986). Acute, 14-dav repeated dosine, and 90-dav
subchronic toxicity studies of carbon tetrachloride in CD-I mice. Fundamental and Applied
Toxicology, 7(3), 454-463

HERO ID: 194400

Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

3. Test Substance
Purity
Test substance
reported to be HPLC
grade and >99% pure.
High
1
1
1

6. Randomized
Allocation
Study reports
randomizing the mice
but does not discuss
the allocation to
groups
Medium
2
1
2
Exposure
Characterization
7. Preparation and
Storage of Test
Substance
Study reports daily
preparation of solution,
but does not report
storage.
Medium
2
1
2
75

-------
Carbon tetrachloride
Study reference:
Haves, J. R., Condie, L. W., Borzelleca, J. F. (1986). Acute, 14-dav repeated dosins, and 90-dav
subchronic toxicity studies of carbon tetrachloride in CD-I mice. Fundamental and Applied
Toxicology, 7(3), 454-463

HERO ID: 194400

Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

8. Consistency of
Exposure
Administration
Administration details
are provided, including
gavage volume and
time of day of
administration. No
inconsistencies in
exposures across
groups were noted.
High
1
1
1

9. Reporting of
Doses/Concentrati
ons
Dose reported in
mg/kg bw; initial body
weight not reported.
Medium
2
2
4

10. Exposure
Frequency and
Duration
Animals gavaged daily
for 90 days
High
1
1
1

11. Number of
Exposure Groups
and Dose Spacing
4 nonzero doses
ranging 100-fold were
used. Effects were
seen at all doses, so it
is not clear that the
lowest dose was low
enough.
Medium
2
1
2

12. Exposure
Route and Method
See footnote at end of
page.1
High
1
1
1
Test Organism
13. Test Animal
Characteristics
Test animal species,
strain, sex, lifestage,
and source were
reported and
appropriate. Initial
body weights were not
reported.
Medium
2
2
4
14. Adequacy and
Consistency of
Animal Husbandry
Conditions
All husbandry
conditions were
described and
appropriate.
High
1
1
1

15. Number per
Group
20/sex/dose were
tested
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.
76

HERO ID: 194400

Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

16. Outcome
Assessment
Methodology
Only liver and kidney
were examined
microscopically
Medium
2
2
4

17. Consistency of
Outcome
Assessment
No inconsistencies in
outcome assessment
were noted by the
authors.
High
1
1
1
Outcome
18. Sampling
Adequacy
Mortality, body
weight,
histopathology, and
organ weights were
reportedly evaluated in
all animals;
hematology and serum
chemistry evaluated in
subgroups of 8-
10/sex/dose due to low
blood volume of mice.
Medium
2
1
2
Assessment
19. Blinding of
Assessors
Although study reports
observing animals for
signs of intoxication,
no results were
reported, so lack of
blinding would not be
of concern. No other
subjective outcomes
were evaluated
Not Rated
NA
NA
NA

20. Negative
Control Response
Responses of both
naive and vehicle
controls were reported
for all endpoints other
than hematology.
Responses appeared to
be as expected and
without excessive
variability.
High
1
1
1
Confounding /
Variable Control
21. Confounding
Variables in Test
Design and
Procedures
Initial body weight and
food and water intake
were not reported.
Low
3
2
6
77

-------
Carbon tetrachloride
Study reference:
Haves, J. R., Condie, L. W., Borzelleca, J. F. (1986). Acute, 14-dav repeated dosing, and 90-dav
subchronic toxicity studies of carbon tetrachloride in CD-I mice. Fundamental and Applied
Toxicology, 7(3), 454-463

HERO ID: 194400





Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

22. Health
Outcomes
Unrelated to
Exposure
Study reports that there
were no compound-
related deaths, but
there were several
mortalities in the
vehicle control and
high dose groups (in
males) and in vehicle
control and all
exposure groups (in
females); these were
presumably gavage
errors.
Medium
2
1
2

23. Statistical
Methods
Statistical methods
were reported and
appropriate to the data.
High
1
1
1
Data
Presentation and
Analysis
24. Reporting of
Data
There are unexplained
inconsistencies in the
numbers of animals
exposed and evaluated
for histopathology vs
the numbers of animals
for which
histopathology results
are reported. Although
the authors report that
histopathology was
evaluated in all control
and exposed mice,
results are reported for
only 10/sex/dose (vs
20/sex/dose exposed
and evaluated for
organ weights). The
authors do not explain
this apparent
discrepancy.
Low
3
2
6

Sum of scores:

29
49
78

-------
Carbon tetrachloride
Study reference:
Haves, J. R., Condie, L. W., Borzelleca, J. F. (1986). Acute, 14-dav repeated dosine, and 90-dav
subchronic toxicity studies of carbon tetrachloride in CD-I mice. Fundamental and Applied
Toxicology, 7(3), 454-463
HERO ID: 194400
Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
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:
1.690
Overall Score:
Nearest *:
1.7
Overall Quality Level:
High
79

-------
Carbon tetrachloride
3.6. Animal toxicity evaluation results of Nagano et al 2007 for a 13-week inhalation study in
rats and mice study on renal, hepatic, hematological and immune, clinical
chemistry/biochemical, and body weight outcomes
Study reference:
Nagano, K., Umeda, Y., Saito, M., Nishizawa, T., Ikawa, N., Arito, H., Yamamoto, S., Fukushima, S.
(2007b). Thirteen-week inhalation toxicitv of carbon tetrachloride in rats and mice. Journal of
Occupational Health, 49(4), 249-259

HERO ID: 194237

Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

1. Test Substance
Identity
Analytical-grade CC14
High
1
2
2
Test Substance
2. Test Substance
Source
source clearly
identified..
High
1
1
1

3. Test Substance
Purity
purity specified (98%);
each lot analyzed for
stability and purity.
High
1
1
1

4. Negative and
Vehicle Controls
used appropriate
concurrent negative
control group (clean
air) under the same
conditions as treated
groups.
High
1
2
2
Test Design
5. Positive
Controls
this metric is not rated/
applicable because a
positive control is not
indicated by this study
type.
Not Rated
NA
NA
NA

6. Randomized
Allocation
Animals allocated
using stratified
randomization into
weight-matched
groups
Medium
2
1
2
Exposure
Characterization
7. Preparation and
Storage of Test
Substance
The method and
equipment used to
generate the test
substance as a vapor
were reported and
appropriate.
High
1
1
1
8. Consistency of
Exposure
Administration
Details of exposure
administration were
clearly reported and
were consistent across
study groups.
High
1
1
1
80

-------
Carbon tetrachloride
Study reference:
Nagano, K., Umeda, Y., Saito, M., Nishizawa, T., Ikawa, N., Arito, H., Yamamoto, S., Fukushima, S.
(2007b). Thirteen-week inhalation toxicitv of carbon tetrachloride in rats and mice. Journal of
Occupational Health, 49(4), 249-259

HERO ID: 194237





Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

9. Reporting of
Doses/Concentrati
ons
Target and analytical
concentrations were
reported and
appropriate.
High
1
2
2

10. Exposure
Frequency and
Duration
The exposure
frequency and duration
of exposure were
reported and
appropriate.
High
1
1
1

11. Number of
Exposure Groups
and Dose Spacing
The number of
exposure groups and
dose/concentration
spacing were justified
by study authors
High
1
1
1

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 was
obtained through the
reported commercial
source. The test animal
species, strain, sex,
and age were
specified. Starting
body weight was not
reported, but the
authors note that
animals were
randomized into
weight-matched
groups. The authors
also don't explicitly
mention health status
of the animals. These
omissions are unlikely
to have a substantial
impact on results.
Medium
2
2
4
81

-------
Carbon tetrachloride
Study reference:
Nagano, K., Umeda, Y., Saito, M., Nishizawa, T., Ikawa, N., Arito, H., Yamamoto, S., Fukushima, S.
(2007b). Thirteen-week inhalation toxicitv of carbon tetrachloride in rats and mice. Journal of
Occupational Health, 49(4), 249-259

HERO ID: 194237

Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

14. Adequacy and
Consistency of
Animal Husbandry
Conditions
All husbandry
conditions were
reported and adequate.
Conditions were the
same for control and
treated groups.
High
1
1
1

15. Number per
Group
The number of animals
per study group was
reported, appropriate
for the study type and
outcome analysis, and
consistent with studies
of the same or similar
type
High
1
1
1

16. Outcome
Assessment
Methodology
The outcome
assessment
methodology
addressed or reported
the intended 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
adequate. Endpoints
were evaluated in an
adequate number of
animals in each group.
High
1
1
1

19. Blinding of
Assessors
Most outcomes were
not subjective; this
metric is not
rated/applicable for
initial histopathology
review.
Not Rated
NA
NA
NA
82

HERO ID: 194237

Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

20. Negative
Control Response
The biological
responses of the
negative control
groups were adequate.
High
1
1
1

21. Confounding
Variables in Test
Design and
Procedures
There was a lack of
reporting of respiratory
rates; but this lack of
reporting is not likely
to have a significant
impact on results.
Medium
2
2
4
Confounding /
Variable Control
22. Health
Outcomes
Unrelated to
Exposure
Data on attrition and
health outcome
unrelated to exposure
for each study group
were not reported; the
lack of reporting is
unlikely to have a
substantial impact on
results.
Medium
2
1
2
Data
23. Statistical
Methods
Statistical methods
were clearly described
and appropriate for
datasets
High
1
1
1
Presentation and
Analysis
24. Reporting of
Data
Data for exposure-
related findings were
presented for all
outcomes by exposure
group and sex
High
1
2
2

Sum of scores:

29
35
High: >=
Medium: >=
1 and <1.7
=1.7 and <2.3
Overall Score = Sum of Weighted
Scores/Sum of Metric Weighting Factors:
1.207
Overall Score:
Nearest *:
1.2
Low: >=2.3 and <=3
Overall Quality Level:
High
83

-------
Carbon tetrachloride
4. Chronic Toxicity Studies
4.1. Animal toxicity evaluation results of Adams et al 1952 for a 6-month inhalation
exposures in rats, guinea pigs, rabbits, and monkeys study on renal, hepatic,
respiratory, cardiovascular, hematological and immune, nutrition and nutrition and
Study reference:
Adams, E. M., Spencer, H. C., Rowe, V. K., McCollister, D. D., Irish, D. D. (1952). VaDor toxicity of
carbon tetrachloride determined by experiments on laboratory animals. Archives of Environmental
and Occupational Health, 6(1), 50-66

HERO ID: 62373

Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

3. Test Substance
Purity
Test substance purity
not reported, but paper
reports purification of
commercial product by
redistillation and
confirmation of
identity by infrared
absorption
spectroscopy. Minor
contaminants were
identified at low (?
0.05%) concentrations.
Medium
2
1
2
Test Design
4. Negative and
Vehicle Controls
Both untreated and
sham-treated control
groups were used.
High
1
2
2
5. Positive
Controls
Positive controls not
typical for this study
type
Not Rated
NA
NA
NA
84

-------
Carbon tetrachloride
Study reference:
Adams, E. M., Spencer, H. C., Rowe, V. K., McCollister, D. D., Irish, D. D. (1952). Vapor toxicity of
carbon tetrachloride determined by experiments on laboratory animals. Archives of Environmental
and Occupational Health, 6(1), 50-66

HERO ID: 62373





Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

6. Randomized
Allocation
Study did not describe
method of animal
allocation
Low
3
1
3

7. Preparation and
Storage of Test
Substance
Method of vapor
generation was
incompletely reported
(equipment not
specified; temperature
used to achieve
vaporization was not
reported) but there is
no reason to believe
there would be an
impact on animal
exposure, as vapor
concentrations were
reportedly analyzed
regularly and within
10% of nominal.
Medium
2
1
2
Exposure
Characterization
8. Consistency of
Exposure
Administration
Exposures at different
concentrations were
administered for
different durations,
making it difficult to
discern effects of
changing duration
from effects of
changing
concentration.
Low
3
1
3

9. Reporting of
Doses/Concentrati
ons
Air concentrations
were reported, but it is
not clear whether these
were nominal or actual
concentrations.
Analysis of chamber
concentrations was by
combustion analysis,
which is likely an
insensitive method.
Low
3
2
6
85

-------
Carbon tetrachloride
Study reference:
Adams, E. M., Spencer, H. C., Rowe, V. K., McCollister, D. D., Irish, D. D. (1952). Vapor toxicity of
carbon tetrachloride determined by experiments on laboratory animals. Archives of Environmental
and Occupational Health, 6(1), 50-66

HERO ID: 62373





Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

10. Exposure
Frequency and
Duration
Exposures were 7
hr/day, 5 d/week for
durations ranging up to
about 6 months.
High
1
1
1

11. Number of
Exposure Groups
and Dose Spacing
7 exposure
concentrations were
tested in rats and
guinea pigs, with an
overall range of 80-
fold. 5 concentrations
with a range of 20 fold
were tested in rabbits
and monkeys.
Concentrations were
sufficient to identify
effect levels.
High
1
1
1

12. Exposure
Route and Method
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, and source
(in-house colony) were
reported. Study
reports choosing
animals for the study
based on health during
pre-exposure
observation period.
Age and initial body
weight were not
reported.
Medium
2
2
4

14. Adequacy and
Consistency of
Animal Husbandry
Conditions
Animal husbandry
conditions other than
the exposure chamber
were not reported.
Low
3
1
3
86

-------
Carbon tetrachloride
Study reference:
Adams, E. M., Spencer, H. C., Rowe, V. K., McCollister, D. D., Irish, D. D. (1952). Vapor toxicity of
carbon tetrachloride determined by experiments on laboratory animals. Archives of Environmental
and Occupational Health, 6(1), 50-66

HERO ID: 62373





Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

15. Number per
Group
Group sizes were
15/sex for rats, 8/sex
for guinea pigs, 2/sex
for rabbits, and 2
monkeys.
Medium
2
1
2

16. Outcome
Assessment
Methodology
Outcome assessment
methodology was
described, and
outcomes included
body weight and
weights and
histopathology of liver,
kidney, lung, heart,
and spleen. Authors
note that limited blood
chemistry and
hematology endpoints
were assessed "in
many cases".
High
1
2
2
Outcome
Assessment
17. Consistency of
Outcome
Assessment
Authors note that
limited blood
chemistry, liver lipids,
and hematology
endpoints were
assessed "in many
cases" but do not
specify which groups
were evaluated.
Low
3
1
3

18. Sampling
Adequacy
Details regarding
outcome sampling
were not reported.
Low
3
1
3

19. Blinding of
Assessors
Endpoints were not
subjective.
Not Rated
NA
NA
NA

20. Negative
Control Response
Control responses
were reported only for
body weights and
organ weights.
Low
3
1
3
87

-------
Carbon tetrachloride
Study reference:
Adams, E. M., Spencer, H. C., Rowe, V. K., McCollister, D. D., Irish, D. D. (1952). Vapor toxicity of
carbon tetrachloride determined by experiments on laboratory animals. Archives of Environmental
and Occupational Health, 6(1), 50-66
HERO ID: 62373
Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score
Confounding /
Variable Control
21. Confounding
Variables in Test
Design and
Procedures
Initial body weight,
food/water intake, and
respiratory rate were
not reported.
Low
3
2
6
22. Health
Outcomes
Unrelated to
Exposure
Health outcomes
unrelated to exposure
were not reported.
High
1
1
1
Data
Presentation and
Analysis
23. Statistical
Methods
Statistical analysis was
conducted and
methodology
described; the method
did not account for
multiple comparisons.
Medium
2
1
2
24. Reporting of
Data
All data were reported
qualitatively without
indication of which
control group(s) was
compared for
statistical analysis.
Low
3
2
6
High: >=1 and <1.7
Medium: >=1.7 and <2.3
Low: >=2.3 and <=3
Sum of scores:

29
61
Overall Score = Sum of Weighted
Scores/Sum of Metric Weighting Factors:
2.103
Overall Score:
Nearest *:
2.1
Overall Quality Level:
Low
Study Quality
Comment:
The reviewer downgraded this study's overall quality rating. They noted: Limited (predominantly
qualitative) reporting of results, varying exposure durations. Note: The original calculated score for
this study was 2.1. This value is not presented above because the final rating was changed based on
professional judgement.
88

-------
Carbon tetrachloride
4.2. Animal toxicity evaluation results of DuPont et al 2001 for cancer inhalation-rats
(liver), mice (liver, adrenal gland) study on cancer outcomes
Study reference:
DuPont, (2001). Lone Term Inhalation Toxicitv Studies of Five Chlorinated Hydrocarbons in F344
Rats and BCF1 Mice. Advances in Prevention of Occupational Respiratory Diseases

HERO ID: 4215943

Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

1. Test Substance
Identity
Test substance
identified by name.
Medium
2
2
4
Test Substance
2. Test Substance
Source
Source identified
Medium
2
1
2

3. Test Substance
Purity
Purity reported and
such that effects likely
due to test substance.
High
1
1
1

4. Negative and
Vehicle Controls
Concurrent negative
controls were included.
High
1
2
2
Test Design
5. Positive
Controls
Positive controls not
required.
Not Rated
NA
NA
NA

6. Randomized
Allocation
Study reported that
animals were
randomly allocated.
High
1
1
1

7. Preparation and
Storage of Test
Substance
The method and
equipment used to
generate the vapor
were reported.
High
1
1
1

8. Consistency of
Exposure
Administration
Exposures were
administered
consistently
High
1
1
1
Exposure
Characterization
9. Reporting of
Doses/Concentrati
ons
Concentrations were
reported
High
1
2
2
10. Exposure
Frequency and
Duration
Duration and
frequency were
reported.
High
1
1
1

11. Number of
Exposure Groups
and Dose Spacing
The number of
exposure groups and
dose spacing were
reported.
High
1
1
1

12. Exposure
Route and Method
Exposure route and
method were reported.
High
1
1
1
89

-------
Carbon tetrachloride
Study reference:
DuPont, (2001). Lone Term Inhalation Toxicity Studies of Five Chlorinated Hydrocarbons in F344
Rats and BCF1 Mice. Advances in Prevention of Occupational Respiratory Diseases

HERO ID: 4215943

Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

13. Test Animal
Characteristics
The source, species,
strain, sex, and age
were reported. Health
status and initial body
weight were not
reported.
Medium
2
2
4
Test Organism
14. Adequacy and
Consistency of
Animal Husbandry
Conditions
Housing, feed type,
and water were
reported. No other
conditions were
reported.
Medium
2
1
2

15. Number per
Group
The number of animals
per group was
appropriate.
High
1
1
1

16. Outcome
Assessment
Methodology
Outcome assessment
methodology was
reported.
High
1
2
2

17. Consistency of
Outcome
Assessment
Outcome assessment
was consistent.
High
1
1
1
Outcome
Assessment
18. Sampling
Adequacy
All animals were
examined for the
outcomes of interest
High
1
1
1

19. Blinding of
Assessors
Blinding was not
required.
Not Rated
NA
NA
NA

20. Negative
Control Response
Negative control
responses were
appropriate.
High
1
1
1
Confounding /
21. Confounding
Variables in Test
Design and
Procedures
No confounding
variable in test design
and procedures were
reported.
High
1
2
2
Variable Control
22. Health
Outcomes
Unrelated to
Exposure
No health outcomes
unrelated to exposure
were reported.
High
1
1
1
90

-------
Carbon tetrachloride
Study reference:
DuPont, (2001). Lone Term Inhalation Toxicity Studies of Five Chlorinated Hydrocarbons in F344
Rats and BCF1 Mice. Advances in Prevention of Occupational Respiratory Diseases
HERO ID: 4215943
Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score
Data
Presentation and
Analysis
23. Statistical
Methods
Statistical analysis was
reported and
appropriate for the
outcome of interest.
High
1
1
1
24. Reporting of
Data
Data were presented
for cancer outcomes.
Survival, clinical
signs, and body weight
were 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
37
Overall Score = Sum of Weighted
Scores/Sum of Metric Weighting Factors:
1.276
Overall Score:
Nearest *:
1.3
Overall Quality Level:
High
91

-------
Carbon tetrachloride
92

-------
Carbon tetrachloride
4.3. Animal toxicity evaluation results of Nagano et al 2007 for a 2-year bioassay study on
cancer, mortality, hepatic, renal, respiratory, endocrine, clinical chemistry/biochemical,
and nutrition and metabolic/adult exposure body weight outcomes
Study reference:
Nagano, K., Sasaki, T., Umeda, Y., Nishizawa, T., Ikawa, N., Ohbayashi, H., Arito, H., Yamamato,
S., Fukushima, S. (2007a). Inhalation carcinogenicity and chronic toxicitv of carbon tetrachloride in
rats and mice. Inhalation Toxicology, 19(13), 1089-1103

HERO ID: 194127

Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

1. Test Substance
Identity
The test substance was
identified definitively.
High
1
2
2
Test Substance
2. Test Substance
Source
The source of the test
substance was
reported, including
manufacturer;
however, the batch/lot
number was not
reported, although
identity was verified
by analytical means
(gas chromatography)
by the study
laboratory.
High
1
1
1

3. Test Substance
Purity
The test substance
purity and composition
were such that any
observed effects were
highly likely to be due
to the test substance
itself. The purity was
reported as 99.8% and
other components were
identified with purities
provided.
High
1
1
1
Test Design
4. Negative and
Vehicle Controls
The study authors
reported using an
appropriate concurrent
negative control group.
High
1
2
2
5. Positive
Controls
Positive control group
is not indicated by
study type.
Not Rated
NA
NA
NA
93

-------
Carbon tetrachloride
Study reference:
Nagano, K., Sasaki, T., Umeda, Y., Nishizawa, T., Ikawa, N., Ohbayashi, H., Arito, H., Yamamato,
S., Fukushima, S. (2007a). Inhalation carcinogenicity and chronic toxicitv of carbon tetrachloride in
rats and mice. Inhalation Toxicology, 19(13), 1089-1103

HERO ID: 194127





Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

6. Randomized
Allocation
The study reported that
the animals were
divided by stratified
randomization;
however, there were
minor limitations in
the allocation method
due to use of a non-
random component
(body weight-matched
grouping).
Medium
2
1
2
Exposure
Characterization
7. Preparation and
Storage of Test
Substance
The test substance
preparation methods
were reported and
appropriate for the test
substance. The method
and equipment for
generating the test
substance as a vapor
were reported and
appropriate. Although
not reported, test
substance storage
conditions were
considered appropriate
based on observation
of stability of the test
substance before and
after use by gas
chromatography and
infrared spectrometry
analysis.
High
1
1
1

8. Consistency of
Exposure
Administration
Details of exposure
methods were reported
and exposures were
administered
High
1
1
1

consistently for the
study groups.




94

-------
Carbon tetrachloride
Study reference:
Nagano, K., Sasaki, T., Umeda, Y., Nishizawa, T., Ikawa, N., Ohbayashi, H., Arito, H., Yamamato,
S., Fukushima, S. (2007a). Inhalation carcinogenicity and chronic toxicitv of carbon tetrachloride in
rats and mice. Inhalation Toxicology, 19(13), 1089-1103

HERO ID: 194127





Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

9. Reporting of
Doses/Concentrati
ons
Concentrations were
reported without
ambiguity. Mean
measured
concentrations were
reported based on
chamber
concentrations
monitored every 15
minutes during the
exposures by gas
chromatography.
High
1
2
2

10. Exposure
Frequency and
Duration
The exposure
frequency and duration
of exposure were
reported and were
appropriate for the
study type and
outcomes of interest.
High
1
1
1
95

-------
Carbon tetrachloride
Study reference:
Nagano, K., Sasaki, T., Umeda, Y., Nishizawa, T., Ikawa, N., Ohbayashi, H., Arito, H., Yamamato,
S., Fukushima, S. (2007a). Inhalation carcinogenicity and chronic toxicitv of carbon tetrachloride in
rats and mice. Inhalation Toxicology, 19(13), 1089-1103

HERO ID: 194127





Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
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;
however, the highest
concentration (125
ppm) resulted in early
mortality of most
animals. Therefore,
there were an
insufficient number of
animals in this group
for statistical analysis
of some endpoints,
including terminal
body weights, organ
weights, clinical
chemistry, and
urinalysis. Two lower
concentrations, 5 and
25 ppm, were also
included in the study
and a sufficient
number of animals
survived the duration
of exposure for
statistical analysis on
the same endpoints.
Medium
2
1
2

12. Exposure
Route and Method
The route and method
of exposure were
reported and 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
was not reported.
Medium
2
2
4
96

-------
Carbon tetrachloride
Study reference:
Nagano, K., Sasaki, T., Umeda, Y., Nishizawa, T., Ikawa, N., Ohbayashi, H., Arito, H., Yamamato,
S., Fukushima, S. (2007a). Inhalation carcinogenicity and chronic toxicitv of carbon tetrachloride in
rats and mice. Inhalation Toxicology, 19(13), 1089-1103

HERO ID: 194127





Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

14. Adequacy and
Consistency of
Animal Husbandry
Conditions
All husbandry
conditions were
reported, including
temperature, humidity,
and light-dark cycle,
and were adequate and
no differences were
reported for the test
substance-exposed and
control groups.
High
1
1
1

15. Number per
Group
The number of animals
per study group
(50/sex/group) was
reported and
appropriate for the
study type.
High
1
1
1

16. Outcome
Assessment
Methodology
The outcome
assessment
methodology
addressed the intended
outcomes of interest
and was sensitive for
the outcomes of
interest.
High
1
2
2
Outcome
Assessment
17. Consistency of
Outcome
Assessment
Details of the outcome
assessment protocol
were reported and
outcomes were
assessed consistently
across study groups
using the same
protocol.
High
1
1
1

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
97

-------
Carbon tetrachloride
Study reference:
Nagano, K., Sasaki, T., Umeda, Y., Nishizawa, T., Ikawa, N., Ohbayashi, H., Arito, H., Yamamato,
S., Fukushima, S. (2007a). Inhalation carcinogenicity and chronic toxicitv of carbon tetrachloride in
rats and mice. Inhalation Toxicology, 19(13), 1089-1103

HERO ID: 194127





Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

19. Blinding of
Assessors
No subjective
outcomes were
reported so I
considered this metric
not applicable. Blood
samples were analyzed
automatically and
histopathology was not
described as a re-
evaluation.
Not Rated
NA
NA
NA

20. Negative
Control Response
The biological
responses of the
negative control were
adequate.
High
1
1
1
Confounding /
Variable Control
21. Confounding
Variables in Test
Design and
Procedures
There were no
confounding
differences among the
study groups in initial
body weight.
Respiratory rate,
however, was not
reported.
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 study groups
were noted.
Medium
2
1
2
Data
Presentation and
Analysis
23. Statistical
Methods
The statistical methods
were clearly described
and appropriate for the
data.
High
1
1
1
98

-------
Carbon tetrachloride
24. Reporting of
Data
See footnote at end of TT. ,
i High
page.
1
2
2
High: >=1 and <1.7
Medium: >=1.7 and <2.3
Low: >=2.3 and <=3
Sum of scores:

29
36
Overall Score = Sum of Weighted
Scores/Sum of Metric Weighting Factors:
1.241
Overall Score:
Nearest *:
1.2
Overall Quality Level:
High
1 Metrics that received a "High" rating met the criteria as discussed in the Applications of Systematic Review for
TSCA Risk Evaluation.
99

-------
Carbon tetrachloride
5. Reproductive/Developmental Toxicity Studies
5.1. Animal toxicity evaluation results of Schwetz et al 1974 for inhalation developmental
toxicity study in rats study on growth (early life) and development outcomes
Study reference:
B. A. Schwetz, B. K. J. Leone, P. J. Gehrins (1974). Embrvo- and Fetotoxcitiv of Inhaled Carbon
Tetrachloride 1,1-Dichloroethane and Methyl Ethyl Ketone in Rats. Toxicology and Applied
Pharmacology, 28(1,1), 452-464

HERO ID: 62395

Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

1. Test Substance
Identity
Reagent grade CC14
High
1
2
2
Test Substance
2. Test Substance
Source
Source and lot number
were reported. Lot No.
9256, Burdick &
Jackson Lab, Inc.,
Muskegon, Michigan
High
1
1
1

3. Test Substance
Purity
99.9%; listed an
unknown component
of 0.1%; determined
by gas-liquid
chromatography
High
1
1
1

4. Negative and
Vehicle Controls
Control animals for
each experiment
exposed concurrently
to filtered room air
High
1
2
2
Test Design
5. Positive
Controls
This metric is not
rated/applicable for
this 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
Exposure
Characterization
7. Preparation and
Storage of Test
Substance
the method and
equipment used to
generate the test
substance as a vapor
was reported and
appropriate; storage
conditions were not
reported
Medium
2
1
2
100

-------
Carbon tetrachloride
Study reference:
B. A. Schwetz, B. K. J. Leone, P. J. Gehrins (1974). Embrvo- and Fetotoxcitiv of Inhaled Carbon
Tetrachloride 1,1-Dichloroethane and Methyl Ethyl Ketone in Rats. Toxicology and Applied
Pharmacology, 28(1,1), 452-464

HERO ID: 62395





Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

8. Consistency of
Exposure
Administration
Details of exposure
administration were
reported and exposures
were administered
consistently across
study groups
High
1
1
1

9. Reporting of
Doses/Concentrati
ons
nominal concentrations
were reported and
vapor concentration
was measured
analytically in the
chamber and reported.
High
1
2
2

10. Exposure
Frequency and
Duration
7 hr/day GD 6-15
High
1
1
1

11. Number of
Exposure Groups
and Dose Spacing
Two vapor
concentrations tested;
one concentration in an
initial experiment and
the other in a second
experiment. Each
experiment had its own
control group. It is not
clear if these
experiments were
conducted
concurrently.
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
Adult, Sprague
Dawley female rats;
starting body weight
was reported
High
1
2
2
101

-------
Carbon tetrachloride
Study reference:
B. A. Schwetz, B. K. J. Leone, P. J. Gehrins (1974). Embrvo- and Fetotoxcitiv of Inhaled Carbon
Tetrachloride 1,1-Dichloroethane and Methyl Ethyl Ketone in Rats. Toxicology and Applied
Pharmacology, 28(1,1), 452-464

HERO ID: 62395





Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

14. Adequacy and
Consistency of
Animal Husbandry
Conditions
Husbandry conditions
were reported, but
conditions were not
specific for
temperature, humidity,
and light cycle.
Medium
2
1
2

15. Number per
Group
The number of animals
per study group was
reported, appropriate
for the study type
High
1
1
1

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
Outcome
Assessment
17. Consistency of
Outcome
Assessment
The outcome
assessment
methodology
addressed or reported
the intended outcomes
of interest
High
1
1
1
18. Sampling
Adequacy
Sampling for the
outcomes of interest
were adequate;
developmental
endpoints were
evaluated for litters.
High
1
1
1

19. Blinding of
Assessors
Not applicable; initial
pathology review; no
other subjective
outcomes were
assessed
Not Rated
NA
NA
NA

20. Negative
Control Response
The biological
responses of the
negative control group
was adequate
High
1
1
1
102

-------
Carbon tetrachloride
Study reference:
B. A. Schwetz, B. K. J. Leone, P. J. Gehrins (1974). Embrvo- and Fetotoxcitiv of Inhaled Carbon
Tetrachloride 1,1-Dichloroethane and Methyl Ethyl Ketone in Rats. Toxicology and Applied
Pharmacology, 28(1,1), 452-464
HERO ID: 62395
Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score
Confounding /
Variable Control
21. Confounding
Variables in Test
Design and
Procedures
The study reported
minor differences
among the study
groups with respect to
food consumption of
dams; however, there
was no effect on the
conception rate or
number of
implantations or size
of litters.
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
Medium
2
1
2
Data
Presentation and
Analysis
23. Statistical
Methods
Statistical methods
were not specified in
the methodology
section of the paper,
but are statistical tests
used were specified
and clear in the results
tables.
Medium
2
1
2
24. Reporting of
Data
Data for exposure-
related findings were
presented for all
outcomes by exposure
group
High
1
2
2
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:
1.310
Overall Score:
Nearest *:
1.3
Overall Quality Level:
High
103

-------
Carbon tetrachloride
5.2. Animal toxicity evaluation results of Narotsky et al 1997
Study reference:
Narotskv, M. G., Peeram, R. A., Kavlock, R. J. (1997). Effect of dosine vehicle on the developmental
toxicity of bromodichloromethane and carbon tetrachloride in rats. Fundamental and Applied
Toxicology, 40(1), 30-36

HERO ID: 194607





Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
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
See footnote at end of
page.1
High
1
2
2

5. Positive
Controls
A positive control
group is not required
for study type.
Not Rated
NA
NA
NA
Test Design
6. Randomized
Allocation
Method for allocation
"assured a
homogeneous
distribution of body
weights among
groups".
Medium
2
1
2
Exposure
7. Preparation and
Storage of Test
Substance
Information on
stability of dosing
formulations is not
provided and
frequency of
preparation is not
reported.
Medium
2
1
2
Characterization
8. Consistency of
Exposure
Administration
See footnote at end of
page.1
High
1
1
1

9. Reporting of
Doses/Concentrati
ons
See footnote at end of
page.1
High
1
2
2
1 Metrics that received a "High" rating met the criteria as discussed in the Applications of Systematic Review for
TSCA Risk Evaluation.
104

-------
Carbon tetrachloride
Study reference:
Narotskv. M. G., Pesram, R. A., Kavlock, R. J. (1997). Effect of dosins vehicle on the developmental
toxicity of bromodichloromethane and carbon tetrachloride in rats. Fundamental and Applied
Toxicology, 40(1), 30-36

HERO ID: 194607





Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

10. Exposure
Frequency and
Duration
Animals were exposed
only on GD 6-15.
More complete
information on
developmental effects
of CC14 could be
determined if animals
were exposed through
the entire gestation
period.
Medium
2
1
2

11. Number of
See footnote at end of
page.1





Exposure Groups
and Dose Spacing
High
1
1
1

12. Exposure
Route and Method
See footnote at end of
page.1
High
1
1
1

13. Test Animal
Characteristics
Age of animals was
not reported.
Medium
2
2
4
Test Organism
14. Adequacy and
Consistency of
Animal Husbandry
Conditions
See footnote at end of
page.1
High
1
1
1

15. Number per
Group
12-13 dams per group
High
1
1
1

16. Outcome
Assessment
Methodology
Main focus of study
was full-litter
resorption.
High
1
2
2
Outcome
17. Consistency of
Outcome
Assessment
See footnote at end of
page.1
High
1
1
1
Assessment
18. Sampling
Adequacy
See footnote at end of
page.1
High
1
1
1

19. Blinding of
Assessors
Outcomes were not
subjective.
Not Rated
NA
NA
NA

20. Negative
Control Response
See footnote at end of
page.1
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.
105

-------
Carbon tetrachloride
Study reference:
Narotskv. M. G., Pesram, R. A., Kavlock, R. J. (1997). Effect of dosins vehicle on the developmental
toxicity of bromodichloromethane and carbon tetrachloride in rats. Fundamental and Applied
Toxicology, 40(1), 30-36
HERO ID: 194607
Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score
Confounding /
Variable Control
21. Confounding
Variables in Test
Design and
Procedures
See footnote at end of
page.1
High
1
2
2
22. Health
Outcomes
Unrelated to
Exposure
See footnote at end of
page.1
High
1
1
1
Data
Presentation and
Analysis
23. Statistical
Methods
See footnote at end of
page.1
High
1
1
1
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:

29
34
Overall Score = Sum of Weighted
Scores/Sum of Metric Weighting Factors:
1.172
Overall Score:
Nearest *:
1.2
Overall Quality Level:
High
106

-------
Carbon tetrachloride
6. In Vitro Studies
6.1. In vitro evaluation results of Araki et al 2004
Study reference:
Araki, A., Kamieaitao, N., Sasaki, T., Matsushima, T. (2004). Mutagenicity of carbon tetrachloride
and chloroform in Salmonella typhimurium TA98, TA100, TA1535, and TA1537, and Escherichia
coli WP2uvrA/pKM101 and WP2/pKM101, using a gas exposure method. Environmental and
Molecular Mutagenesis, 43(2), 128-133

HERO ID: 194641

Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

1. Test Substance
Identity
The test substance was
identified by CASRN.
High
1
2
2
Test Substance
2. Test Substance
Source
The source of the test
substance was
reported, including
manufacturer and
batch/lot number.
High
1
1
1

3. Test Substance
Purity
The test substance
purity was reported.
High
1
1
1

4. Negative and
Vehicle Controls
Negative control was
reported.
High
1
2
2
Test Design
5. Positive
Controls
The authors reported
testing positive control
substances by the pour
plate method, but not
the gas-phase exposure
method.
Medium
2
2
4
6. Assay
procedures
Study authors
described the methods
and procedures.
High
1
1
1

7. Standards for
tests
Standards for test
provided. The QC part
of this test criteria may
not be applicable.
Not Rated
NA
NA
NA
Exposure
Characterization
8. Preparation and
Storage of Test
Substance
This may not be
applicable since the
test chemical was
purchased from a
commercial vendor
and can be used with
or without storage.
Not Rated
NA
NA
NA

9. Consistency of
Exposure
Administration
Authors reported the
details of exposure
administration.

NA
1
NA
107

-------
Carbon tetrachloride
Study reference:
Araki, A., Kamisaitao, N., Sasaki, T., Matsushima, T. (2004). Mutagenicity of carbon tetrachloride
and chloroform in Salmonella typhimurium TA98, TA100, TA1535, and TA1537, and Escherichia
coli WP2uvrA/pKM101 and WP2/pKM101, using a gas exposure method. Environmental and
Molecular Mutagenesis, 43(2), 128-133

HERO ID: 194641

Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

10. Reporting of
Doses/Concentrati
ons
The exposure
doses/concentrations
or amounts of test
substance were
reported.
High
1
2
2

11. Number of
Exposure Groups
and Concentration
Spacing
Exposure duration was
reported.
High
1
2
2

12. Exposure
Route and Method
The number of
exposure groups and
dose/concentration
spacing were justified
by study authors.
High
1
1
1

13. Metabolic
Activation
Study authors reported
exposures were
conducted in the
presence and absence
of metabolic activation
and the type and
source, method of
preparation.
High
1
1
1

14. Test Model
Authors provided
descriptive information
on the test model.
High
1
2
2
Test Model
15. Number per
Group
The authors provided
details about the tester
strains used in this
study.
High
1
1
1
Outcome
Assessment
16. Outcome
Assessment
Methodology
The authors reported
the outcome
methodology for the
study.
High
1
2
2
17. Consistency of
Outcome
Assessment
Outcome assessment
was consistent.
High
1
1
1
108

HERO ID: 194641

Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

18. Sampling
Adequacy
Sampling adequacy
was reported for the
outcome(s) of interest
including more data
values per dose group
from different
experiments.
High
1
2
2

19. Blinding of
Assessors
This metric is not
applicable.
Not Rated
NA
NA
NA
Confounding /
Variable Control
20. Confounding
Variables in Test
Design and
Procedures
No confounding
variables identified.
High
1
2
2
21. Confounding
Variables in
Outcomes
Unrelated to
Exposure
Authors did not report
any differences in
study groups that was
not related to chemical
exposure.
High
1
1
1

22. Data Analysis
Authors reported
statistical analysis of
the data.
High
1
1
1
Data
Presentation and
Analysis
23. Data
Interpretation
Authors followed the
two-fold rule for
mutagenicity in
individual
experiments.
High
1
2
2
24. Cytotoxicity
Data
The study authors
reported cytotoxicity
information.
High
1
1
1

25. Reporting of
Data
Authors reported
exposure-related
findings as well as data
from the negative
controls.
High
1
2
2
High: >-1 and <1.7
Medium: >=1.7 and <2.3
Low: >=2.3 and <=3
Sum of scores:

33
34
Overall Score = Sum of Weighted
Scores/Sum of Metric Weighting Factors:
1.030
Overall Score:
Nearest *:
1.0
109

-------
Carbon tetrachloride
Study reference:
Araki, A., Kamieaitao, N., Sasaki, T., Matsushima, T. (2004). Mutagenicity of carbon tetrachloride
and chloroform in Salmonella typhimurium TA98, TA100, TA1535, and TA1537, and Escherichia
coli WP2uvrA/pKM101 and WP2/pKM101, using a gas exposure method. Environmental and
Molecular Mutagenesis, 43(2), 128-133
HERO ID: 194641
Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

Overall Quality Level:
High
110

-------
Carbon tetrachloride
6.2. In vitro evaluation results of Garberg et al 1988
Study reference:
Garbere, P., Akerblom, E. L., Bolcsfoldi, G. (1988). Evaluation of a eenotoxicitv test measuring
DNA-strand breaks in mouse lymphoma cells by alkaline unwinding and hydroxyapatite elution.
Mutation Research, 203(3), 155-176

HERO ID: 7271

Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

1. Test Substance
Identity
The test substance was
clearly identified.
High
1
2
2
Test Substance
2. Test Substance
Source
The source of the test
substance reported
including
manufacturer, but the
batch/lot number not
provided.
Medium
2
1
2

3. Test Substance
Purity
Although the authors
did not report the
purity of the chemical,
it may be of a minor
concern since the
chemical is from a
standard company.
Medium
2
1
2

4. Negative and
Vehicle Controls
Test authors report
using a concurrent
negative control group.
High
1
2
2
Test Design
5. Positive
Controls
The authors do no
report a concurrent
positive control group.
But it may not be a
concern since they
have used known
genotoxic chemicals in
this study.
Not Rated
NA
NA
NA

6. Assay
procedures
Assay procedures were
reported in detail.
High
1
1
1

7. Standards for
tests
The QC part of this
test criteria may not be
applicable.
Not Rated
NA
NA
NA
Exposure
Characterization
8. Preparation and
Storage of Test
Substance
This may not be
applicable since the
test chemical was
purchased from a
commercial vendor
and can be used with
or without storage.
Not Rated
NA
NA
NA
111

-------
Carbon tetrachloride
Study reference:
Garbers, P., Akerblom, E. L., Bolcsfoldi, G. (1988). Evaluation of a eenotoxicitv test measuring
DNA-strand breaks in mouse lymphoma cells by alkaline unwinding and hydroxyapatite elution.
Mutation Research, 203(3), 155-176

HERO ID: 7271





Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

9. Consistency of
Exposure
Administration
Details of exposure
administration were
reported.
High
1
1
1

10. Reporting of
Doses/Concentrati
ons
Doses/concentrations
were reported.
High
1
2
2

11. Number of
Exposure Groups
and Concentration
Spacing
Exposure duration was
reported.
High
1
2
2

12. Exposure
Route and Method
Number of exposure
groups and
concentration spacing
were reported.
High
1
1
1

13. Metabolic
Activation
Tests were done with
and without metabolic
activation.
High
1
1
1
Test Model
14. Test Model
The authors used a
standard genotoxicity
test model.
High
1
2
2
15. Number per
Group
The authors reported
the number of cells per
group.
High
1
1
1

16. Outcome
Assessment
Methodology
The outcome
assessment
methodology was
reported.
High
1
2
2
Outcome
Assessment
17. Consistency of
Outcome
Assessment
Outcome assessment
was consistent.
High
1
1
1

18. Sampling
Adequacy
Adequate.
High
1
2
2

19. Blinding of
Assessors
This metric is not
applicable.
Not Rated
NA
NA
NA
112

-------
Carbon tetrachloride
Study reference:
Garbers, P., Akerblom, E. L., Bolcsfoldi, G. (1988). Evaluation of a eenotoxicitv test measuring
DNA-strand breaks in mouse lymphoma cells by alkaline unwinding and hydroxyapatite elution.
Mutation Research, 203(3), 155-176

HERO ID: 7271





Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score
Confounding /
Variable Control
20. Confounding
Variables in Test
Design and
Procedures
See footnote at end of
page.1
High
1
2
2
21. Confounding
Variables in
Outcomes
Unrelated to
Exposure
See footnote at end of
page.1
High
1
1
1

22. Data Analysis
The authors did not
conduct statistical
analysis.
Low
3
1
3
Data
Presentation and
Analysis
23. Data
Interpretation
Data interpretation was
consistent.
High
1
2
2
24. Cytotoxicity
Data
Authors reported
cytotoxicity data (cell
viability).
Unacceptable
4
1
4

25. Reporting of
Data
Data was reported for
all doses.
High
1
2
2


Sum of scores:

31
38
High: >=
Medium: >=
1 and <1.7
=1.7 and <2.3
Overall Score = Sum of Weighted
Scores/Sum of Metric Weighting Factors:
1.226
Overall Score:
Nearest *:
1.21
Low: >=2.3 and <=3







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.
1 Metrics that received a "High" rating met the criteria as discussed in the Applications of Systematic Review for
TSCA Risk Evaluation.
113

-------
Carbon tetrachloride
6.3. In vitro evaluation results of Imperial et al 1976 for a genotoxicity-bacterial reverse
mutation study
Study reference:
Imperial Chemical, Indus (1976). Mutagenicity testing with salmonella tvDhimurium strains on
plates, of gases, liquids and solids for Imperial Chemical Industries Limited with attachments

HERO ID: 4213903

Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

1. Test Substance
Identity
Test substance
identified; CASRN not
reported.
Medium
2
2
4
Test Substance
2. Test Substance
Source
Test manufacturer of
the substance was
reported, but batch/lot
number was not
reported.
Medium
2
1
2

3. Test Substance
Purity
The purity and grade
of the test substance
was not reported.
Low
3
1
3

4. Negative and
Vehicle Controls
Authors reported the
use of negative
controls.
High
1
2
2

5. Positive
Controls
Authors reported use
of positive controls.
High
1
2
2
Test Design
6. Assay
procedures
Assay procedure was
described with limited
assay details.
Low
3
1
3

7. Standards for
tests
The QC part of this
test criteria may not be
applicable.
Not Rated
NA
NA
NA

8. Preparation and
Storage of Test
Substance
This may not be
applicable since the
test chemical was
purchased from a
commercial vendor
and can be used with
or without storage.
Not Rated
NA
NA
NA
Exposure
Characterization
9. Consistency of
Exposure
Administration
Although exposure
administration
information was
provided it is
incomplete making it
less consistent.
Low
3
1
3

10. Reporting of
Doses/Concentrati
ons
Authors reported three
doses/concentrations
of the test chemical.
High
1
2
2
114

-------
Carbon tetrachloride
Study reference:
Imperial Chemical, Indus (1976). Mutagenicity testing with salmonella tvphimurium strains on
plates, of gases, liquids and solids for Imperial Chemical Industries Limited with attachments
HERO ID: 4213903
Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

11. Number of
Exposure Groups
and Concentration
Spacing
The exposure duration
reported was lower
than standard assays.
Low
3
2
6
12. Exposure
Route and Method
Although the number
of exposure groups
was sufficient, the
higher and highest
exposure
concentrations were
highly toxic.
Low
3
1
3
13. Metabolic
Activation
The authors reported
the use of metabolic
activation, however,
the methods lack the
details of the protocol.
Low
3
1
3
Test Model
14. Test Model
The authors reported
the strain types, their
properties and the
description of the test
model, but provided
limited details.
Medium
2
2
4
15. Number per
Group
The authors mentioned
the adaptation of a a
standard assay method.
However, they did not
provide details of the
number and replicates
used per study group.
Unacceptable
4
1
4
Outcome
Assessment
16. Outcome
Assessment
Methodology
The reporting was
incomplete and it was
unclear whether
methods were sensitive
for the outcome of
interest
Low
3
2
6
17. Consistency of
Outcome
Assessment
The authors did not
provide specifics about
the execution of the
study protocol.
Low
3
1
3
115

HERO ID: 4213903

Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable, or
Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

18. Sampling
Adequacy
Details regarding
sampling of outcomes
were not fully
reported.
Low
3
2
6

19. Blinding of
Assessors
This metric is not
applicable for this
study.
Not Rated
NA
NA
NA
Confounding /
Variable Control
20. Confounding
Variables in Test
Design and
Procedures
Details about the
number of organisms
used per group were
not reported. These
deficiencies are likely
to have a substantial
impact on results.
Low
3
2
6

21. Confounding
Variables in
Outcomes
Unrelated to
Exposure
Data on outcome
differences unrelated
to exposure were not
reported.
Low
3
1
3

22. Data Analysis
Although data is
available for
calculations, the high
toxicity seen at two
higher doses might
impact the analysis.
Low
3
1
3
Data
23. Data
Interpretation
High toxicity makes
the interpretation of
data difficult.
Low
3
2
6
Presentation and
Analysis
24. Cytotoxicity
Data
Although the
endpoints of
cytotoxicity were
defined, the methods
of measurements were
not fully described or
reported.
Low
3
1
3

25. Reporting of
Data
Study authors reported
data for all exposure
groups.
High
1
2
2

Sum of scores:

32
75
116

-------
Carbon tetrachloride
Study reference:
Imperial Chemical, Indus (1976). Mutagenicity testing with salmonella tvphimurium strains on
plates, of gases, liquids and solids for Imperial Chemical Industries Limited with attachments
HERO ID: 4213903
Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High,
Medium, Low,
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:
2.394
Overall Score:
Nearest *:
2.41
Overall Quality Level:
Unacceptable1
Study Quality
Comment:
Footnote 1: Consistent with our Application of A Systematic Review in TSCARisk
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.
117

-------
Carbon tetrachloride
6.4. In vitro evaluation results of Cummings et al 2000
Study reference:
Cummines, B. S., Lash, L. H. (2000). Metabolism and toxicitv of trichloroethvlene and S-(l,2-
dichlorovinyl)-L-cysteine in freshly isolated human proximal tubular cells. Toxicological Sciences,
53(2), 458-466
HERO ID: 194686
Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score
Test Substance
1. Test Substance
Identity
Test substance identity
was clearly stated
High
1
2
2
2. Test Substance
Source
Test substance
obtained from Sigma,
manufacturer was not
reported
High
1
1
1
3. Test Substance
Purity
A purity of 95% was
determined by HPLC
analysis
High
1
1
1
Test Design
4. Negative and
Vehicle Controls
It is assumed that the
negative control was
solvent alone, but it is
not explicitly stated,
and it is unclear
whether a control, or
all samples, were
pretreated prior to
exposure
Low
3
2
6
5. Positive
Controls
No positive control,
not necessary
Not Rated
NA
NA
NA
6. Assay
procedures
Procedures are
reported, but some
details are unclear. It
is not known whether
all cells were pre-
treated with wither
metyrapone or solvent
control prior to TCE,
or if some cells were
treated with TCE only
(there is confusion
between what is stated
in text and what is in
the figure)
Medium
2
1
2
7. Standards for
tests
Another study using a
similar LDH activity
assay as a measure of
cytotoxicity was cited.
High
1
1
1
118

-------
Carbon tetrachloride
Study reference:
Cumminss, B. S., Lash, L. H. (2000). Metabolism and toxicity of trichloroethvlene and S-(l,2-
dichlorovinyl)-L-cysteine in freshly isolated human proximal tubular cells. Toxicological Sciences,
53(2), 458-466

HERO ID: 194686

Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

8. Preparation and
Storage of Test
Substance
Preparation and
storage were not
reported
Unacceptable
4
1
4

9. Consistency of
Exposure
Administration
No signs of
inconsistencies were
found
High
1
1
1
Exposure
Characterization
10. Reporting of
Doses/Concentrati
ons
Dose concentrations
were clearly described
High
1
2
2
11. Number of
Exposure Groups
and Concentration
Spacing
Exposure duration was
appropriate for this
endpoint
High
1
2
2

12. Exposure
Route and Method
Minimum number
required as per PECO
(2 dose groups and a
negative control)
High
1
1
1

13. Metabolic
Activation
Not applicable to this
assay
Not Rated
NA
NA
NA

14. Test Model
The test model was
appropriate.
High
1
2
2
Test Model
15. Number per
Group
Two separate samples
of hPT cells were
isolated from two
human patients (n =4)
High
1
1
1

16. Outcome
Assessment
Methodology
Methodology was
detailed appropriately
High
1
2
2
Outcome
Assessment
17. Consistency of
Outcome
Assessment
No inconsistencies
were apparent.
High
1
1
1
18. Sampling
Adequacy
All of the sample were
assayed
High
1
2
2

19. Blinding of
Assessors
Not applicable,
endpoints were not
subjective
Not Rated
NA
NA
NA
119

HERO ID: 194686

Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score
Confounding /
Variable Control
20. Confounding
Variables in Test
Design and
Procedures
The numbers (n) of
replicates used were
appropriate, however,
there was a large range
in the number of cells
per replicate used for
the LDH activity assay
(0.5 to 10 x 10A6
cells). Ideally the cell
numbers should have
been standardized,
although activity was
/mg of protein.
Low
3
2
6

21. Confounding
Variables in
Outcomes
Unrelated to
Exposure
No unrelated exposure
outcomes were
apparent
High
1
1
1

22. Data Analysis
Statistical analysis was
appropriate
High
1
1
1

23. Data
Interpretation
Interpretation was
acceptable based on
the data reported
High
1
2
2
Data
Presentation and
Analysis
24. Cytotoxicity
Data
Question does not
seem applicable to this
study as the main
endpoint evaluated
was cytotoxicity
Not Rated
NA
NA
NA

25. Reporting of
Data
There is uncertainty
about the data reported
given the descriptions
in the text.
Low
3
2
6

Sum of scores:

31
47
High: >=
Medium: >=
1 and <1.7
=1.7 and <2.3
Overall Score = Sum of Weighted
Scores/Sum of Metric Weighting Factors:
1.516
Overall Score:
Nearest *:
1.5
Low: >=2.3 and <=3

Overall Quality Level:

High

120

-------
Carbon tetrachloride
7. References
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carbon tetrachloride determined by experiments on laboratory animals. Arch
Environ Occup Health 6: 50-66.
Allis. IW: Ward. TR: Seelv. IC: Simmons. IE. (1990). Assessment of hepatic indicators of
subchronic carbon tetrachloride injury and recovery in rats. Fundam Appl
Toxicol 15: 558-570. http://dx.doi.org/10.1016/0272-0590(90)90041 -H
Araki. A: Kamigaitao. N: Sasaki. T: Matsushima. T. (2004). Mutagenicity of carbon
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and TA1537, and Escherichia coli WP2uvrA/pKM101 and WP2/pKM101, using a
gas exposure method. Environ Mol Mutagen 43: 128-133.
http://dx.doi.org/10.1002/em.20005
Benson. IM: Springer. PL. (1999). Improved risk estimates for carbon tetrachloride.
Final report. (PE-FC04-96AL76406). Albuquerque, New Mexico: U.S. Pepartment
of Energy.
Bruckner. IV: Mackenzie. WF: Muralidhara. S: Luthra. R: Kvle. GM: Acosta. P. (1986). Oral
toxicity of carbon tetrachloride: Acute, subacute, and subchronic studies in rats.
Fundam Appl Toxicol 6: 16-34.
Civo Institute Tno. (1985). Fixed versus variable levels of exposure in inhalation toxicity
testing with reference to the workplace studies with acetaltehyde and carbon
tetrachloride. (OTS: OTS0000413-0; 8EHQ Num: FYI-AX-0685-0413; PCN: NA;
TSCATS ReflP: 35053; CIS: NA).
Condie. LW: Laurie. RP: Mills. T: Robinson. M: Bercz. IP. (1986). Effect of gavage vehicle
on hepatotoxicity of carbon tetrachloride in CP-1 mice: corn oil versus Tween-60
aqueous emulsion. Toxicol Sci 7: 199-206.
Cummings. BS: Lash. LH. (2000). Metabolism and toxicity of trichloroethylene and S-
(l,2-dichlorovinyl)-L-cysteine in freshly isolated human proximal tubular cells.
Toxicol Sci 53: 458-466. http://dx.doi.Org/10.1093/toxsci/53.2.458
PuPont. (2001). Long Term Inhalation Toxicity Studies of Five Chlorinated
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