"CDA United States
itm Environmental Protection Agency
Office of Chemical Safety and
Pollution Prevention
Final Risk Evaluation for
C.I. Pigment Violet 29
(Anthra[2,l,9-def:6,5,10-d'eT]diisoquinoline-
1,3,8,10(2H,9H)-tetrone)
Systematic Review Supplemental File:
Data Quality Evaluation of Human Health Hazard Studies
CASRN: 81-33-4
ft
H
,o
o"
N
H
o
January 2021
-------
This document is a compilation of tables for the data extraction and evaluation for C.I. Pigment Violet
29 (CASRN 81-33-4). Each table shows the data point or set or information element that was extracted
and evaluated from a data source in accordance with Appendix D of the Application of Systematic
Review in TSCA Risk Evaluations (U.S. EPA. 20.1.8). If the source contains more than one data set or
information element, the review provides an overall confidence score for each data set or information
element that is found in the source. Therefore, it is possible that a source may have more than one
overall quality/confidence score.
Table of Contents
Table 1. Acute Oral Toxicity Study with Rats, (BASF, 1975b) 3
Table 2. Acute Oral Toxicity Study with Rats, (BASF, 1978d) 7
Table 3. Acute Oral Toxicity Study with Rats, (Rupprich and Weigand, 1984c) 11
Table 4. Acute Inhalation Toxicity Study with Rats, (BASF, 1975a) 14
Table 5. Acute Inhalation Toxicity Study with Rats, (BASF, 1978b) 21
Table 6. Acute Intraperitoneal Toxicity Study with Mice, (BASF, 1975e) 27
Table 7. Acute Intraperitoneal Toxicity Study with Mice, (BASF, 1978c) 31
Table 8. Reproduction/Developmental Toxicity Screening Test with Rats, (Stark et al., 2013) 35
Table 9. Acute Dermal Irritation Study, (BASF, 1975d) 38
Table 10. Acute Dermal Irritation Study, (BASF, 1978e) 42
Table 11. Acute Dermal Irritation Study, (Rupprich and Weigand, 1984a) 46
Table 12. Eye Irritation Study, (BASF, 1975c) 49
Table 13. Eye Irritation Study, (BASF, 1978a) 53
Table 14. Eye Irritation Study, (Rupprich and Weigand, 1984b) 57
Table 15. Local Lymph Node Assay, (lohnson, 1999) 60
Table 16. Study of the Mutagenic Potential in Strains of Salmonella typhimurium (AMES Test) and Escherichia
coli, (lung and Weigand, 1983) 64
Table 17. Gene Mutation Assay in Chinese Hamster V79 Cells In Vitro, (Wollny, 2012) 68
Table 18. Effects of Subchronically Inhaled Carbon Black, (Elder et al., 2005) 72
Table 19. Effects of Chronically Inhaled Carbon Black, (Nikula et al., 1995) 75
Page 2 of 79
-------
Table 1. Acute C
Siiidv kclcivncc
~rnl Toxicity Study with Rnts. ('* * * "'™-)
liASI". I'J"7?. Aculeoral lo\icil> willi mis. IJASI-" Report WY/454. Product Sal'e(> Basel. I5ASI-"
Scliwei/ \(>. S\\ii/ei'land.|as reported in 1 ranslaled P\ 29 l o\ Siiinniai'ies. Product Sal°el>
Basel. I5AS1- Scliwei/ \(>. Swil/erland..Ianuar> 31. 201S|. HIIRO II): 4"73I52<).
Note:
Study guideline was not indicated in the study report
Domain
Metric
Qualitative
Determination
[Le., High,
Medium, Low,
Unacceptable,
or Not rated]
Comments
Metric
Score
Metric
Weighting
Factor
Weighted
Score
Test Substance
1. Test
substance
identity
Medium
CASRN number was
provided (81-33-4)
but other expected
details were not
discussed in the
study. For instance,
the physical nature
of the test substance
was not described
but it is inferred to
be solid state based
on the
physical/chemical
properties of PV29.
2
2
4
2. Test
substance
source
Low
No details were
provided about the
source and lot
number of the test
substance.
3
1
3
3.Test
substance
purity
Low
No details were
provided about the
test substance purity.
3
1
3
Test setup
4. Negative
controls
Low
A concurrent
negative control
group was not
reported. It is
inferred that the
laboratory did not
include the negative
control because
water (vehicle)
would not be
triggering a
response.
3
2
6
5. Positive
controls
Not rated
Not rated/applicable
- Positive controls
are not necessary for
this study type.
NR
NR
NR
6.
Randomized
allocation
Low
The study report did
not state how
animals were
3
1
3
Page 3 of 79
-------
allocated to study
groups.
7. Preparation
and storage of
test substance
Low
Test substance is
likely poorly soluble
in water based on the
physicochemical
properties of the
CASRN. The study
report states that the
test substance was
prepared as a 50%
aqueous suspension
in water; however,
no details were
provided on test
substance
preparation (e.g.,
stirring, and whether
homogenous when
administered) and it
is not evident that
the aqueous
suspension was
homogenous when
dosing was
performed.
3
1
3
Exposure
characterization
8.
Consistency
of Exposure
administration
Low
Details of exposure
administration were
not fully addressed.
The study report
states that a single
dose was
administered via
gavage to each
animal; however, the
dosing volume was
not reported so it is
not evident that
exposure
administration was
the same for all
animals.
3
1
3
9. Reporting
of doses /
concentrations
HighA
1
2
2
10. Exposure
frequency and
duration
HighA
1
1
1
11. Number
of exposure
groups and
dose spacing
HighA
1
1
1
Page 4 of 79
-------
12. Exposure
route and
method
HighA
1
1
1
13. Test
animal
characteristics
Medium
Health status and age
at initiation were not
reported.
2
2
4
Test organisms
14. Adequacy
and
consistency of
animal
husbandry
conditions
Low
Study provided
minimal information
on the adequacy of
animal husbandry
conditions.
3
1
3
15. Number
per group
HighA
1
1
1
16. Outcome
assessment
methodology
Medium
Study generally
describes that
investigators
observed mortality
and clinical signs at
various timepoints
during the 14-day
observation period.
However, details on
how those
observations were
collected were not
provided.
2
2
4
Outcome
Assessment
17.
Consistency
of outcome
assessment
Medium
It is inferred that the
investigators used
the same outcome
assessment method
for the treated
animals based on
details provided in
the study. However,
the study did not
address the measures
that the investigators
put in place to have
consistency in the
outcome assessment.
2
1
2
18. Sampling
adequacy
HighA
1
1
1
19. Blinding
of assessors
Not rated
It is not typically
discussed in these
studies
NR
NR
NR
20. Negative
Control
Response
Not rated
Not rated/applicable
- A negative control
group was not
included.
NR
NR
NR
Confounding/
variable control
21.
Confounding
Medium
Lack of reporting of
food/water intake
2
2
4
Page 5 of 79
-------
variables in
test setup and
procedures
22. Outcomes
unrelated to
exposure
Low
It is not possible to
determine if there
were confounding
variables with the
limited information
given in the report.
3
1
3
Data
presentation
and analysis
23. Statistical
methods
Not rated
Reviewer implied
that the investigators
did not conduct a
statistical analysis.
NR
NR
NR
24. Reporting
of data
Medium
Outcome data were
provided. It would
have been helpful to
have outcome data
for the vehicle
control.
2
2
4
Sum of scores:
42
27
56
High
Medium
Low
Overall Score =
Sum of Weighted
Scores/Sum of
Metric Weighting
Factors:
2.074
Overall
Score
(Rounded):
2.1
>1 and <1.7
>1.7 and <2.3
>2.3 and <3
Overall Quality Level:
Medium
Footnote A: This metric met the criteria for high confidence as expected for this type of study.
Page 6 of 79
-------
Table 2. Acute Oral Toxicity Study with Rats. (™ *
Stud\ Reference:
IJASI-". lyx. Siudj report lor CAS XI-33-4. Acule oral io\icil> willi nils. BASI-" Report
"7"7/3()ll. |as reported in Translated I'N^'J To\ Siininiaries. Product Salcl\ liasel. I5ASI-"
Schwei/ A(>. S\\ii/erland..lanuar> 31.20IS|. III-'.KO II): 4"73I530.
Note:
Study guideline was not indicatec
in the study report
Domain
Metric
Qualitative
Determination
[Le., High,
Medium, Low,
Unacceptable,
or Not rated]
Comments
Metri
c
Score
Metric
Weighti
ng
Factor
Weighted
Score
Test Substance
1. Test
substance
identity
Medium
CASRN number was
provided (81-33-4) but
other expected details
were not discussed in the
study. For instance, the
physical nature of the test
substance was not
described but it is
inferred to be solid state
based on the
physical/chemical
properties of PV29.
2
2
4
2. Test
substance
source
Low
No details were provided
about the source and lot
number of the test
substance.
3
1
3
3.Test
substance
purity
Low
No details were provided
about the test substance
purity.
3
1
3
Test setup
4. Negative
controls
Low
A concurrent negative
control group was not
reported. It is inferred
that the laboratory did
not include the negative
control because water
(vehicle) would not be
triggering a response.
3
2
6
5. Positive
controls
Not rated
Not rated/applicable -
Positive controls are not
necessary for this study
type.
NR
NR
NR
6.
Randomize
d allocation
Low
The study report did not
state how animals were
allocated to study groups.
3
1
3
Exposure
characterization
7.
Preparation
and storage
of test
substance
Low
Test substance
preparation was not fully
reported. The vehicle
(0.5% aqueous solution
of
carboxymethylcellulose,
50% suspension with test
3
1
3
Page 7 of 79
-------
item) was stated, but
methods of preparation
(e.g., whether methods
ensured that test item
suspension was
homogenous) and storage
were not addressed.
8.
Consistenc
y of
Exposure
administrat
ion
Low
Details of exposure
administration were not
fully reported. The study
report states that the test
substance was
administered as a single
gavage application to
each animal, but the
dosing volume was not
reported so it is not
evident that exposure
administration was the
same for all animals.
3
1
3
9.
Reporting
of doses /
concentrati
ons
HighA
1
2
2
10.
Exposure
frequency
and
duration
HighA
1
1
1
11.
Number of
exposure
groups and
dose
spacing
HighA
1
1
1
12.
Exposure
route and
method
HighA
1
1
1
13. Test
animal
characterist
ics
Medium
Health status and age at
initiation were not
reported.
2
2
4
Test organisms
14.
Adequacy
and
consistency
of animal
husbandry
conditions
Low
Study provided minimal
information on the
adequacy of animal
husbandry conditions.
3
1
3
Page 8 of 79
-------
15.
Number
per group
High
1
1
1
16.
Outcome
assessment
methodolo
gy
Medium
Study generally describes
that investigators
observed mortality and
clinical signs at various
timepoints during the 14-
day observation period.
However, details on how
those observations were
collected were not
provided.
2
2
4
Outcome
Assessment
17.
Consistenc
y of
outcome
assessment
Medium
It is inferred that the
investigators used the
same outcome
assessment method for
the treated animals based
on details provided in the
study. However, the
study did not address the
measures that the
investigators put in place
to have consistency in the
outcome assessment.
2
1
2
18.
Sampling
adequacy
HighA
1
1
1
19.
Blinding of
assessors
Not rated
It is not typically
discussed in these
studies.
NR
NR
NR
20.
Negative
Control
Response
Not rated
Not rated/applicable - A
negative control group
was not included.
NR
NR
NR
Confounding/
variable control
21.
Confoundi
ng
variables in
test setup
and
procedures
Medium
Lack of reporting of
food/water intake and
respiratory rate
2
2
4
22.
Outcomes
unrelated
to exposure
Low
It is not possible to
determine if there were
confounding variables
with the limited
information given in the
report.
3
1
3
Data presentation
and analysis
23.
Statistical
methods
Not rated
Reviewer implied that
the investigators did not
conduct a statistical
analysis.
NR
NR
NR
Page 9 of 79
-------
24.
Reporting
of data
Medium
Outcome data were
provided. It would have
been helpful to have
outcome data for the
vehicle control.
2
2
4
Sum of scores:
42
27
56
High
Medium
Low
Overall Score = Sum of
Weighted Scores/Sum
of Metric Weighting
Factors:
2.074
Overall
Score
(Round
ed):
2.1
>1 and <1.7
>1.7 and
<2.3
>2.3 and <3
Overall Quality Level:
Medium
Footnote A: This metric met the criteria for high confidence as expected for this type of study.
Page 10 of 79
-------
Table 3. Acute Oral Toxicity Study with Rnts. (" :~1"
Sludj
Reference:
Rupprich. V Weigand. \\. 1 *>S4. l esti(lie aculc oral (o\ici(\ in llic male and female \\ islar
ral. Iloechsl. Pharma Research To\icolog\. Report No. X4.0225. Report dale: Ma\ 2. 1 *>S4.
III.RO II): 4^31531.
Note:
Study guideline was not indicated in the study report
Domain
Metric
Qualitative
Determination
[Le., High,
Medium, Low,
Unacceptable,
or Not rated]
Comments
Metric
Score
Metric
Weighting
Factor
Weighted
Score
1. Test
substance
identity
High
The test substance
was identified
definitively and the
specific form was
characterized
1
2
2
2. Test
substance
source
Medium
Source was
incompletely
reported.
2
1
2
Test Substance
3.Test
substance
purity
Medium
Product contained
80% active
ingredient
(Perylimid); other
components were
reported as 10%
KOH, 8% diverse
organic
contaminations,
which were not
identified, approx
1% inorganic salts,
and approx 1%
water.
2
1
2
4. Negative
controls
Not rated
A concurrent
negative control
group is not
required for this
study type.
NR
NR
NR
Test setup
5. Positive
controls
Not rated
A concurrent
positive control
group is not
required for this
study type.
NR
NR
NR
6.
Randomized
allocation
Low
The study did not
report how animals
were allocated to
study groups.
3
1
3
Exposure
characterization
7. Preparation
and storage of
test substance
Low
The study report
states that the test
substance was
prepared as a
suspension in the
3
1
3
Page 11 of 79
-------
carrier, 2% starch
sludge, but no
further details on
preparation (e.g.,
homogeneity of
suspension,
solubility in starch
sludge) or storage
of the test substance
were reported.
8.
Consistency
of Exposure
administration
Medium
Consistent dosing
volume was
reported but, the
study report does
not specifically
state that exposures
were otherwise
administered
consistently (e.g., at
the same time of
day).
2
1
2
9. Reporting
of doses /
concentrations
HighA
1
2
2
10. Exposure
frequency and
duration
HighA
1
1
1
11. Number
of exposure
groups and
dose spacing
HighA
1
1
1
12. Exposure
route and
method
HighA
1
1
1
13. Test
animal
characteristics
Medium
Health status and
age at initiation
were not reported.
2
2
4
Test organisms
14. Adequacy
and
consistency of
animal
husbandry
conditions
HighA
1
1
1
15. Number
per group
HighA
1
1
1
Outcome
Assessment
16. Outcome
assessment
methodology
HighA
1
2
2
17.
Consistency
of outcome
assessment
HighA
1
1
1
Page 12 of 79
-------
18. Sampling
adequacy
HighA
1
1
1
19. Blinding
of assessors
Not rated
It is not typically
discussed in these
studies.
NR
NR
NR
20. Negative
Control
Response
Not rated
A negative control
group was not
included.
NR
NR
NR
Confounding/
variable control
21.
Confounding
variables in
test setup and
procedures
Medium
Lack of reporting of
food/water intake
and respiratory rate
2
2
4
22. Outcomes
unrelated to
exposure
HighA
1
1
1
Data
presentation
and analysis
23. Statistical
methods
High
The data was
provided, but
statistical analysis
is not required
1
1
1
24. Reporting
of data
HighA
1
2
2
Sum of scores:
29
26
37
High
Medium
Low
Overall Score =
Sum of Weighted
Scores/Sum of
Metric Weighting
Factors:
1.423
Overall
Score
(Rounded):
1.4
>1 and <1.7
>1.7 and <2.3
>2.3 and <3
Overall Quality Level:
HIGH
Footnote A: This metric met the criteria for high confidence as expected for this type of study.
Page 13 of 79
-------
Table 4. Acute Inhalation Toxicity Study with Rats. (° 4 ^ * °""r")
S(ud\ Reference:
liASI". I')"7?. Acule inhalation lo\icil> with i*als. BASK Report WY/454. Product Sal°el>
Basel. I5AS1- Scliwei/ A(>. Swii/erland. |as reported in 1 ranslaled PY2') l o\ Siininiai'ies.
Product Salel> Basel. BASI-" Scliwei/ A(>. Swii/crland..lanuan 31. 20IX|. III'.KO II)
4^31525.
Note:
Study report indicated that this study was not conducted according to a test guideline
Domain
Metric
Qualitative
Determination
[i.e., High,
Medium,
Low,
Unacceptable,
or Not rated]
Comments
Metric
Score
Metric
Weighting
Factor
Weighted
Score
Test Substance
1. Test
substance
identity
Medium
CASR number
was provided
(81-33-4) but
other expected
details were not
discussed in the
study. For
instance, the
physical nature
of the test
substance was
ambiguously
characterized
mentioning
both vapors
and dust.
2
2
4
2. Test
substance
source
Low
No details were
provided about
the test
substance
source.
3
1
3
3.Test
substance
purity
Low
No details were
provided about
the test
substance
purity.
3
1
3
4. Negative
controls
Medium
The study did
not use a
vehicle control.
The study used
a concurrent air
control.
2
2
4
Test setup
5. Positive
controls
Not rated
A positive
control is not
necessary for
this study.
NR
NR
NR
6.
Randomized
allocation
Low
The study did
not provide
details on the
randomized
3
1
3
Page 14 of 79
-------
allocation of
animals.
7. Preparation
and storage of
test substance
Low
The study did
not discuss
details about
the preparation
and/or storage
conditions of
the test
substance.
These details
are important
to determine if
the animals
were properly
exposed to a
well-
characterized
test substance
under carefully
controlled
conditions.
3
1
3
Exposure
characterization
8.
Consistency
of Exposure
administration
Unacceptable
Reviewer
cannot
determine
whether
consistency of
exposure was
achieved due to
lack of
analytical
method to
measure
exposure in the
chamber (e.g.,
only nominal
concentrations
were reported).
4
1
4
9. Reporting
of doses /
concentrations
Unacceptable
Nominal but
not actual
concentrations
were reported.
Nominal
concentrations
are usually
quite close to
actual
concentrations
for gases, but
they can be
much greater
for vapor and
aerosols. This
creates a major
uncertainty in
the study.
4
2
8
Page 15 of 79
-------
10. Exposure
frequency and
duration
Low
Rats were
exposed in an
atmosphere
saturated with
vapors for 8
hrs. The
exposure
duration is not
typical for an
acute inhalation
study and this
was not
explained.
3
1
3
11. Number
of exposure
groups and
dose spacing
Low
Air control and
one exposure
concentration
were
conducted. The
objective of the
test was not
described
which would
have helped to
understand if a
single test
concentration
or multiple
concentrations
would be
appropriate.
3
1
3
12. Exposure
route and
method
Unacceptable
The study
aimed at
investigating
animal toxicity
to an
atmosphere
saturated with
vapors of the
volatile
component of
PV29. Since
the study said
that dust is
expected by
inhalation, this
is an
inappropriate
exposure
method.
Further,
specific details
were missing
such as the
equipment and
method used to
generate the
4
1
4
Page 16 of 79
-------
chamber
atmosphere,
description of
the inhalation
chamber,
failure to use
an analytical
method to
analyze the test
atmosphere
concentrations.
Also, the
authors
admitted the
limitations of
the study by
indicating that
"the inhalation
hazard test is
insufficient for
non-volatile
substances".
13. Test
animal
characteristics
Low
Study provided
minimal
information on
the test animal
characteristics
(e.g., strain,
health status,
age).
3
2
6
14. Adequacy
and
consistency of
animal
husbandry
conditions
Low
Study provided
minimal
information on
the adequacy of
animal
husbandry
conditions.
3
1
3
Test organisms
15. Number
per group
Medium
Number of
animals per
treatment
group/sex was
considered
adequate for an
acute inhalation
study. There
were observed
variations in
the number of
animals for air
control groups
(3 rats/sex) and
treatment group
(6 rats/sex), but
no explanation
was offered to
2
1
2
Page 17 of 79
-------
account for the
difference.
16. Outcome
assessment
methodology
Low
Significant
deficiencies in
the reported
outcome
assessment
methodology
{i.e., limited
information
available).
3
2
6
17.
Consistency
of outcome
assessment
Low
Details
regarding the
execution of
the study
protocol for
outcome
assessment
(e.g., timing of
assessment
across groups)
were not
discussed.
3
1
3
Outcome Assessment
18. Sampling
adequacy
Medium
Details
regarding
sampling of
outcomes were
not reported.
Mortality
incidence was
recorded in the
data table at
five exposure
times (3 min,
10 min, 1 hr, 3
hrs and 8 hrs).
The reviewer
implied that the
investigators
assessed
mortality and
clinical signs
frequently
during the 8-hr
exposure, but
this was not
explicitly
explained in
the report.
Rats were
observed for 7
days after
cessation of
exposure.
2
1
2
Page 18 of 79
-------
19. Blinding
of assessors
Not rated
Blinding is not
typically done
for acute
inhalation
studies that are
assessing
mortality,
clinical signs
(e.g., irritation)
and gross
pathology.
NR
NR
NR
20. Negative
Control
Response
Low
The biological
responses of
the negative
control
group(s) were
reported, but
the responses
for the negative
controls have
high
uncertainties
due to the
exposure
characterization
issues in the
study.
3
1
3
Confounding/
variable control
21.
Confounding
variables in
test setup and
procedures
Low
Although initial
body weight
was reported,
the post-
treatment body
weights were
not reported to
confirm the
study's claim
that the
treatment did
not affect body
weight. It is not
possible to
determine if
there were
confounding
variables with
the limited
information
given in the
report.
3
2
6
22. Outcomes
unrelated to
exposure
Low
It is not
possible to
determine
whether health
outcomes
unrelated to
exposure
3
1
3
Page 19 of 79
-------
affected
reported
outcomes given
the limited
information in
the report.
Data presentation
and analysis
23. Statistical
methods
Not rated
Reviewer
implied that the
investigators
did not conduct
a statistical
analysis
because it was
not necessary
(e.g., one
control group,
one treatment
group, no
effects
observed).
NR
NR
NR
24. Reporting
of data
Low
Outcome data
were minimally
provided and
discussed.
3
2
6
Sum of scores:
28
82
High
Medium
Low
Overall Score
= Sum of
Weighted
Scores/Sum of
Metric
Weighting
Factors:
2.929
Overall
Score
(Rounded):
2.9 1
>1 and <1.7
>1.7 and <2.3
>2.3 and <3
Overall Quality Level:
Unacceptable1
Footnote 1: Consistent with our Application of 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.
Page 20 of 79
-------
Table 5. Acute Inhalation Toxicity Study with Rats. (™ *
S(ud\ Reference:
HASI-". IVX. Sludj report lor CAS XI-33-4. Acule inhalalion lo\icil> willi r;iIs. I5ASI-" Report
7"7/3()ll. |;is reported in Translaled PY2') To\ Summaries. Product Salcl\ liasel. I5ASI-"
Scliwei/AC. S\\ii/erland..lanuan 31. 201S|. III'.RO II): 473152f».
Note:
Study report indicated that this study was not conducted according to a test guideline
Domain
Metric
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable,
or Not rated]
Comments
Metri
c
Score
Metric
Weighting
Factor
Weighted
Score
Test Substance
1. Test
substance
identity
Medium
CASR number
was provided (81-
33-4) but other
expected details
were not discussed
in the study. For
instance, the
physical nature of
the test substance
was ambiguously
characterized
mentioning both
vapors and dust.
2
2
4
2. Test
substance
source
Low
No details were
provided about the
test substance
source.
3
1
3
3.Test
substance
purity
Low
No details were
provided about the
test substance
purity.
3
1
3
4. Negative
controls
Unacceptable
The study did not
use a vehicle
control. The study
used a concurrent
air control.
4
2
8
Test setup
5. Positive
controls
Not rated
A positive control
is not necessary
for this study.
NR
NR
NR
6. Randomized
allocation
Low
The study did not
provide details on
the randomized
allocation of
animals.
3
1
3
Exposure
characterization
7. Preparation
and storage of
test substance
Low
The study did not
discuss details
about the
preparation and/or
storage conditions
of the test
substance. These
3
1
3
Page 21 of 79
-------
details are
important to
determine if the
animals were
properly exposed
to a well-
characterized test
substance under
carefully
controlled
conditions.
8. Consistency
of Exposure
administration
Unacceptable
Reviewer cannot
determine whether
consistency of
exposure was
achieved due to
lack of analytical
method to measure
exposure in the
chamber (e.g.,
only nominal
concentrations
were reported).
4
1
4
9. Reporting of
doses/
concentrations
Unacceptable
Nominal but not
actual
concentrations
were reported.
Nominal
concentrations are
usually quite close
to actual
concentrations for
gases, but they can
be much greater
for vapor and
aerosols. This
creates a major
uncertainty in the
study.
4
2
8
10. Exposure
frequency and
duration
Low
Rats were exposed
in an atmosphere
saturated with
vapors for 7 hrs.
The exposure
duration is not
typical for an
acute inhalation
study and this was
not explained.
3
1
3
11. Number of
exposure
groups and
dose spacing
Low
Study included
one exposure
concentration but
no mention about
the air control
groups. The
3
1
3
Page 22 of 79
-------
objective of the
test was not
described which
would have helped
to understand if a
single test
concentration or
multiple
concentrations
would be
appropriate.
12. Exposure
route and
method
Unacceptable
The study aimed at
investigating
animal toxicity to
an atmosphere
saturated with
vapors of the
volatile
component of
PV29. Since the
study said that
dust is expected by
inhalation, this is
an inappropriate
exposure method.
Further, specific
details were
missing such as
the equipment and
method used to
generate the
chamber
atmosphere,
description of the
inhalation
chamber, failure to
use an analytical
method to analyze
the test
atmosphere
concentrations.
Also, the authors
admitted the
limitations of the
study by indicating
that "the inhalation
hazard test is
insufficient for
non-volatile
substances".
4
1
4
Test organisms
13. Test animal
characteristics
Low
Study provided
minimal
information on the
test animal
characteristics
3
2
6
Page 23 of 79
-------
(e.g., strain, health
status, age).
14. Adequacy
and
consistency of
animal
husbandry
conditions
Low
Study provided
minimal
information on the
adequacy of
animal husbandry
conditions.
3
1
3
15. Number
per group
Low
Number of
animals per
treatment
group/sex was
considered
adequate for an
acute inhalation
study. Report did
not report the
number of animals
for air control
groups. Reviewer
assumed that the
investigators
might have used
the air control
groups from the
previous 8-hr
acute inhalation
toxicity study.
3
1
3
Outcome
Assessment
16. Outcome
assessment
methodology
Low
Significant
deficiencies in the
reported outcome
assessment
methodology (i.e.,
limited
information
available).
3
2
6
17.
Consistency of
outcome
assessment
Low
Details regarding
the execution of
the study protocol
for outcome
assessment (e.g.,
timing of
assessment across
groups) were not
discussed.
3
1
3
18. Sampling
adequacy
Medium
Details regarding
sampling of
outcomes were not
reported. Mortality
incidence was
recorded in the
data table at five
exposure times (3
min, 10 min, 1 hr,
3 hrs and 7 hrs).
2
1
2
Page 24 of 79
-------
The reviewer
implied that the
investigators
assessed mortality
and clinical signs
frequently during
the 8-hr exposure,
but this was not
explicitly
explained in the
report. Rats were
observed for 7
days after
cessation of
exposure.
19. Blinding of
assessors
Not rated
Blinding is not
typically done for
acute inhalation
studies that are
assessing
mortality, clinical
signs (e.g.,
irritation) and
gross pathology.
NR
NR
NR
20. Negative
Control
Response
Unacceptable
The biological
responses of the
negative control
group(s) were not
addressed in the
study.
4
1
4
Confounding/
variable control
21.
Confounding
variables in test
setup and
procedures
Low
Although initial
body weight was
reported, the post-
treatment body
weights were not
reported to
confirm the
study's claim that
the treatment did
not affect body
weight. It is not
possible to
determine if there
were confounding
variables with the
limited
information given
in the report.
3
2
6
22. Outcomes
unrelated to
exposure
Low
It is not possible to
determine whether
health outcomes
unrelated to
exposure affected
reported outcomes
given the limited
3
1
3
Page 25 of 79
-------
information in the
report.
Data presentation
and analysis
23. Statistical
methods
Not rated
Reviewer implied
that the
investigators did
not conduct a
statistical analysis
because it was not
necessary (e.g.,
one control group,
one treatment
group, no effects
observed).
NR
NR
NR
24. Reporting
of data
Unacceptable
Data presentation
was inadequate
(e.g., the report
does not
differentiate
among findings
between air
control and
treatment groups).
4
2
8
Sum of scores:
28
90
High
Medium
Low
Overall Score =
Sum of Weighted
Scores/Sum of
Metric Weighting
Factors:
3.214
Overall
Score
(Rounded):
3.2 1
>1 and <1.7
>1.7 and <2.3
>2.3 and <3
Overall Quality Level:
Unacceptable1
Footnote 1: Consistent with our Application of 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,
seven of the metrics were rated as unacceptable. As such, the study is considered unacceptable and the score is presented
solely to increase transparency.
Page 26 of 79
-------
Table 6. Acute Intraperitoneal Toxicity Study with Alice. ('* * ~>nns"~)
Sludj
Reference:
liASI". 1V5. Siimman of luxicological in\eMigalions with ( AS XI-33-4. Acule inlraperiluneal
l«i\icil> willi mice. I5AS1- Report WY/454. |;is reported in 1 ranslaled PY2') lo\ Siimmai'ies.
Product Salcl\ liasel. I5ASI-" Scliwei/ A(>. Switzerland. Januan 31. 201 S|. IIKRO II): 4"73I52"7.
Note:
Study report indicated that this study was not conducted according to a test guideline but was
conducted according to an internal protocol.
Domain
Metric
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable,
or Not rated]
Comments
Metric
Score
Metric
Weighting
Factor
Weighted
Score
Test Substance
1. Test
substance
identity
Medium
CASRN number was
provided (81-33-4)
but other expected
details were not
discussed in the
study. For instance,
the physical nature
of the test substance
was not described
but it is inferred to
be solid state based
on the
physical/chemical
properties of PV29.
2
2
4
2. Test
substance
source
Low
No details were
provided about the
source and lot
number of the test
substance.
3
1
3
3.Test
substance
purity
Low
No details were
provided about the
test substance purity.
3
1
3
Test setup
4. Negative
controls
Low
A concurrent
negative control
group was not
reported. It is
inferred that the
laboratory had
historical data testing
mice with
carboxymethyl
cellulose (vehicle)
and showing no
mortality.
Carboxymethyl
cellulose is non-
toxic.
3
2
6
5. Positive
controls
Not rated
Not rated/applicable
- A concurrent
positive control
group is not required
for this study type.
NR
NR
NR
Page 27 of 79
-------
6.
Randomized
allocation
Low
The study report did
not state how
animals were
allocated to study
groups.
3
1
3
7. Preparation
and storage of
test substance
Low
Test substance
preparation was not
fully reported. The
vehicle (0.5%
aqueous
carboxylmethyl
cellulose, 21.5%,
46.4% or 50%
aqueous suspension)
was stated, but the
methods of
preparation (e.g.,
whether methods
ensured that test item
suspension was
homogenous) and
storage were not
addressed.
3
1
3
Exposure
characterization
8.
Consistency
of Exposure
administration
Low
Details of exposure
administration were
not fully reported.
The study report
states that the test
substance was
administered as a
single intraperitoneal
application but the
volume administered
was not reported.
3
1
3
9. Reporting
of doses /
concentrations
HighA
1
2
2
10. Exposure
frequency and
duration
High
Single I.P injection
1
1
1
11. Number
of exposure
groups and
dose spacing
High
3 exposure groups
1
1
1
12. Exposure
route and
method
HighA
1
1
1
Test organisms
13. Test
animal
characteristics
Low
Study provided
minimal information
on the test animal
characteristics (e.g.,
strain, health status,
age).
3
2
6
Page 28 of 79
-------
14. Adequacy
and
consistency of
animal
husbandry
conditions
Low
Study provided
minimal information
on the adequacy of
animal husbandry
conditions.
3
1
3
15. Number
per group
High
5 animals per sex per
exposure group
1
1
1
Outcome
Assessment
16. Outcome
assessment
methodology
Medium
Study generally
describes that
investigators
observed mortality
and clinical signs at
various timepoints
during the 14-day
observation period.
However, details on
how those
observations were
collected were not
provided.
2
2
4
17.
Consistency
of outcome
assessment
Low
Details regarding the
execution of the
study protocol for
outcome assessment
(e.g., timing of
assessment across
groups) were not
reported, and these
deficiencies are
likely to have a
substantial impact on
results.
3
1
3
18. Sampling
adequacy
HighA
1
1
1
19. Blinding
of assessors
Not rated
It is not typically
discussed in these
studies.
NR
NR
NR
20. Negative
Control
Response
Not rated
Not rated/applicable
- A negative control
group was not
included.
NR
NR
NR
Confounding/
variable control
21.
Confounding
variables in
test setup and
procedures
Low
Although initial
body weight was
reported, the post-
treatment body
weights were not
reported to confirm
the study's claim
that the treatment did
not affect body
weight. It is not
possible to determine
if there were
3
2
6
Page 29 of 79
-------
confounding
variables with the
limited information
given in the report.
22. Outcomes
unrelated to
exposure
Low
It is not possible to
determine if there
were confounding
variables with the
limited information
given in the report.
3
1
3
Data
presentation
and analysis
23. Statistical
methods
Not rated
Reviewer implied
that the investigators
did not conduct a
statistical analysis.
NR
NR
NR
24. Reporting
of data
Low
Outcome data were
minimally provided
and discussed.
3
2
6
Overall Score:
46
27
63
High
Medium
Low
Overall Score =
Sum of Weighted
Scores/Sum of
Metric Weighting
Factors:
2.333
Overall
Score
(Rounded):
2.3
>1 and <1.7
>1.7 and <2.3
>2.3 and <3
Overall Quality Level:
Low
Footnote A: This metric met the criteria for high confidence as expected for this type of study.
Page 30 of 79
-------
Table 7. Acute Intraperitoneal Toxicity Study with Alice. ('* * )
Sludj
Reference:
IJASI-". I')"7#. Sludj reporl lor CAS XI-33-4. Acule inlraperiloneal lo\icil> willi mice. UASI-"
Report "7"7/3(»(!. |as reported in Translaled I'N^'J To\ Summaries. Product Salcl> liasel. I5ASI-"
Scliwci/ A(>. S\\ii/ei'land..lanuai'> 31. 20IS|. III-'.KO II): 4"73I52X.
Note:
Study report indicated that this study was not conducted according to a test guideline but was
conducted according to an internal protocol.
Domain
Metric
Qualitative
Determination
[Le., High,
Medium, Low,
Unacceptable,
or Not rated]
Comments
Metric
Score
Metric
Weighting
Factor
Weighted
Score
Test Substance
1. Test
substance
identity
Medium
CASRN number was
provided (81-33-4)
but other expected
details were not
discussed in the
study. For instance,
the physical nature
of the test substance
was not described
but it is inferred to
be solid state based
on the
physical/chemical
properties of PV29.
2
2
4
2. Test
substance
source
Low
No details were
provided about the
source and lot
number of the test
substance.
3
1
3
3.Test
substance
purity
Low
No details were
provided about the
test substance purity.
3
1
3
Test setup
4. Negative
controls
Low
A concurrent
negative control
group was not
reported. It is
inferred that the
laboratory had
historical data testing
mice with
carboxymethyl
cellulose (vehicle)
and showing no
mortality.
Carboxymethyl
cellulose is non-
toxic.
3
2
6
5. Positive
controls
Not rated
Not rated/applicable
- A concurrent
positive control
group is not required
for this study type.
NR
NR
NR
Page 31 of 79
-------
6.
Randomized
allocation
Low
The study report did
not state how
animals were
allocated to study
groups.
3
1
3
7. Preparation
and storage of
test substance
Low
Test substance
preparation was not
fully reported. The
vehicle (0.5%
aqueous
carboxylmethyl
cellulose, 46.4% or
50% aqueous
suspension) was
stated, but the
methods of
preparation (e.g.,
whether methods
ensured that test item
suspension was
homogenous) and
storage were not
addressed.
3
1
3
Exposure
characterization
8.
Consistency
of Exposure
administration
Low
Details of exposure
administration were
not fully reported.
The study report
states that the test
substance was
administered as a
single intraperitoneal
application but the
volume administered
was not reported.
3
1
3
9. Reporting
of doses /
concentrations
HighA
1
2
2
10. Exposure
frequency and
duration
High
Single I.P injection
1
1
1
11. Number
of exposure
groups and
dose spacing
High
3 exposure groups
1
1
1
12. Exposure
route and
method
HighA
1
1
1
Test organisms
13. Test
animal
characteristics
Low
Study provided
minimal information
on the test animal
characteristics (e.g.,
strain, health status,
age).
3
2
6
Page 32 of 79
-------
14. Adequacy
and
consistency of
animal
husbandry
conditions
Low
Study provided
minimal information
on the adequacy of
animal husbandry
conditions.
3
1
3
15. Number
per group
High
5 animals per sex per
exposure group
1
1
1
Outcome
Assessment
16. Outcome
assessment
methodology
Medium
Study generally
describes that
investigators
observed mortality
and clinical signs at
various timepoints
during the 14-day
observation period.
However, details on
how those
observations were
collected were not
provided.
2
2
4
17.
Consistency
of outcome
assessment
Low
Details regarding the
execution of the
study protocol for
outcome assessment
(e.g., timing of
assessment across
groups) were not
reported, and these
deficiencies are
likely to have a
substantial impact on
results.
3
1
3
18. Sampling
adequacy
HighA
1
1
1
19. Blinding
of assessors
Not rated
It is not typically
discussed in these
studies.
NR
NR
NR
20. Negative
Control
Response
Not rated
Not rated/applicable
- A negative control
group was not
included.
NR
NR
NR
Confounding/
variable control
21.
Confounding
variables in
test setup and
procedures
Low
Although initial
body weight was
reported, the post-
treatment body
weights were not
reported to confirm
the study's claim that
the treatment did not
affect body weight.
It is not possible to
determine if there
were confounding
3
2
6
Page 33 of 79
-------
variables with the
limited information
given in the report.
22. Outcomes
unrelated to
exposure
Low
It is not possible to
determine if there
were confounding
variables with the
limited information
given in the report.
3
1
3
Data
presentation
and analysis
23. Statistical
methods
Not rated
Reviewer implied
that the investigators
did not conduct a
statistical analysis.
NR
NR
NR
24. Reporting
of data
Medium
Outcome data were
provided. It would
have been helpful to
have outcome data
for the vehicle
control.
2
2
4
Overall Score:
45
27
61
High
Medium
Low
Overall Score =
Sum of Weighted
Scores/Sum of
Metric Weighting
Factors:
2.259
Overall
Score
(Rounded):
2.3
>1 and <1.7
>1.7 and <2.3
>2.3 and <3
Overall Quality Level:
Low
Footnote A: This metric met the criteria for high confidence as expected for this type of study.
Page 34 of 79
-------
Table 8. Rcprod
Sludj
Uefcrciice:
iiction/Dcvclopmcntnl Toxicity Screening Test with Rnts. -¦ -1- -¦ *•««-»)
Siai'k. 1).. Trciimaiin. S.. \ an Ka\en/\\aa>. B. 2013. Kcprodiiclion/dc\clopmcnlal To\icil>
Screening lost with \\ isiar Kals Oral Adiiiinislration <(>a\agc). BASI-" ST.. (.crmain. Projecl
No. K0K0223/I ICK.2. l or BASI- SI.. Cermain. III.KO II): -T3I53X.
Note:
Study report indicates the study was conducted according to OECD TG 421 and OPPTS 870.3550
Domain
Metric
Qualitative
Determination
[Le., High,
Medium, Low,
Unacceptable,
or Not rated]
Comments
Metric
Score
Metric
Weighting
Factor
Weighted
Score
Test Substance
1. Test
substance
identity
High
The test substance
was identified
definitively and
detailed analysis of
the characterization
including a
description of the
form was provided.
1
2
2
2. Test
substance
source
High
Test item was
received by the
submitter and the
batch number was
provided.
1
1
1
3.Test
substance
purity
High
Purity was
characterized in the
appendix of the
study.
1
1
1
Test setup
4. Negative
controls
HighA
1
2
2
5. Positive
controls
Not rated
No positive controls
were needed for this
study.
NR
NR
NR
6.
Randomized
allocation
Medium
Animals were
distributed
according to weight
so that weight
variations did not
exceed 20% of the
mean weight of
each sex.
2
1
2
Exposure
characterization
7. Preparation
and storage of
test substance
HighA
1
1
1
8.
Consistency
of Exposure
administration
HighA
1
1
1
9. Reporting
of doses /
concentrations
HighA
1
2
2
Page 35 of 79
-------
10. Exposure
frequency and
duration
HighA
1
1
1
11. Number
of exposure
groups and
dose spacing
HighA
1
1
1
12. Exposure
route and
method
HighA
1
1
1
13. Test
animal
characteristics
HighA
1
2
2
Test organisms
14. Adequacy
and
consistency of
animal
husbandry
conditions
HighA
1
1
1
15. Number
per group
HighA
1
1
1
16. Outcome
assessment
methodology
HighA
1
2
2
17.
Consistency
of outcome
assessment
HighA
1
1
1
Outcome
Assessment
18. Sampling
adequacy
HighA
1
1
1
19. Blinding
of assessors
Not rated
Initial
histopathology
review was the only
subjective
assessment
conducted, and this
metric is not
applicable.
NR
NR
NR
20. Negative
Control
Response
HighA
1
1
1
Confounding/
variable control
21.
Confounding
variables in
test setup and
procedures
HighA
1
2
2
22. Outcomes
unrelated to
exposure
HighA
1
1
1
Page 36 of 79
-------
Data
presentation
and analysis
23. Statistical
methods
HighA
1
1
1
24. Reporting
of data
HighA
1
2
2
Sum of scores:
23
29
30
High
Medium
Low
Overall Score =
Sum of Weighted
Scores/Sum of
Metric Weighting
Factors:
1.034
Overall
Score
(Rounded):
1.0
>1 and <1.7
>1.7 and <2.3
>2.3 and <3
Overall Quality Level:
HIGH
Footnote A: This metric met the criteria for high confidence as expected for this type of study.
Page 37 of 79
-------
Table 9. Acute Dermal Irritation Study. ('* * ")
Sliulj
Ucfercnce:
liASI". I')"7?. Skin irrilalion s(ud\. liASI-" Report WY/454. Product Sal'e(> Basel. HASI-"
Sclmei/ ACi.Swii/erland. |;is reported in 1 ranslaled l'\ 2') To\ Summaries. Product Sal'e(\
Basel. I5ASI Sclmei/ \(.. S\\ii/erland..laniian 31. 20IX|. III KO II): 4'73I532.
Note:
Study guideline was not indicated in
the study report
Domain
Metric
Qualitative
Determination
[Le., High,
Medium, Low,
Unacceptable,
or Not rated]
Comments
Metric
Score
Metric
Weighting
Factor
Weighted
Score
Test Substance
1. Test
substance
identity
Medium
CASRN number
was provided (81-
33-4) but other
expected details
were not
discussed in the
study. For
instance, the
physical nature of
the test substance
was not described
but it is inferred to
be solid state
based on the
physical/chemical
properties of
PV29.
2
2
4
2. Test
substance
source
Low
No details were
provided about
the source and lot
number of the test
substance.
3
1
3
3.Test
substance
purity
Low
No details were
provided about
the test substance
purity.
3
1
3
Test setup
4. Negative
controls
Medium
Use of a negative
control was not
reported, but this
is not considered
to have a
substantial impact
on results since
untreated skin
usually serves as
the negative
control in this
type of study.
2
2
4
5. Positive
controls
Not rated
Positive controls
are typically not
necessary for this
study type.
NR
NR
NR
Page 38 of 79
-------
6.
Randomized
allocation
Not rated
Only two
individual animals
were tested, so
randomization
was not required.
NR
NR
NR
7. Preparation
and storage of
test substance
Low
The study report
states that the test
substance was
prepared as a 50%
aqueous
suspension in
water; however,
no details were
provided on test
substance
preparation (e.g.,
stirring, and
whether
homogenous
when applied).
3
1
3
Exposure
8. Consistency
of Exposure
administration
Low
Few details were
provided on
application of the
test substance to
skin so it is not
clear that
exposures were
consistent.
3
1
3
characterization
9. Reporting
of doses /
concentrations
Low
Study report states
that test substance
was given as a
50% aqueous
suspension, but no
details are
provided on the
actual amount
(e.g., grams) of
test substance
administered in
the application.
3
2
6
10. Exposure
frequency and
duration
HighA
1
1
1
11. Number
of exposure
groups and
dose spacing
HighA
1
1
1
12. Exposure
route and
method
HighA
1
1
1
Test organisms
13. Test
animal
characteristics
Medium
Health status and
age at initiation of
treatment were
not reported.
2
2
4
Page 39 of 79
-------
14. Adequacy
and
consistency of
animal
husbandry
conditions
Low
Study provided
minimal
information on the
adequacy of
animal husbandry
conditions.
3
1
3
15. Number
per group
Low
Only two animals
were treated.
3
1
3
16. Outcome
assessment
methodology
Low
Significant
deficiencies in the
reported outcome
assessment
methodology (i.e.,
limited
information).
3
2
6
17.
Consistency
of outcome
assessment
HighA
1
1
1
18. Sampling
adequacy
HighA
1
1
1
Outcome
Assessment
19. Blinding
of assessors
Not rated
It is not typically
discussed in these
studies. Note that
the grading of
dermal responses
is subjective.
Training in
observing the
dermal responses
and translating
them to a score
promotes
harmonization of
subjective results.
NR
NR
NR
20. Negative
Control
Response
Not rated
Negative controls
were not required
for the study.
NR
NR
NR
21.
Confounding
variables in
test setup and
procedures
Medium
Initial food/water
intake were not
reported but this
is not likely to
have a significant
impact on results.
2
2
4
Confounding/
variable control
22. Outcomes
unrelated to
exposure
Low
It is not possible
to determine if
there were
confounding
variables with the
limited
information given
in the report.
3
1
3
Page 40 of 79
-------
Data
presentation
and analysis
23. Statistical
methods
Not rated
Reviewer implied
that the
investigators did
not conduct a
statistical
analysis.
NR
NR
NR
24. Reporting
of data
High
Dermal responses
were reported for
both female
rabbits at different
timepoints.
1
2
2
Sum of scores:
41
26
56
High
Medium
Low
Overall Score =
Sum of Weighted
Scores/Sum of
Metric
Weighting
Factors:
2.154
Overall Score
(Rounded):
2.2
>1 and <1.7
>1.7 and <2.3
>2.3 and <3
Overall Quality Level:
Medium
Footnote A: This metric met the criteria for high confidence as expected for this type of study.
Page 41 of 79
-------
Table 10. Acute Dermal Irritation Study. (° 4 ^ ' 0"7° -)
Sludj
Ucfercnce:
BASI-". I'HX. Sludj report lor CAS XI-33-4. Skin ii'i'ilalion sintl>. UASI-" Report "7"7/360. |;is
reported in Translaled PY2') To\ Siininiai'ies. Product Salcl\ liasel. I5ASI-" Sclmei/ AC.
S\\ii/erland..lanuan 31.20IS|. III KO II)! 4^31533.
Note:
Study report did not indicate whether a test guideline was followed.
Domain
Metric
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable,
or Not rated]
Comments
Metric
Score
Metric
Weighting
Factor
Weighted
Score
Test Substance
1. Test
substance
identity
Medium
CASRN number
was provided (81-
33-4) but other
expected details
were not discussed
in the study. For
instance, the
physical nature of
the test substance
was not described
but it is inferred to
be solid state based
on the
physical/chemical
properties of PV29.
2
2
4
2. Test
substance
source
Low
No details were
provided about the
source and lot
number of the test
substance.
3
1
3
3.Test
substance
purity
Low
No details were
provided about the
test substance
purity.
3
1
3
Test setup
4. Negative
controls
Medium
Use of a negative
control was not
reported, but this is
not considered to
have a substantial
impact on results
since untreated skin
usually serves as
the negative control
in this type of
study.
2
2
4
5. Positive
controls
Not rated
Positive controls
are typically not
necessary for this
study type.
NR
NR
NR
6.
Randomized
allocation
Not rated
Only two
individual animals
were tested, so
NR
NR
NR
Page 42 of 79
-------
randomization was
not required.
7. Preparation
and storage of
test substance
Low
The study report
states that the test
substance was
prepared as a 50%
aqueous suspension
in water; however,
no details were
provided on test
substance
preparation (e.g.,
stirring, and
whether
homogenous when
applied).
3
1
3
8.
Consistency
of Exposure
administration
Low
Few details were
provided on
application of the
test substance to
skin so it is not
clear that exposures
were consistent.
3
1
3
Exposure
characterization
9. Reporting
of doses /
concentrations
Low
Study report states
that test substance
was given as a 50%
aqueous
suspension, but no
details are provided
on the actual
amount (e.g.,
grams) of test
substance
administered in the
application.
3
2
6
10. Exposure
frequency and
duration
HighA
1
1
1
11. Number
of exposure
groups and
dose spacing
HighA
1
1
1
12. Exposure
route and
method
HighA
1
1
1
Test organisms
13. Test
animal
characteristics
High
Health status and
age at initiation of
treatment were not
reported.
1
2
2
14. Adequacy
and
consistency of
animal
Medium
Study provided
minimal
information on the
adequacy of animal
2
1
2
Page 43 of 79
-------
husbandry
conditions
husbandry
conditions.
15. Number
per group
Low
Only three animals
were treated.
3
1
3
16. Outcome
assessment
methodology
Low
Significant
deficiencies in the
reported outcome
assessment
methodology (i.e.,
limited
information).
3
2
6
17. Consistency
of outcome
assessment
HighA
1
1
1
18. Sampling
adequacy
HighA
1
1
1
Outcome
Assessment
19. Blinding
of assessors
Not rated
It is not typically
done. Note that the
grading of dermal
responses is
subjective. Training
in observing the
dermal responses
and translating
them to a score
promotes
harmonization of
subjective results.
NR
NR
NR
20. Negative
Control
Response
Not rated
Negative controls
were not required
for the study.
NR
NR
NR
Confounding/
21.
Confounding
variables in
test setup and
procedures
Medium
Initial food/water
intake were not
reported but this is
not likely to have a
significant impact
on results.
2
2
4
variable control
22. Outcomes
unrelated to
exposure
Low
It is not possible to
determine if there
were confounding
variables with the
limited information
given in the report.
3
1
3
Data
presentation
and analysis
23. Statistical
methods
Not rated
Reviewer implied
that the
investigators did
not conduct a
statistical analysis.
NR
NR
NR
24. Reporting
of data
High
Dermal responses
were reported for
male and female
1
2
2
Page 44 of 79
-------
rabbits at different
timepoints.
Sum of scores:
39
26
53
High
Medium
Low
Overall Score =
Sum of Weighted
Scores/Sum of
Metric Weighting
Factors:
2.038
Overall
Score
(Rounded):
2.0
>1 and <1.7
>1.7 and <2.3
>2.3 and <3
Overall Quality Level:
Medium
Footnote A: This metric met the criteria for high confidence as expected for this type of study.
Page 45 of 79
-------
Table 11. Acute Dermal Irritation Study. (" :~1"
Sludj
Reference:
Kupprich. Y. Weigand. \\. I')X4. Penlimid I'oslinii llie acule dermal irrilanl elTecls/causlic
elTecls on the rahhil e\e. Iloechsl Pliarma Research Toxicology. Cermain. Report No. X4.022X.
lor l arhen Nord. Work llochsl. III.KO il): 4"\JI534
Note:
Study was conducted according to OECD TG 404 Acute Dermal Irritation / Corrosion (1981).
Domain
Metric
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable,
or Not rated]
Comments
Metric
Score
Metric
Weighting
Factor
Weighted
Score
1. Test
substance
identity
High
The test substance
was identified
definitively and the
specific form was
characterized
1
2
2
2. Test
substance
source
Medium
No details were
provided about the
source and lot
number of the test
substance.
2
1
2
Test Substance
3.Test
substance
purity
Medium
Product contained
80% active
ingredient
(Perylimid); other
components were
reported as 10%
KOH, 8% diverse
organic
contaminations,
which were not
identified, approx
1% inorganic salts,
and approx 1%
water.
2
1
2
4. Negative
controls
Not rated
In acute dermal
studies, negative
controls are not
generally used.
NR
NR
NR
Test setup
5. Positive
controls
Not rated
Positive controls
not required for the
study.
NR
NR
NR
6.
Randomized
allocation
Not rated
Only one group was
included, so
randomization was
not required.
NR
NR
NR
Exposure
characterization
7. Preparation
and storage of
test substance
Low
Amount applied
was given but the
storage and
solubility was not
given. 500mg may
not dissolve in
3
1
3
Page 46 of 79
-------
0.3ml of 0.9% NaCl
solution.
8.
Consistency
of Exposure
administration
HighA
1
1
1
9. Reporting
of doses /
concentrations
High
500mg was applied
in 0.3ml of 0.9%
NaCl solution
1
2
2
10. Exposure
frequency and
duration
HighA
1
1
1
11. Number
of exposure
groups and
dose spacing
HighA
1
1
1
12. Exposure
route and
method
HighA
1
1
1
13. Test
animal
characteristics
Medium
Details were not
reported including
age and sex.
2
2
4
Test organisms
14. Adequacy
and
consistency of
animal
husbandry
conditions
High
Husbandry
conditions were
reported
1
1
1
15. Number
per group
HighA
1
1
1
16. Outcome
assessment
methodology
HighA
1
2
2
17.
Consistency
of outcome
assessment
HighA
1
1
1
Outcome
Assessment
18. Sampling
adequacy
HighA
1
1
1
19. Blinding
of assessors
Not rated
It is not typically
discussed in these
studies. Note that
the grading of
dermal responses is
subjective. Training
in observing the
dermal responses
and translating
them to a score
promotes
NR
NR
NR
Page 47 of 79
-------
harmonization of
subjective results.
20. Negative
Control
Response
Not rated
Negative controls
were not required
for the study.
NR
NR
NR
Confounding/
variable control
21.
Confounding
variables in
test setup and
procedures
Medium
Initial food/water
intake and
respiratory rate
were not reported
but this is not likely
to have a significant
impact on results.
2
2
4
22. Outcomes
unrelated to
exposure
HighA
1
1
1
Data
presentation
and analysis
23. Statistical
methods
High
The data was
provided, but
statistical analysis
is not required
1
1
1
24. Reporting
of data
HighA
1
2
2
Sum of scores:
25
25
33
High
Medium
Low
Overall Score =
Sum of Weighted
Scores/Sum of
Metric Weighting
Factors:
1.320
Overall
Score
(Rounded):
1.3
>1 and <1.7
>1.7 and <2.3
>2.3 and <3
Overall Quality Level:
HIGH
Footnote A: This metric met the criteria for high confidence as expected for this type of study.
Page 48 of 79
-------
Table 12. F.yc Trritntion Study. ('* *
Sludj
Reference:
liASI". I')75. F.je li'rilalion Siud\. liASI-" Report WY/454. Product Sal'e(\ Basel. li.ASI-"
Sclmei/ A(>. Swii/ei'land. |;is reported in 1 ranslaled PY2') lo\ Summaries. I'roducl Sal'e(\
liasel. HASI-" Scliwei/ ACi. S\\ii/erland..lanuan 31. 20IS|. III'.KO II): 4"73I5I<>
Note:
Study guideline was not indicated in the study report
Domain
Metric
Qualitative
Determination
[Le., High,
Medium, Low,
Unacceptable,
or Not rated]
Comments
Metric
Score
Metric
Weighting
Factor
Weighted
Score
Test Substance
1. Test
substance
identity
Medium
CASRN number was
provided (81-33-4)
but other expected
details were not
discussed in the
study. For instance,
the physical nature
of the test substance
was not described
but it is inferred to
be solid state based
on the
physical/chemical
properties of PV29.
2
2
4
2. Test
substance
source
Low
No details were
provided about the
source and lot
number of the test
substance.
3
1
3
3.Test
substance
purity
Low
No details were
provided about the
test substance purity.
3
1
3
4. Negative
controls
High
The eye treated with
talcum powder
served as the
negative control
1
2
2
Test setup
5. Positive
controls
Not rated
Positive control
animals are not
required for this
study.
NR
NR
NR
6.
Randomized
allocation
Not rated
Only two individual
animals were tested,
so randomization is
typically not
required.
NR
NR
NR
Exposure
characterization
7. Preparation
and storage of
test substance
Low
The study did not
discuss details about
the preparation
and/or storage
conditions of the test
substance.
3
1
3
Page 49 of 79
-------
8.
Consistency
of Exposure
administration
HighA
1
1
1
9. Reporting
of doses /
concentrations
HighA
1
2
2
10. Exposure
frequency and
duration
HighA
1
1
1
11. Number
of exposure
groups and
dose spacing
High
The test typically
applies a single dose
to one of the eyes of
the experimental
animal.
1
1
1
12. Exposure
route and
method
HighA
1
1
1
13. Test
animal
characteristics
Low
Study provided
minimal information
on the test animal
characteristics (e.g.,
strain, health status,
age).
3
2
6
Test organisms
14. Adequacy
and
consistency of
animal
husbandry
conditions
Low
Study provided
minimal information
on the adequacy of
animal husbandry
conditions.
3
1
3
15. Number
per group
Medium
Generally at least
three animals are
used for eye
irritation tests. But in
this case, study
authors used only 2
animals.
2
1
2
Outcome
Assessment
16. Outcome
assessment
methodology
Medium
The method used to
score irritation was
not discussed.
However, it is
understood the
scoring scale as it is
standard for the eye
irritation tests. Other
details were not
discussed (e.g.,
criteria for study
termination).
2
2
4
17.
Consistency
of outcome
assessment
Medium
It is inferred that the
control (n=l) and
treated (n=l) were
exposed using the
2
1
2
Page 50 of 79
-------
same method based
on details provided
in the study.
However, the study
did not address the
measures that the
investigators put in
place (e.g., training
of staff in scoring) to
have consistency in
the outcome
assessment.
18. Sampling
adequacy
High
Only two animals
were used and in
each case one eye
was used for test
substance and one
eye for control
substance. The
reviewers monitored
the animals during
and after treatment
from 10 min
onwards till day 8th.
1
1
1
19. Blinding
of assessors
Not rated
It is not discussed in
these studies. Note
that the grading of
ocular responses is
subjective. Training
in observing the
ocular responses and
translating them to a
score promotes
harmonization of
subjective results.
NR
NR
NR
20. Negative
Control
Response
HighA
1
1
1
Confounding/
21.
Confounding
variables in
test setup and
procedures
Low
It is not possible to
determine if there
were confounding
variables with the
limited information
given in the report.
3
2
6
variable control
22. Outcomes
unrelated to
exposure
Low
It is not possible to
determine if there
were confounding
variables with the
limited information
given in the report.
3
1
3
Data
presentation
and analysis
23. Statistical
methods
Not rated
Data not amenable
for statistics
NR
NR
NR
24. Reporting
of data
High
Ocular responses
were reported for
1
2
2
Page 51 of 79
-------
control and treated
eyes in both female
rabbits.
Sum of scores:
38
27
51
High
Medium
Low
Overall Score =
Sum of Weighted
Scores/Sum of
Metric Weighting
Factors:
1.889
Overall
Score
(Rounded):
1.9
>1 and <1.7
>1.7 and <2.3
>2.3 and <3
Overall Quality Level:
Medium
Footnote A: This metric met the criteria for high confidence as expected for this type of study.
Page 52 of 79
-------
Table 13. F.yc Trritntion Study. (° 4 ^ '0"70 )
Sludj
Reference:
IJASI-". iyx. li'rilalion S(iid\. HASI-" Report "77/3(iO. Product Salct\ liasel. HASI-" Sclmei/
A(>. Swii/erland. |;is reporled in Translated PY2') l o\ Siininiai'ies. Product Sal'e(\ Basel.
I5AS1- Sclmei/ AC. Sw it/erland. .lanuan 31. 201 S|. HERO II): 4731520
Note:
Study guideline was not indicated in the study report
Domain
Metric
Qualitative
Determination
[Le., High,
Medium, Low,
Unacceptable,
or Not rated]
Comments
Metric
Score
Metric
Weighting
Factor
Weighted
Score
Test Substance
1. Test
substance
identity
Medium
CASRN number was
provided (81-33-4)
but other expected
details were not
discussed in the
study. For instance,
the physical nature
of the test substance
was not described
but it is inferred to
be solid state based
on the
physical/chemical
properties of PV29.
2
2
4
2. Test
substance
source
Low
No details were
provided about the
source and lot
number of the test
substance.
3
1
3
3.Test
substance
purity
Low
No details were
provided about the
test substance purity.
3
1
3
4. Negative
controls
High
The eye treated with
talcum powder
served as the
negative control
1
2
2
Test setup
5. Positive
controls
Not rated
Positive control
animals are not
required for the test
type.
NR
NR
NR
6.
Randomized
allocation
Not rated
Only two individual
animals were tested,
so randomization is
typically not
required.
NR
NR
NR
Exposure
characterization
7. Preparation
and storage of
test substance
Low
The study did not
discuss details about
the preparation
and/or storage
conditions of the test
substance.
3
1
3
Page 53 of 79
-------
8.
Consistency
of Exposure
administration
HighA
1
1
1
9. Reporting
of doses /
concentrations
HighA
1
2
2
10. Exposure
frequency and
duration
HighA
1
1
1
11. Number
of exposure
groups and
dose spacing
High
The test typically
applies a single dose
to one of the eyes of
the experimental
animal.
1
1
1
12. Exposure
route and
method
HighA
1
1
1
13. Test
animal
characteristics
Low
Study provided
minimal information
on the test animal
characteristics (e.g.,
strain, health status,
age).
3
2
6
Test organisms
14. Adequacy
and
consistency of
animal
husbandry
conditions
Low
Study provided
minimal information
on the adequacy of
animal husbandry
conditions.
3
1
3
15. Number
per group
High
Three animals were
tested, each animal
received test
substance in one eye
and Talcum powder
as control in the
other eye.
1
1
1
Outcome
Assessment
16. Outcome
assessment
methodology
Medium
The method used to
score irritation was
not discussed.
However, it is
understood the
scoring scale as it is
standard for the eye
irritation tests. Other
details were not
discussed (e.g.,
criteria for study
termination).
2
2
4
17.
Consistency
of outcome
assessment
Medium
It is inferred that the
control (n=l) and
treated (n=l) were
exposed using the
2
1
2
Page 54 of 79
-------
same method based
on details provided
in the study.
However, the study
did not address the
measures that the
investigators put in
place (e.g., training
of staff in scoring) to
have consistency in
the outcome
assessment.
18. Sampling
adequacy
High
Three animals were
used and in each
case one eye was
used for test
substance and one
eye for control
substance. The
reviewers monitored
the animals during
and after treatment at
different timepoints.
1
1
1
19. Blinding
of assessors
Not Rated
It is not discussed in
these studies. Note
that the grading of
ocular responses is
subjective. Training
in observing the
ocular responses and
translating them to a
score promotes
harmonization of
subjective results.
NR
NR
NR
20. Negative
Control
Response
HighA
1
1
1
Confounding/
21.
Confounding
variables in
test setup and
procedures
Low
It is not possible to
determine if there
were confounding
variables with the
limited information
given in the report.
3
2
6
variable control
22. Outcomes
unrelated to
exposure
Low
It is not possible to
determine if there
were confounding
variables with the
limited information
given in the report.
3
1
3
Data
presentation
and analysis
23. Statistical
methods
Not rated
Data not amenable
for statistics
NR
NR
NR
24. Reporting
of data
High
Ocular responses
were reported for
1
2
2
Page 55 of 79
-------
control and treated
eyes in male rabbits.
Sum of scores:
37
27
50
High
Medium
Low
Overall Score =
Sum of Weighted
Scores/Sum of
Metric Weighting
Factors:
1.852
Overall
Score
(Rounded):
1.9
>1 and <1.7
>1.7 and <2.3
>2.3 and <3
Overall Quality Level:
Medium
Footnote A: This metric met the criteria for high confidence as expected for this type of study.
Page 56 of 79
-------
Table 14. F.yc Trritntion Study.
Sludj
Reference:
Rupprich. V Weigand. \\. 1 'JS4. Penlimid Testing (lie aculc ii'i'ilanl elTecls/causlic elTecls on
llie rahhil e\e. Iloechsl Pliarma Research Toxicology. Germain. Report No. X4.022'). l''or
l arhen Nord. Work llochsl. III.RO II): 4"\3I524
Note:
Test was conducted according to the OECD TG 405 Acute Eye Irritation / Corrosion (1981)
Domain
Metric
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable,
or Not rated]
Comments
Metric
Score
Metric
Weighting
Factor
Weighted
Score
1. Test
substance
identity
High
The test substance
was identified
definitively and the
specific form was
characterized.
1
2
2
2. Test
substance
source
Medium
Source was
incompletely
reported.
2
1
2
Test Substance
3.Test
substance
purity
Medium
Product contained
80% active
ingredient
(Perylimid); other
components were
reported as 10%
KOH, 8% diverse
organic
contaminations,
which were not
identified, approx
1% inorganic salts,
and approx 1%
water.
2
1
2
4. Negative
controls
High
The untreated eye
served as the
negative control.
1
2
2
Test setup
5. Positive
controls
Not Rated
Positive controls
not required for the
study.
NR
NR
NR
6.
Randomized
allocation
Not Rated
Only one group was
included, so
randomization is
typically not
required.
NR
NR
NR
Exposure
characterization
7. Preparation
and storage of
test substance
Low*
Details regarding
storage conditions
of the test substance
in saline were not
reported, neither
was timeframe
between
formulation
3
1
3
Page 57 of 79
-------
Sliulj
Uefcrence:
Kupprich. V Weijiand. \\. I')S4. Penlimid l esling llie acule irriliinl elTecls/cauMic elTecls on
(lie rahhil e\e. Iloechsl Pliarma Research To\icolo»\. Cennain. Report No. X4.022'). l or
l-arl>cn Nord. Work llochsl. III KO II): -T3I524
preparation and use.
Amount applied
was given but the
storage and
solubility was not
given. lOOmg may
not dissolve in
0.05ml of 0.9%
NaCl solution.
8.
Consistency
of Exposure
administration
HighA
1
1
1
9. Reporting
of doses /
concentrations
High
lOOmg was applied
in 0.3ml of 0.9%
NaCl solution
1
2
2
10. Exposure
frequency and
duration
HighA
1
1
1
11. Number
of exposure
groups and
dose spacing
HighA
1
1
1
12. Exposure
route and
method
HighA
1
1
1
13. Test
animal
characteristics
Medium
Details were not
reported including
age and sex.
2
2
4
Test organisms
14. Adequacy
and
consistency of
animal
husbandry
conditions
High
Husbandry
conditions were
reported
1
1
1
15. Number
per group
HighA
1
1
1
16. Outcome
assessment
methodology
HighA
1
2
2
Outcome
Assessment
17.
Consistency
of outcome
assessment
HighA
1
1
1
18. Sampling
adequacy
HighA
1
1
1
Page 58 of 79
-------
Sludj
Ucl'crcnce:
Kupprich. V Weigand. \\. I')X4. Penlimid TeMing llie acule irrilanl cITccls/caiislic elTecls on
(lie rahhil e\e. lloechM Pliarma Research Toxicology. Germain. Report No. X4.022'). l or
l arhen Nord. Work llochsl. III KO II): 4'73I524
19. Blinding
of assessors
Not Rated
No subjective
outcomes were
assessed.
NR
NR
NR
20. Negative
Control
Response
HighA
1
1
1
Confounding/
variable control
21.
Confounding
variables in
test setup and
procedures
HighA
1
2
2
22. Outcomes
unrelated to
exposure
HighA
1
1
1
Data
presentation
and analysis
23. Statistical
methods
High
The data was
provided, but
statistical analysis
is not required
1
1
1
24. Reporting
of data
HighA
1
2
2
Sum of scores:
26
28
34
High
Medium
Low
Overall Score =
Sum of Weighted
Scores/Sum of
Metric Weighting
Factors:
1.214
Overall
Score
(Rounded):
1.2
>1 and <1.7
>1.7 and <2.3
>2.3 and <3
Overall Quality Level:
HIGH
Footnote A: This metric met the criteria for high confidence as expected for this type of study.
Page 59 of 79
-------
Table 15. T.ocnl T.ymph Node Assay. (*"* *""")
S(ii(l\ Reference:
Johnson. I.R. Pentium
Laboratory. 1 K. Project No. C
1-': Local L\mpli Node Ass;i\. Central Toxicology
I'l./!'/(»1 *)4. Lor liASL Aklicngcsellschari. Germain.
III'.RO II): -P3I53"7.
Note:
Study report indicates that test was conducted according to OECD TG 406: Skin sensitization
(1992)
Domain
Metric
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable,
or Not rated]
Comments
Metric
Score
Metric
Weighting
Factor
Weighted
Score
1. Test
substance
identity
High
The test
substance was
identified
definitively
and the
specific form
was
characterized
1
2
2
Test Substance
2. Test
substance
source
High
Test item was
received by
the submitter
and the batch
number was
provided.
1
1
1
3.Test
substance
purity
High
Given as 90%
and the dose
calculations
were adjusted
to purity
1
1
1
4. Negative
and vehicle
controls
HighA
1
2
2
Test setup
5. Positive
controls
High
Positive
control study
was
conducted
within 6
months of
study and was
appropriate.
1
1
1
6.
Randomized
allocation
Low
Allocation of
animals into
study groups
was not
reported.
3
1
3
Exposure
characterization
7. Preparation
and storage of
test substance
Medium
Details
regarding
storage
conditions of
the test
2
1
2
Page 60 of 79
-------
S(ii(l\ Reference:
Johnson. I.U. I«)«W. Pentium
l.ahoralon. 1 K. Project No. (
1-': Local Lymph Node Assay. Central Toxicology
I'l./P/61 *)4. l-"or IJASI-" Akliengesellschari. Germany.
lir.KO II): -P3I53"7.
substance in
propylene
glycol were
not reported.
8.
Consistency
of exposure
administration
HighA
1
1
1
9. Reporting
of doses /
concentrations
High
The
administered
doses were
reported
without
ambiguity.
1
2
2
10. Exposure
frequency and
duration
HighA
1
1
1
11. Number
of exposure
groups and
dose spacing
High
It is unclear fi
the highest
concentration
was high
enough to
induce a
response.
1
1
1
12. Exposure
route and
method
High
The route and
method of
exposure were
reported.
1
1
1
13. Test
animal
characteristics
Medium
Details were
not reported
including age,
health status,
and starting
body weight.
2
2
4
Test organisms
14. Adequacy
and
consistency of
animal
husbandry
conditions
HighA
All husbandry
conditions
were reported
and the only
difference was
the exposure.
1
1
1
15. Number
per group
HighA
1
1
1
Outcome Assessment
16. Outcome
assessment
methodology
High
The outcome
assessment
methodology
addressed the
intended
outcomes of
interest and
1
2
2
Page 61 of 79
-------
S(ii(l\ Reference:
Johnson. I.U. I«)«W. Pcnlimid I": Local I.Miiph Node Ass;i\. ( cnlral To\icolo»\
l.ahoralon. 1 K. Projccl No. CTI./l'/fil')-!. l-'or I5ASI-" Aklicngcscllschafl. (>crnian\.
III'.KO II): WW.
was sensitive
for the
outcome of
interest.
17.
Consistency
of outcome
assessment
High
Details of the
outcome of
assessment
protocols and
reported
outcomes
were assessed
consistently.
1
1
1
18. Sampling
adequacy
HighA
1
1
1
19. Blinding
of assessors
Not rated
It is not
typically
discussed in
these studies.
NR
NR
NR
20. Negative
control
response
High
The biological
responses of
the negative
control group
were
adequate.
1
1
1
21.
Confounding
variables in
test setup and
procedures
HighA
1
2
2
Confounding/
variable control
22. Outcomes
unrelated to
exposure
High
Due to heavy
precipitation
of the test
substance the
bacterial lawn
could only be
evaluated to
the
penultimate
highest dose.
1
1
1
Data presentation
and analysis
23. Statistical
methods
High
The data was
reported, but
the
statistically
analysis was
not required
as the test
substance did
not cause
significant
change.
1
1
1
Page 62 of 79
-------
S(ii(l\ Reference:
Johnson. I.U. I«)«W. Penlimid I": Local I.Miiph Node Ass;i\. ( enlral To\icolo»\
l.ahoralon. 1 K. Projecl No. ( TI./I'/M'U. l-'or I5ASI-" Aklioii^csollschiil'l. (.ci-iii;ni\.
III'.KO II): WW.
24. Reporting
of data
High
Data was
presented for
all outcomes.
1
2
2
Sum of
scores:
27
30
35
High
Medium
Low
Overall Score
= Sum of
Weighted
Scores/Sum
of Metric
Weighting
Factors:
1.167
Overall Score
(Rounded):
1.2
>1 and <1.7
>1.7 and <2.3
>2.3 and <3
Overall Quality Level:
HIGH
Footnote A: This metric met the criteria for high confidence as expected for this type of study.
Page 63 of 79
-------
Table 16. Study of the Mutagenic Potential in Strains of Salmonella typhimurium (AMES Test)
and Ksdieridiia coli. ( )
Siudj Reference':
Jung. R.. Weigand. \\. I')X3. Penlimid Siudj oil lie Mutagenic Potential in Sirains ol°
Stihiioiicllti lyi'liinmrimii (AMI-'.S Tesl) and Escherichia coli. Iloechsl . \ Ul ioniiosel Isclui l"l.
(iermain. Report No. S3.0(i'J5. l-'or Iloechsl. l-'ahrcnrorschung. (iermain. HIIRO II):
4731535.
Note:
Study report did not indicate the authors followed a test guideline
Domain
Metric
Qualitative
Determination
[Le., High,
Medium, Low,
Unacceptable,
or Not rated]
Comments
Metric
Score
Metric
Weighting
Factor
Weighted
Score
Test Substance
1. Test
substance
identity
High
The test
substance was
identified
definitively
and the
specific form
was
characterized
1
2
2
2. Test
substance
source
Medium
The source
was
incompletely
reported.
2
1
2
3.Test
substance
purity
High
See note at
the bottom of
the table.
1
1
1
4. Negative
controls
High
Solvent
control was
used as
negative
control
1
2
2
Test setup
5. Positive
controls
High
The positive
controls were
included and
the response
was
appropriate.
1
2
2
6. Assay
procedure
HighA
1
1
1
7. Standards
for test
Not rated
This metric is
not applicable
for this
endpoint
NR
NR
NR
Exposure
characterization
8. Preparation
and storage of
test substance
Medium
The test
substance was
prepared on
the day of the
test, but
storage
information
2
1
2
Page 64 of 79
-------
S(ud\ Reference:
Junti. K.. Wciiiimd. \\. 1 *>S3. Penlimid S(iid\ oil lie Muhiiicnic Poion I i;i 1 in Mniins of
Suliiioncllu typliinmrimii (AMI-IS Tesl) iind Escherichia coli. Iloechsl . \ Ul ioniiesel Isclui l"l.
(>crm;in\. Report No. X3.0(»,.)5. l-'oi* Iloechsl. l-~:ihreiil'orsclinnu. (>crm;iin. HIIRO II):
4^31535.
was not
provided.
9. Consistency
of exposure
administration
HighA
1
1
1
10. Reporting
of
concentrations
High
The tested
doses were
reported
without
ambiguity.
1
2
2
11. Exposure
duration
High
48 to 72hr
with and
without
metabolic
activation.
1
2
2
12. Number of
exposure
groups and
dose spacing
HighA
1
1
1
13. Metabolic
activation
High
Metabolic
activation is
reported and
performed
using
Mammalian
Microsomal
Fraction S9
Mix
1
1
1
14. Test model
High
Bacterial and
Salmonella
typhimurium
was chosen
based on
historical
success in in
vitro
experiments.
1
2
2
Test Model
15. Number
per group
High
The number
of exposed
cells/
replicate was
not reported.
The number
of replicates/
concentration
was
appropriate.
1
1
1
Page 65 of 79
-------
S(ud\ Reference:
Jung. K.. Wcigand. \\. 1 *>S3. Pcnlimid Siud> oil lie Mucigenic Polcnlial in Strains of
Suliiioncllu typliinmrimii (AMI-IS Tesl) and Escherichia coli. Iloechsl Aklicngcscllschafl.
(>crm;in\. Report No. S3.0(i'J5. l-'or Iloechsl. l-'ahrcnforschiing. (>erman\. III'.RO II):
4 "'J 1535.
16. Outcome
assessment
methodology
High
The outcome
assessment
methodology
addressed the
intended
outcome of
interest and
was sensitive
1
2
2
Outcome
Assessment
17. Consistency
of outcome
assessment
High
Details of the
outcome of
assessment
protocols and
reported
outcomes
were assessed
consistently
1
1
1
18. Sampling
adequacy
HighA
1
2
2
19. Blinding
of assessors
Not rated
It is not
typically
discussed in
these studies.
NR
NR
NR
Confounding/
variable control
20.
Confounding
variables in
test setup and
procedures
HighA
1
2
2
21.
Confounding
variables in
outcomes
unrelated to
exposure
HighA
1
1
1
22. Data
analysis
High
Statistical
methods,
calculation
and methods
were not
required
1
1
1
Data
presentation and
analysis
23. Data
interpretation
High
Evaluation
criteria
appeared to
be limited to
positive
controls,
defined as a
significant
increase in
1
2
2
Page 66 of 79
-------
S(ud\ Reference:
Jung. K.. Weigand. \\. I')X3. Penlimid Siud\ oil lie Mulagenic Poienlial in Si r;iins of
Suliiioncllu typliinmrimii (AMI-IS lost I ;iihI Escherichia coli. Ilocchsl . \ Ul ioniiesel Isclui l"l.
(iermain. Report No. X3.0(»,.)5. l-"or Ilocchsl. l-~:ihroiil'orsclinnu. Germain. III'.RO II):
4^31535.
revertant
colonies
24.
Cytotoxicity
data
Not rated
This was not
a cytotoxicity
test rather a
mutagenicity
test, this
Metric should
not be applied
NR
NR
NR
25. Reporting
of data
HighA
1
2
2
Sum of
scores:
23
33
35
High
Medium
Low
Overall
Score = Sum
of Weighted
Scores/Sum
of Metric
Weighting
Factors:
1.061
Overall Score
(Rounded):
1.1
>1 and <1.7
>1.7 and <2.3
>2.3 and <3
Overall Quality Level:
HIGH
Footnote A: This metric met the criteria for high confidence as expected for this type of study.
Page 67 of 79
-------
Table 17. Ccnc Mutation Assay in Chinese Hamster V79 Cells Tn Vitro. (" "" - ""*'*)
Sludj
Reference:
Wollin. II. 2012. (iene Mulalion Ass;i\ in Chinese llanisler \"") ( ells In Yiirn (\ ""J/IIPRT)
with Paliogen Yiolel 5011. Marian (Aloiesl Cell Research (.nihil, (iermain. Report No.
1443105. lor BASI- SI!, Cermain. III.RO II): 4_\3I53(..
Note:
Study report indicates it was conducted according to OECD TG 467/ OPPTS 870.5300
Domain
Metric
Qualitative
Determination
[Le., High,
Medium, Low,
Unacceptable,
or Not rated]
Comments
Metric
Score
Metric
Weighting
Factor
Weighted
Score
1. Test
substance
identity
High
The test
substance was
identified
definitively, and
the specific form
was
characterized
1
2
2
Test Substance
2. Test
substance
source
Medium
The source was
incompletely
reported.
2
1
2
3.Test
substance purity
High
Given as 90%
and the dose
calculations
were adjusted to
purity
1
1
1
4. Negative
controls
High
Solvent control
was used as
negative control
1
2
2
5. Positive
controls
High
The positive
controls were
included and the
response was
appropriate
(induction of
positive effect).
1
2
2
6. Assay
procedure
HighA
1
1
1
Test setup
7. Standards for
test
High
Mutant colonies
per 106 cell
identified in
solvent control
should be within
the laboratory
historical
controls and
positive control
substance is
expected to
produce
significant
increase in
1
1
1
Page 68 of 79
-------
Sliulj
Ucfercnce:
Wollin. II. 2012. (iene Mulalion Assaj in Chinese llamsler \"") ( ells In Yiirn (V'i/IIPUT)
with Palio^en Yiolel 5011. Marian (Aloicsl Cell Research (.nihil, (icrmain. Report No.
1443105. l-or BASI- SI.. (iermain. III.KO II): 4_'3I53(..
mutant colony
frequency.
8. Preparation
and storage of
test substance
Medium
The test
substance was
prepared on the
day of the test,
but storage
information was
not provided.
2
1
2
9. Consistency
of exposure
administration
HighA
1
1
1
Exposure
characterization
10. Reporting
of
concentrations
High
The tested doses
were reported
without
ambiguity.
1
2
2
11. Exposure
duration
High
4hr and 24hr
with and without
metabolic
activation
1
2
2
12. Number of
exposure
groups and dose
spacing
HighA
1
1
1
13. Metabolic
activation
High
Metabolic
activation is
reported and
performed using
Mammalian
Microsomal
Fraction S9 Mix
1
1
1
14. Test model
High
V79 cell line
was chosen
based on
historical
success in in
vitro
experiments.
1
2
2
Test Model
15. Number per
group
High
The number of
exposed
cells/replicates
was not reported.
The number of
replicates/
concentration
was appropriate
1
1
1
Outcome
Assessment
16. Outcome
assessment
methodology
High
The outcome
assessment
methodology
1
2
2
Page 69 of 79
-------
Sludj
Ucl'crcncc:
Wollin. II. 2012. (iene Mulalion Assaj in Chinese llainsler \"") ( ells In Yiirn (V'i/IIPUT)
with Paliogcn Yiolcl 5011. Marian C\lo(csl Cell Research (.nihil, (icrmain. Report No.
1443105. l-or BASI- SI.. (icrmain. III.KO II): 4_\3I53(..
addressed the
intended
outcome of
interest and was
sensitive
17. Consistency
of outcome
assessment
High
Details of the
outcome of
assessment
protocols and
reported
outcomes were
assessed
consistently
1
1
1
18. Sampling
adequacy
HighA
1
2
2
19. Blinding of
assessors
Not rated
It is not typically
discussed in
these studies.
NR
NR
NR
Confounding/
variable control
20.
Confounding
variables in test
setup and
procedures
High
There were no
differences
reported among
study groups
apart from
precipitation of
the test
substance in the
higher doses.
1
2
2
21.
Confounding
variables in
outcomes
unrelated to
exposure
HighA
1
1
1
22. Data
analysis
High
Statistical
methods,
calculation and
methods were
presented
1
1
1
Data
presentation
and analysis
23. Data
interpretation
High
Evaluation
criteria appeared
to be limited to
positive controls,
defined as a
significant
increase in
revertant
colonies
1
2
2
24. Cytotoxicity
data
Not rated
This is not a
cytotoxicity test
rather a
NR
NR
NR
Page 70 of 79
-------
Sludj
Uefcrenco:
Wollin. II. 2012. (.one Muliilion Ass;i\ in Chinese llamsler \"") ( ells In Yiim (V'i/IIPUT)
with Paliogen Yiolel 5011. Marian (Alolosl Coll Research (.nihil. (iermain. Report No.
1443105. I»r BASI- SI., Germain. III.KO II): 4_'3I53(..
mutagenicity
test, \ so this
metric is not
applicable
25. Reporting
of data
HighA
1
2
2
Sum of scores:
24
34
36
High
Medium
Low
Overall Score =
Sum of
Weighted
Scores/Sum of
Metric
Weighting
Factors:
1.059
Overall Score
(Rounded):
1.1
>1 and <1.7
>1.7 and <2.3
>2.3 and <3
Overall Quality Level:
HIGH
Footnote A: This metric met the criteria for high confidence as expected for this type of study.
Page 71 of 79
-------
Table 18. Effects of Suhchronicnlly Inhaled Carbon Black. J - -1- -¦ "'ww:")
S(ud\ Reference:
l-'.lder el al.. 2005. l-'.ITecls of Suhclironic;ill> Inhaled Cai'hon lilack in Three Species. 1.
Rolen (ion Kinetics. Lung Inrianinialion. and llislopalholugt. III.KO II): XXI')4
Note:
This study analyzed the inhalation effects of Carbon Black, an analogue of C.I. Pigment Violet
29.
Domain
Metric
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable,
or Not rated]
Comments
Metric
Score
Metric
Weighting
Factor
Weighted
Score
Test Substance
1. Test substance
identity
High
The test
substance was
identified
definitively,
and the
specific form
was
characterized
1
2
2
2. Test substance
source
High
The Test
Substance
source was
reported
1
1
1
3.Test substance
purity
High
Test substance
purity was
reported
1
1
1
4. Negative
controls
High
Negative
controls were
reported
1
2
2
Test setup
5. Positive
controls
Not rated
Positive
control animals
are not
required for
this study.
NR
NR
NR
6. Randomized
allocation
High
Test organisms
were randomly
allocated to
exposure
groups
1
1
1
7. Preparation
and storage of
test substance
High
Test substance
preparation
was fully
reported.
1
1
1
Exposure
characterization
8. Consistency of
Exposure
administration
High
Details of
exposure
administration
was fully
reported.
1
1
1
9. Reporting of
doses /
concentrations
HighA
1
2
2
Page 72 of 79
-------
S(ud\ Reference:
l-'.lder el al.. 2005. l-'.ITecls of Suhclironic;ill> Inhaled Carhon lilack in Three Species. 1.
Rolen (ion kinetics. Lung lnfl;iiiiiii;i(ion. and llislopalhologt. III.KO II): XXI')4
10. Exposure
frequency and
duration
HighA
1
1
1
11. Number of
exposure groups
and dose spacing
HighA
1
1
1
12. Exposure
route and method
HighA
1
1
1
13. Test animal
characteristics
HighA
1
2
2
Test organisms
14. Adequacy
and consistency
of animal
husbandry
conditions
Not Assessed
NA
NA
NA
15. Number per
group
HighA
1
1
1
16. Outcome
assessment
methodology
HighA
1
2
2
17. Consistency
of outcome
assessment
HighA
1
1
1
Outcome
Assessment
18. Sampling
adequacy
HighA
1
1
1
19. Blinding of
assessors
HighA
1
1
1
20. Negative
Control
Response
High
No effects
reported in
controls
1
1
1
Confounding/
variable control
21. Confounding
variables in test
setup and
procedures
High
No
confounding
variables
1
2
2
22. Outcomes
unrelated to
exposure
Med
Not Reported
2
1
2
Data presentation
23. Statistical
methods
HighA
1
1
1
and analysis
24. Reporting of
data
HighA
1
2
2
Sum of scores:
23
29
High
Medium
Low
Overall Score
= Sum of
Weighted
Scores/Sum of
1.034
Overall
Score
(Rounded):
1
Page 73 of 79
-------
S(ud\ Reference:
l-'.lder el ill.. 2005. l-'.ITecls (il° Suhclironic;ill> Inhaled Crlxui lilack in Tlnvc Species. 1.
Rolen (ion kinetics. I.iing Inriiininiiiliiin. ;ind llislopalhologt. III.KO II): XXI'J-l
Metric
Weighting
Factors:
>1 and <1.7
>1.7 and <2.3
>2.3 and <3
Overall
Quality
Level:
High
Footnote A: This metric met the criteria for high confidence as expected for this type of study.
Page 74 of 79
-------
Table 19. Effects of Chronically Inhaled Carbon Black. (* "" " * ""r)
S(ud\ Reference:
Nikula el ;il.. I')')5. Comparali\e Pulinon;ir> Toxicides and Carcinogenicities of Chmnicallv
Inhaled Diesel IMiausl and Carbon lilack in 1-344 Rals. III.KO II): ^.(.41
Note:
This study analyzed the inhalation effects of Carbon Black, an analogue of C.I. Pigment Violet
29.
Domain
Metric
Qualitative
Determination
[i.e., High,
Medium, Low,
Unacceptable,
or Not rated]
Comments
Metri
c
Score
Metric
Weighting
Factor
Weighted
Score
1. Test substance
identity
High
Elftex-12
furnace black
1
2
2
Test Substance
2. Test substance
source
High
Cabot (Boston,
MA)
1
1
1
3.Test substance
purity
Low
Not reported
3
1
3
4. Negative
controls
High
Negative
(sham) filtered
air controls
were reported
1
2
2
Test setup
5. Positive
controls
Not rated
Positive
control animals
are not
required for
this study.
NR
NR
NR
6. Randomized
allocation
High
Test organisms
were randomly
allocated,
stratified by
body wt, to
exposure
groups
1
1
1
Exposure
characterization
7. Preparation
and storage of
test substance
Medium
Because
generated as
dry aerosol,
preparation
described as
part of
exposure
administration,
but storage not
provided
2
1
2
8. Consistency of
Exposure
administration
High
Details of
exposure
administration
were fully
reported.
1
1
1
9. Reporting of
doses /
concentrations
High
Nominal &
analytical
1
2
2
Page 75 of 79
-------
S(ud\ Reference:
Nikula el al.. I')')5. ( <1111 pa rat i\e Piilmonan Toxicities and Carcinugcnicilics of (hmnicallv
Inhaled Diesel IMiausI and (arhon Black in 1-344 Rals. III.KO II): -'(.(.41
concentrations
reported
10. Exposure
frequency and
duration
High
Duration &
frequency
reported
(16/h/day, 5
d/week, for 24
months
1
1
1
11. Number of
exposure groups
and dose spacing
Medium
Number of
exposure
groups
reported; dose
spacing
adequate in
that conc.
response
observed, but
no NOAEC
established, so
dose selection
not optimal
2
1
2
12. Exposure
route and method
High
Detail of
inhalation
exposure
chamber &
methods
provided.
1
1
1
13. Test animal
characteristics
High
Reported
Details about
species, strain,
sex, age,
source
provided
1
2
2
Test organisms
14. Adequacy
and consistency
of animal
husbandry
conditions
High
Reported
1
1
1
15. Number per
group
High
Reported
1
1
1
16. Outcome
assessment
methodology
High
Reported
1
2
2
Outcome
Assessment
17. Consistency
of outcome
assessment
High
Consistent
1
1
1
18. Sampling
adequacy
High
Adequate
1
1
1
Page 76 of 79
-------
S(ud\ Reference:
Nikula el ;il.. (omparali\e Piilmonan Toxicides and Carcinngenicilies of Chronically
Inhaled Diesel IMiausl and ( arhon lilack in 1-344 Kals. III.KO II): -'(.(.41
19. Blinding of
assessors
Low
Not Reported
3
1
3
20. Negative
Control
Response
High
Low incidence
of effects
reported in
controls
1
1
1
Confounding/
variable control
21. Confounding
variables in test
setup and
procedures
High
Confounding
variables for
mutagenicity
were assayed.
1
2
2
22. Outcomes
unrelated to
exposure
High
Spontaneous
tumor
formation in
controls with
age was
reported
1
1
1
Data presentation
and analysis
23. Statistical
methods
High
Reported
1
1
1
24. Reporting of
data
High
Detailed
Reporting
1
2
2
Sum of scores:
27
33
High
Medium
Low
Overall Score
= Sum of
Weighted
Scores/Sum of
Metric
Weighting
Factors:
1.22
Overall
Score
(Rounded):
1
>1 and <1.7
>1.7 and <2.3
>2.3 and <3
Overall
Quality
Level:
High
Footnote A: This metric met the criteria for high confidence as expected for this type of study.
Page 77 of 79
-------
References
F. (1975a). Acute inhalation toxicity with rats. BASF report XXV/454. In Product Safety Basel.
(XXV/454). Switzerland: BASF Schweiz AG.
F. (1975b). Acute oral toxicity with rats. BASF report XXV/454. (XXV/454). Switzerland: BASF
Schweiz AG.
F. (1975c). Eye irritation study. BASF report XXV/454. In Product Safety Basel. (XXV/454).
Switzerland: BASF Schweiz AG.
F. (1975d). Skin irritation study. BASF report XXV/454. In Product Safety Basel. (XXV/454).
Switzerland: BASF Schweiz AG.
F. (1975e). Summary of toxicological investigations with CAS 81-33-4, Acute intraperitoneal
toxicity with mice. BASF Report XXV/454. In Product Safety Basel. (XXV/454). Switzerland:
BASF Schweiz AG.
F\ (1978a). Eye irritation study. BASF report 77/360. In Product Safety Basel. (77/360).
Switzerland: BASF Schweiz AG.
F\ (1978b). Study report for CAS 81-33-4, Acute inhalation toxicity with rats. BASF report 77/360.
In Product Safety Basel. (77/360). Switzerland: BASF Schweiz AG.
F\ (1978c). Study report for CAS 81-33-4, Acute intraperitoneal toxicity with mice. BASF report
77/360. In Product Safety Basel. Switzerland: BASF Schweiz AG.
f\ (1978d). Study report for CAS 81-33-4, acute oral toxicity with rats. BASF report 77/360. In
Product Safety Basel. (77/360). Switzerland: BASF Schweiz AG.
F\ (1978e). Study report for CAS 81-33-4, skin irritation study. BASF report 77/360. In Product
Safety Basel. (77/360). Switzerland: BASF Schweiz AG.
Eldei \ olein. R; Finkelstein. IN; Driscott. KE; Harkemj i Uberdorstci u (2005). Effects of
subchronically inhaled carbon black in three species I Retention kinetics, lung inflammation, and
histopathology. Toxicol Sci 88: 614-629. http://dx.doi.( 3/toxsci/kfi327.
Johnson. IR. (1999). Perylimid F: Local lymph node assay. Project no. CTL/P/6194. (CTL/P/6194).
Germany: BASF Aktiengesellschaft.
Jung. R; Wei sand. W. (1983). Perylimid study of the mutagenic potential in strains of salmonella
typhimurium (Ames Test) and escherichia coli. (83.0695). Germany: Hoechst
Aktiengesellschaft.
Nikula. KJ; Snipes. MB; Barr. EB; Griffith. WC: Henderso Mauderly. JL. (1995). Comparative
pulmonary toxicities and carcinogenicities of chronically inhaled diesel exhaust and carbon black
in F344 rats. Toxicol Sci 25: 80-94. http://dx.doi.ore/10.1006/]
Rupprich. N: Weieand. W. (1984a). Perylimid testing the acute dermal irritant effects/caustic effects on
the rabbit eye. (84.0228). Germany: Hoechst AG, Pharma Research Toxicology and Pathology.
Rupprich. N: Weieand. W. (1984b). Perylimid testing the acute irritant effects/caustic effects on the
rabbit eye. (84.0229). Germany: Hoechst AG, Pharma Research Toxicology and Pathology.
Rupprich. N: Weieand. W. (1984c). Testing the acute oral toxicity in the male and female Wistar rat.
(84.0225). Germany: Hoechst AG, Pharma Research Toxicology and Pathology.
S; eumann. S; van Ravenzwaav. B. (2013). Reproduction/developmental toxicity screening test
in Wistar rats oral administration (gavage). (80R0223/11C162). Germany: BASF SE.
(2018). Application of systematic review in TSCA risk evaluations. (740-P1-8001).
Washington, DC: U.S. Environmental Protection Agency, Office of Chemical Safety and
Pollution Prevention, https://www.epa.gov/sites/production/files/2018-
06/documents/final application of sr in ts«
Wollny. H. (2012). Gene mutation assay in Chinese hamster V79 cells in vitro (V79/HPRT) with
paliogen violet 5011. (1443105). Germany: BASF SE.
Page 78 of 79
-------
Page 79 of 79
------- |