PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

SEPA

United States	Office of Chemical Safety and

Environmental Protection Agency	Pollution Prevention

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

CASRN: 127-18-4

Systematic Review Supplemental File:

Data Extraction for Human Health Hazard Studies

CI CI

x

CI CI

April 2020, Draft

1


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 DO NOT CITE OR QUOTE

Contents

1	DATA EXTRACTION OF STUDIES CONSIDERED FOR DOSE-RESPONSE
ASSESSMENT	3

Table 1.1. Summary of the epidemiologic database considered for dose-response assessment	3

Table 1.2 Summary of the animal toxicological database considered for dose-response assessment	6

2	DATA EXTRACTION OF STUDIES NOT CONSIDERED FOR DOSE-RESPONSE
ASSESSMENT	13

Table 2.1 Summary of the AnimalToxicological Database for Tetrachloroethylene not considered for dose-response
13

Table 2.2 Summary of the AnimalToxicological Database for Tetrach loroeth ylen e not considered for dose-response
49

2


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 DO NOT CITE OR QUOTE

1 Data extraction of studies considered for dose-response assessment

The tables below present data summaries of animal and epidemiological studies considered for dose-response assessment, as described
in Section 3.2.5 of the Risk Evaluation. Studies that were excluded due to an Unacceptable or Low data quality score are not included.
The presented effect doses/concentrations are values reported by the study authors and do not necessarily represent the PODs used for
risk estimation.

Table 1.1. Summary of the epidemiologic database considered for dose-response assessment

Target Organ/
System

Outcome/ Endpoint

Study Population

Exposure

Results

Reference

Data
Quality
Evaluation

Neurological/
Behavior

Sensory nervous system
function, visual and
auditory evoked
potentials

22 healthy male
volunteers with a mean

age of 26.5 years,
ranging 23 to 35 years of
age, participated in a
study conducted in
former Federal Republic
of Germany

Exposure in inhalation
chamber to 10 ppm and
50 ppm
perchloroethylene,
maintained during a
period of 4d for 4h daily

Statistically significant
mild change in visual
function (visually evoked
potentials) but no change
in transmission of
auditory impulse
(brainstem auditory
evoked potentials)

Altmann et
al. 1990

Medium

Renal

Urinary TP, Alb, B2M,
RBP, TRF, IgG, THG,
GAGs, BB50, HF5, BBA,
PGE2, TXB, PGF1 alpha,
PGF2alpha, IAP, TNAP,
NAG, and FNU,; serum
creatinine, AGBM, B2M,
LAM

50 workers in dry-
cleaning shops (9 men
and 41 women, 17-65
years old) and 50 blood
donors (9 men and 41
women, 17-63 years
old), Europe (country not
specified), date not
provided

Blood and air Perc in
dry-cleaning workers
exposed for 10 years

Significant increase in
frequency of abnormal
levels in Perc-exposed
subjects for urinary
albumin, Beta-2-
microglobulins, retinol-
binding proteins,

transferrin,
immunoglobulin G,
Tamm-Horsfall
glycoproteins,
glycosaminoglycans,
brush-border antigens,
and for serum laminin
fragments.

Mutti et al.
1992

Medium

3


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

Target Organ/
System

Outcome/ Endpoint

Study Population

Exposure

Results

Reference

Data
Quality
Evaluation

Neurological/
Behavior

Pattern memory
(Number correct)

'Dry Cleaner Study
Population' (n=65). men
and women; Detroit,
USA

Percholroethylene.
Cumulative lifetime
exposure levels based

on complete
work histories, hobbies,
and

industrial hygiene
evaluations of subjects in
participating shops:.
Categories: low (n=24,
average 3.4 years at
shop), moderate
(n=18,average 8.1 years
at shop), and high
(n=23, average 20.2
years at shop).

Significant decrease
(6.7%) was observed in
the adjusted mean
performance on the
pattern memory (number
correct) between the low
and high Perc exposure
categories.

Echeverria
et al. 1995

Medium

Neurological/
Behavior

Color confusion index
(CCI)

35 exposed dry-cleaners
and ironers (33 females,
2 males) in Modena,
Italy;; 35 unexposed
controls

Perchloroethylene (Perc)
occupational, 8 hr time-
weighted average (TWA)
mean airborne
concentrations: all
workers (6.23 ppm), dry-
cleaners (7.27 ppm),
ironers (4.80 ppm)

A statistically significant
increase in mean color
confusion index was
observed for Perc
exposed workers and in
dry-cleaners specifically,
compared to unexposed
controls Non-significant

differences were
observed in the mean
color confusion index for

Perc-exposed ironers
compared to unexposed
controls. A statistically
significant correlation
was observed between
perc exposure and color
confusion index among
exposed workers.

Cavalleri et
al 1994

Medium

4


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

5


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

Table 1.2 Summary of the animal toxicological database considered for dose-response assessment

Target
Organ/
System

Study
Type

Species/
Strain/ Sex
(Number/
group)

Exposure
Route

Doses/
Concentrations

Duration

Cancer
Incidence

Effect

Reference

Data Quality
Evaluation

Cancer

Chronic

Rat, Fischer, M/
F (n= 100/
group)

Inhalation,
vapor,
whole body

0, 339, 1356, or
4069 mg/ m3 (0,
50, 200, or 600
ppm)

6 hours/
day,5 days/
week for
104 weeks

600 ppm: 1/ 50
(F) and none in
males

Renal cell carcinoma

fJISA, 1993)

High

Cancer

Chronic

Rat, Fischer, M/
F (n= 100/
group)

Inhalation,
vapor,
whole body

0, 339, 1356, or
4069 mg/ m3 (0,
50, 200, or 600
ppm)

6 hours/
day,5 days/
week for
104 weeks

control: 1/ 50,
50 ppm: 2/ 50,
200 ppm: 1/50,
600 ppm: 2/ 50
(M), only one
control female

Renal cell adenoma

fJISA, 1993)

High

Cancer

Chronic

Mouse, Crj:
BDF1, M/F(n =
100/group)

Inhalation,
vapor,
whole body

0, 68, 339, or
1696 mg/ m3 (0,
10, 50, or 250
ppm

6 hours/
day5days/
week for
104 weeks

50 ppm: 1/ 50
(M) and none in
exposed female
mice

Renal cell adenoma

fJISA, 1993)

High

Cancer

Chronic

Mouse, Crj:
BDF1, M/F (n =
100/group)

Inhalation,
vapor,
whole body

0, 68, 339, or
1696 mg/ m3 0,
10, 50, or 250
ppm

6 hours/
day5days/
week for
104 weeks

50 ppm: 1/ 50
(M) and none in
exposed female
mice

Renal cell carcinoma

fJISA, 1993)

High


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

Target
Organ/
System

Study
Type

Species/
Strain/ Sex
(Number/
group)

Exposure
Route

Doses/
Concentrations

Duration

Cancer
Incidence

Effect

Reference

Data Quality
Evaluation

Cancer

Chronic

Rat, F344/ N, M/
F (n=100/
group)

Inhalation,
vapor,
whole body

0, 1356, or 2713
mg/ m3
(0, 200 or 400
ppm)

103 weeks

control: 0/49;
low dose: 3/49;
high dose:5/ 50
(M) and in one
high-dose
female rat

Tubal cell
hyperplasia

fNTP, 1986)

High

Cancer

Chronic

Rat, F344/ N, M/
F (n=100/
group)

Inhalation,
vapor,
whole body

0, 678, or 1356
mg/m3(0, 100 or
200 ppm)

103 weeks

control: 1/49;
low dose: 3/49;
high dose: 4/ 50
(M)

Renal tubule
adenomas and
adenocarcinomas

fNTP, 1986)

High

Cancer

Chronic

Mouse,
B6C3F1, M/F
(n=98-100/
group)

Inhalation,
vapor,
whole body

mg/ m3

(0, 100 or 200

ppm)

103 weeks

1 low-dose
male mouse

Renal tubule
adenocarcinoma

fNTP, 1986)

High

Hepatic

Chronic

Rat, F344/
DuCrj, M/ F
(n=100/ group)

Inhalation,
vapor,
whole body

0, 339, 1356, or
4069 mg/ m3 (0,
50, 200 or 600
ppm)

6 hours/
day, 5 days/
week for
104 weeks
(sacrificed
at 110
weeks)

LOAEL= 1356
mg/ m3 (M),
spongiosis

LOAEL = 4069
mg/ m3 (M),
hyperplasia

Spongiosis hepatitis
and hyperplasia

(J ISA, 1993)

High

Hepatic

Chronic

Mouse, Crj/
BDF1, M/F
(n=100/ group)

Inhalation,
vapor,
whole body

0, 68, 339, or
1696 mg/ m3 mg/
m3

(0, 10, 50 or 250
ppm)

6 hours/
day, 5 days/
week for
104 weeks
(sacrificed
at 110
weeks)

LOAEL= 339
mg/ m3 (M)

LOAEL = 1696
mg/ m3 (F)

Focal necrosis liver
degeneration

(J ISA, 1993)

High

Renal

Chronic

Rat, F344/
DuCrj, M/ F
(n=100/ group)

Inhalation,
vapor,
whole body

0, 339, 1356, or
4069 mg/ m3
(0, 50, 200 or 600
ppm)

6 hours/
day, 5 days/
week for
104 weeks

LOAEL= 1356
mg/ m3 (M/ F),
increased
relative kidney

Increased relative
kidney weights and
karyomegaly in the
proximal; atypical

(J ISA, 1993)

High


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

Target
Organ/
System

Study
Type

Species/
Strain/ Sex
(Number/
group)

Exposure
Route

Doses/
Concentrations

Duration

Cancer
Incidence

Effect

Reference

Data Quality
Evaluation











(sacrificed
at 110
weeks)

weights and
karyomegaly in
the proximal
tubules

LOAEL = 4069
mg/ m3 (M/ F),
atypical tubular
dilation

LOAEL = 4069
mg/ m3 (M),
exacerbation of
chronic renal
disease

tubular dilation;
exacerbation of
chronic renal
disease





Target
Organ/
System

Study
Type

Species/
Strain/ Sex
(Number/
group)

Exposure
Route

Doses/
Concentrations

Duration

Cancer Incidence

Effect

Reference

Data
Quality
Evaluation

Renal

Chronic

Mouse, Crj/
BDF1, M/F
(n=100/group)

Inhalation,
vapor,
whole
body

0, 68, 166, Or
1696 mg/ m3
(0, 10, 50 or
250 ppm)

6 hours/ day,
5 days/ week
for 104 weeks
(sacrificed at
110 weeks)

LOAEL= 1696
mg/ m3 (M/ F),
relative kidney

weight,
karyomegaly in
the proximal
tubules, and
atypical tubular
dilation

Increased
relative
kidney
weights and
karyomegaly
in the
proximal
tubules and
atypical
tubular
dilation but

was not
statistically
significant

(J ISA, 1993)

High

Hepatic

Chronic

Mouse,
B6C3F1, M/ F

Inhalation,
vapor,

0, 678, 1356
mg/ m3

6 hours/ day,
5 days/ week
for 103 weeks

LOAEL= 678
mg/ m3 (M)

Liver
degeneration

(NIP, 1986)

High


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

Target
Organ/
System

Study
Type

Species/
Strain/ Sex
(Number/
group)

Exposure
Route

Doses/
Concentrations

Duration

Cancer Incidence

Effect

Reference

Data
Quality
Evaluation





(n=98-100/
group)

whole
body

(0, 100 or 200
PPm)



LOAEL= 1356
mg/ m3 (F)

and necrosis
in





Hepatic

Subchroni
c

Mouse, Swiss-
Cox, M (n=12-
15/ group all
doses except
two highest
doses: 4-6/
group)

Oral,
gavage

0, 20, 100,
200, 500,
1000,1500 or
2000 mg/ kg/
day

5 days/ week
for 6 weeks

NOAEL= 20 mg/
kg-day (M)
LOAEL= 100
mg/ kg-day (M)

Increased
liver/ body
weight ratio at
100 mg/ kg-

day;
increased
triglycerides
at 100 mg/
kg-day; no
change at 20
mg/ kg-day

(Buben and
O'Flahertv,
1985)

High

Renal

Chronic

Rat, F344/ N,
M/ F (n=100/
group)

Inhalation,
vapor,
whole
body

0, 1356, or
2713 mg/ m3
(0 200, or
400ppm)

6 hours/ day,
5 days/ week
for 103 weeks

LOAEL= 1356
mg/ m3
(200 ppm) (M/ F)

Karyomegaly

and
cytomegaly of
the proximal
tubules in all
exposed rats

(NIP, 1986)

High

Renal

Chronic

Mouse,
B6C3F1, M/ F
(n=98-100/
group)

Inhalation,
vapor,
whole
body

0, 678, or
1356 mg/ m3
(0, 100 or 200
ppm)

6 hours/ day,
5 days/ week
for 103 weeks

LOAEL= 678
mg/ m3
(M/ F)

Karyomegaly

and
cytomegaly of
the proximal
tubules in all
exposed

mice;
nephrosis
was observed
in exposed
females,
casts
increased in
all exposed
males and in
high-dose
females

(NIP, 1986)

High


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

Target

Study

Species/

Exposure

Doses/

Duration

Cancer Incidence

Effect

Reference

Data

Organ/

Type

Strain/ Sex

Route

Concentrations









Quality

System



(Number/













Evaluation





group)















Develop-

Develop-

Rat, Sprague

Inhalation,

Actual

6 hours/ day,

Maternal LOAEL

Maternal

(Carney et

High

mental

mental

Dawley, F

vapor,

concentration

7 days/ week

= 4069 mg/ m3

toxicity

al„ 2006)







(n=22/ group)

whole

s: 0, 448,

on GDs 0-19

(from summary

(slight, but











body

1689,or 4069



table 4-38)

statistically













mg/ m3





significant,













(0, 66, 249 or



Fetal LOAEL =

decreased













600 ppm)



1696 mg/ m3

body weight













Target



(from summary

gain;













concentration



table 4-38)

decreased













s: 0, 509,





gravid uterine













1696,or 4069





weight); fetal













mg/ m3 (0,





body weight













75, 250 or





and placental













600 ppm)





weight



















decrements,



















increased



















delays in



















thoracic



















vertebral



















ossification





10


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

Target

Study

Species/

Exposure

Doses/

Duration

Cancer Incidence

Effect

Reference

Data

Organ/

Type

Strain/ Sex

Route

Concentrations









Quality

System



(Number/













Evaluation





group)















Reproduct

Reproduct

Rat, Sprague

Inhalation,

0, 678, 2035,

F0: 6 hours/



Increased

(Tinston,

High

ive

ive

Dawley, M/ F

vapor,

or 6782 mg/

day, 5 days/

NOAEL =

death of F1A

1994)







(two-

whole

m3

week for 11

678 mg/ m3 for

and F2A and









generation

body

(0, 100, 300

weeks

parental

F2B pups;









study)



or 1000 ppm)

premating;

systematic

decreased









(n=48/ group)





6 hours/ day,

toxicity

body weight















7 days/ week

(increased death

















for up to 21

of mothers)

















days during

LOAEL = 678

















mating period;

mg/ m3 for F1A

















6 hours/ day,

pups

















5 days/ week



















postmating until



















termination for



















males and 6



















hours/ day,



















5 days/ week



















for females



















postmating



















through GD 20



















(28 litters/



















dose)









Develop-

Developm

Rat, Sprague

Inhalation,

0, 678, or

7 hours/ day on

NOAEL= 678

Decreased

(Nelson et

Medium

mental

ental

Dawley

vapor,

6104 mg/ m3

GDs 7-13 or

mg/ m3

weight gain;

al„ 1979)



Effects



(n = 13-21/

whole

(0, 100 or 900

14-21

LOAEL= 6104

behavioral





(Neurotoxi



group)

body

ppm)

(GDs 13-21

mg/ m37

changes,





city)









litters/ dose,



more















male and



extensive for















female



late















offspring



pregnancy















assessed)



exposure;



















decreased



















brain



















acetylcholine






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

Target

Study

Species/

Exposure

Doses/

Duration

Cancer Incidence

Effect

Reference

Data

Organ/

Type

Strain/ Sex

Route

Concentrations









Quality

System



(Number/
group)













Evaluation

Develop-

Developm

Rat, Sprague

Inhalation,

0, 678, 2035,

F0: 6 hours/

NOAEL =



(Tinston,

High

mental

ental

Dawley (two-

vapor,

or 6782 mg/

day, 5 days/

300 ppm

CNS

1994)







generation

whole

m3

week for 11

LOAEL = 1,000

depression/









study)

body

(0, 100, 300

weeks

ppm

Behavioral









(n=48/ group)



or 1000 ppm)

premating;

6	hours/ day,

7	days/ week
for up to 21
days during

mating period;
6 hours/ day,
5 days/ week
postmating until
termination for
males and 6
hours/ day,
5 days/ week
for females
postmating
through D 20
(28 litters/
dose)



effects
(decreased
activity,
reduced
response to
sound) in F1
pups





12


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

2 Data extraction of studies not considered for dose-response assessment

Table 2.1 Summary of the Epidemiological Database for Perchloroethylene not considered for dose-
response

Target Organ/ System

Outcome/
Endpoint

Study Population

Exposure

Results

Reference

Data
Quality
Evaluation

Acute
Toxicity/Poisoning

Clinical
observations
including nausea,
irritation of the

eyes, sinus
discomfort, and
blood pressure

Five researchers,
1930s, sex and age
not reported

One to two hour
inhalation chamber

exposures at
approximately 500,
1000, 1500, and 2000
PPm

perchloroethylene

Subjects reported
feeling nauseous
and having eye
irritation after a

500 ppm
exposure and
faintness at higher
exposure levels

Carpenter
1937

Low

Acute
Toxicity/Poisoning

Clinical
observations
including nausea,
dizziness, eye
irritation, and
sleepiness

Subject information
not reported

Controlled inhalation
chamber exposure to
approximately 100,
200, 280, 600, and

1000 ppm
perchloroethylene for
an unreported duration

Mild eye irritation,
sinus discomfort,
and light
headedness
reported at lower
concentrations,
more severe
symptoms at

higher
concentrations

Rowe et al.
1952

Low

13


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

Target Organ/ System

Outcome/
Endpoint

Study Population

Exposure

Results

Reference

Data
Quality
Evaluation

Acute
Toxicity/Poisoning

Clinical
observations
including eye
irritation, light
headedness, and
respiratory rate

21 year old male
employee

Accidental
occupational exposure
with estimated mean

perchloroethylene
concentration of 393
ppm

Subject was
initially
unconscious, later
reported eye
irritation, light
headedness, and
faintness

Stewart et al.
1961

Medium

Acute
Toxicity/Poisoning

Clinical
observations
including eye
irritation,
headache,
nausea and
dizziness

Sixteen healthy male
technical employees
ranging in age from
24 to 64 years; five

subjects were
selected for repeated
exposure

7-hour inhalation
chamber exposure to
approximately 100
ppm

perchloroethylene for
1-5 days

Subjects reported
low-grade chronic
sinusitis, a mild
frontal headache,
and mild eye and
throat irritation

Stewart et al.
1970

Medium

Acute
Toxicity/Poisoning

Headache,
nausea,
dizziness, chest
pain, abdominal
pain, irritation of
eyes nose or
throat

12 subjects,
Wisconsin, 1975, 19-
42 years of age

Perchloroethylene,
controlled exposure of
0, 25, 100 ppm for 5.5
hrs

No significant
associations
between
perchloroethylene
exposure and

clinical
observations

Stewart et al.
1977

Medium

14


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

Target Organ/ System

Outcome/
Endpoint

Study Population

Exposure

Results

Reference

Data
Quality
Evaluation

Cancer

Cancer
diagnosis: liver,
kidney, bladder,
pancreas, lung,
cervix, ovary,

Hodgkin's
disease, non-

Hodgkin's
lymphoma, and
multiple myeloma

Adults working in the
Netherlands during
the 1970 census,
including 23,714
women and 5,619
men working as
launderers and dry
cleaners

Occupation in dry
cleaning or laundering
industry served as
surrogate for Perc
exposure

Significant
increase in
incidence of lung,
cervical, and
ovarian cancer
diagnosis and
Hodgkin's disease
(women only), all
other outcomes
were non-
significant

Anderson et
al. 1999

Medium

Cancer

Renal cell
carcinoma
diagnosis

Renal cell carcinoma
cases (n= 315) and
population controls
(n=313), Oklahoma
City, occupational
history through
-1988

Primary occupation in
dry cleaning industry
served as surrogate
for Perc exposure

Non significant
association
between dry
cleaning
occupation and
renal cell
carcinoma in
males (negative)
and females
(positive)

Asal et al.
1988

Medium

15


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

Target Organ/ System

Outcome/
Endpoint

Study Population

Exposure

Results

Reference

Data
Quality
Evaluation

Cancer

Leukemia
incidence

Adults, permanent

residents of five
Upper Cape towns,
Massachusetts, in
1983-1986 (35
leukemia cases, 464

living + 723
deceased controls)

Modeled household

exposure to
perchloroethylene
through the public
water distribution
system; estimated
dose ranged 0.01-
209.4 mg (for no
latency) or 0.01-90.6
mg (for 5-year latency)

A statistically
significant
increase in odds
of leukemia was

observed for
"high" exposure
group vs. non-
exposed to
perchloroethylene,
after 0-year and 5-
year latency
periods (non-
statistically
significant
increase for ever
exposed vs. non-
exposed)

Aschengrau
et al. 1993

Medium

Cancer

Kidney cancer,

liver cancer,
bladder cancer,
Non-Hodgkin's
lymphoma,
Hodgkin's
lymphoma, all
cause cancer
mortality, lung
cancer, cervical
cancer,
esophageal
cancer mortality

5,369 dry cleaners
members of a dry
cleaning union in St.
Louis, men and
women, follow-up
1948-1993

Dry cleaner
occupation,
perchloroethylene the
dominant solvent

Non-significant
increase in
Hodgkin's
lymphoma
mortality for the
entire follow-up
period, and for the
two shorter follow-
up periods

Blair et al.
2003

Medium

16


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

Target Organ/ System

Outcome/
Endpoint

Study Population

Exposure

Results

Reference

Data
Quality
Evaluation

Cancer

Cause-specific
mortality: kidney
cancer, Hodgkin

lymphoma,
Leukemias, ALS

Camp Lejeune, North
Carolina cohort;
n=154,932
median age, start of

follow-up: 20
median age, end of

follow-up: 49
Camp Pendleton,
California cohort
n=154,969
median age, start of

follow-up: 20
median age, end of

follow-up: 49
exposure period:

1975-1985;
mortality follow-up
period: 1979-2008

Chemical name:
Perchloroethylene
(PCE); exposure
matrix: estimated
monthly average PCE

concentration in
Tarawa Terrace water
system (1975-1985)
Mean: 75.7 ug/L,
Median: 84.9 ug/L,
Range: 0-158.1 ug/L;
estimated monthly
average PCE
concentration in
Hadnot Point water
system (1975-1985)
Mean: 15.7 ug/L,
Median: 15.4 ug/L,
Range: 0-38.7 ug/L);
Duration: On average

an individual in the
Camp Lejeune cohort
resided at the base for
18 months.

Positive, non-
significant
associations
observed between

cumulative
exposure to PCE
and mortality due
to kidney cancer.

Bove et al.
2014

High

17


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

Target Organ/ System

Outcome/
Endpoint

Study Population

Exposure

Results

Reference

Data
Quality
Evaluation

Cancer

Excess risk of
renal cell
carcinoma (RCC)

Hospital-based case

control study of
patients diagnosed

with renal cell
carcinoma (RCC) in
Arnsberg, Germany
between 1992 and
2000 (134 cases, 401
gender- and age-
matched controls).

TCE and Perc
exposure probability
and duration were
based on self-
assessment.
Analyses of industries
with exposure to TCE
were based on an
IARC database
(CAREX). A job
exposure matrix (JEM)
was used to assess

exposure to
degreasing agents
(also other agents).

The ORs for RCC

risk were
increased for self-
assessed overall
exposure to TCE.
RCC ORs were
not significantly
elevated based
self assessed
overall exposure
to Perc.

Bruning et al.
2003

High

Cancer

Diffuse large B-
cell lymphoma

Georgia population
(2000 census)

Geocoded toxic
release sites data for
Perc from 1988-1998
EPA's TRI

Significantly
decreased risk for
diffuse large B-cell
lymphoma with
increasing mean
distance (per 1
mile) to Perc TRI
sites.

Bulka et al.
2016

Medium

18


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

Target Organ/ System

Outcome/
Endpoint

Study Population

Exposure

Results

Reference

Data
Quality
Evaluation

Cancer

Mortality from
lymphatic and
haematopoietic
cancer

1704 dry cleaning
workers in four US

cities (San
Francisco/Oakland,
Chicago, Detroit, and
New York)

Employment in a shop
using Perc, mean (sd)
years of employment
for exposed workers
6.2 (5.0)

Significant
elevated SMRs
were observed for
all cancers,
esophageal
cancer, and

trachea,
bronchus, and
lung cancer.
SMRs were
significantly lower
for liver cancer.
No significant
association was
found for kidney
cancer, lymphatic
and

haematopoietic

cancer, and
bladder cancer.

Calvert et al.
2010

Medium

19


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

Target Organ/ System

Outcome/
Endpoint

Study Population

Exposure

Results

Reference

Data
Quality
Evaluation

Cancer

Diagnosis of
cancer in oral

cavity,
oropharynx,
hypopharynx, oral
cavity, and larynx
(detailed list of
codes in text)

Case-control, women
only, 296 cases, 775
controls, diagnosed
2001-2007, general
population, 18-85
years, subset of
I CARE cohort

Perc, exposure
qualitatively stated,

modeled as
cumulative exposure
index (CEI)

Statistically
significant positive

association
between Perc and
head/neck
cancers in
ever/never
analysis; null
association in
continuous
cumulative
exposure
assessment

Carton et al.
2017

Medium

Cancer

Cancers of the
bladder, prostate,
colon, stomach,
rectum, kidney,

pancreas,
esophagus, and
liver, as well as
melanoma and
non-Hodgkin's
lymphoma.

3730 male, Canadian
patients aged 35 to
70 years diagnosed
1979-1985 in 18
largest Montreal
hospitals; 533
controls from
electoral lists in
Quebec. A second
control group
consisted of the
population controls
together with patients
with cancers at sites
distal to the primary
cancer being
assessed..

PERC exposure
determined from self-
reported job history
categorized by
chemists and
industrial hygienists
based on degree of
confidence, frequency,
and relative levels (not
quantitative)

Significant
increase in the OR

for prostate
cancer associated
with Perc
exposure
(substantial), non-
significant OR for
all other cancers

Christensen
et al. 2013

Medium

20


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

Target Organ/ System

Outcome/
Endpoint

Study Population

Exposure

Results

Reference

Data
Quality
Evaluation

Cancer

Renal cell
carcinoma

718 cases (men) of
renal cell carcinoma
from the New
Zeeland Cancer
Registry and 12,758
male controls, 1978-
1986

Occupational (dry-
cleaning and laundry
workers exposed to
perchloroethylene)

Non-significant
elevation in risk of
kidney cancer
among dry-
cleaning workers

Delahunt et
al. 1995

Medium

Cancer

Renal cell
carcinoma

White newly
diagnosed cases with
age- and gender-
stratified random
sample white controls

JEM (developed by
NCI)

No significant
association
between Perc and
RCC for the total
population nor
when separated
by sex.

Dosemeci et
al. 1999

Medium

Cancer

Breast cancer
incidence

920 incident breast
cancer cases, 1293
controls, Cape Cod,
Massachusetts,
1983-1993,

Water distribution
modeled exposure to
Perc-lined public water
distribution pipelines

Perc was not
significantly
associated with
breast cancer, but

there was a
modest increase
in risk in women
with high perc
exposure

Gallagher
2011

Medium

21


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

Target Organ/ System

Outcome/
Endpoint

Study Population

Exposure

Results

Reference

Data
Quality
Evaluation

Cancer

Bladder cancer

113,343 cases and
566,715 matched
controls from the
Nordic Occupational
Cancer (NOCCA)
project (through
2005)

Perc exposure
estimated via linkage
between occupational

codes and Nordic
Occupational Cancer
(NOCCA) project job
exposure matrix (JEM)

No significant
trend in risk with
increasing Perc
exposure,
significant
increase in hazard
ratio was only
observed in the
mid exposure
group

Hadkhale et
al. 2017

Medium

Cancer

Neuroblastoma

Children (75 cases,
14602 controls), ages
<6 born in 1990-2007
in California within 5

km of exposure
monitoring stations,
cases from California
Cancer Registry

Perc (0.186 ppbV) in
ambient air, pollution
monitoring stations
used to estimate
maternal exposure
during pregnancy from
birth certificate
address

Non-significant
positive
association
between Perc and
neuroblastomas
per interquartile

increase in
exposure at 5km
radius

Heck et al.
2013

Medium

Cancer

Astrocytic brain
cancer risk

Men in southern
Louisiana, United
States, exposed from

1978- 1980; in
northern New Jersey

and Philadelphia,
Pennsylvania, United
States, exposed from
1979- 1981 (n=620,
300 cases, 320
controls)

Perchloroethylene, low
exposure (1)

Chi trend= -0.65.
Exposure not
significantly
associate with
astrocytic brain
cancer

Heineman et
al. 1994

Medium

22


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

Target Organ/ System

Outcome/
Endpoint

Study Population

Exposure

Results

Reference

Data
Quality
Evaluation

Cancer

Kidney cancer

(total,
parenchymal
cancer, pelvical
cancer,
unspecified
cancer) , lung
cancer

1,644,958
economically active
men in the census of
year

1960 and 1,154,091
economically active
women in the census
of year 1970. from
the Swedish family
Center Database

Occupation as
launderers and dry
cleaners (with perc
mentioned as solvent
used in dry cleaning)

Non-significant
elevations in
excess risk of total
kidney cancer and
renal parenchymal
cancer in men;
Significant
elevations of
pelvical or renal

unspecified
cancers in men.

Ji et al. 2005

Medium

Cancer

Cancer mortality

Lockheed Martin
aircraft manufacturing
factory workers in
Burbank, California
(employed after
January 1, 1960;
followed up through
December 31, 2008)

Years of exposure to

Perc based on job
histories and industrial
hygiene surveys

No significant
trend for any
specific cancer or
total cancer by
increasing years
of exposure.

Lipworth et
al. 2011

High

Cancer

Total cancer
incidence, liver,

pancreas;
bladder kidney,
lymphomas

Men and women
(n=378 cancer
cases), aged 20-64,
working on laundry
and dry-cleaning
shops in Denmark in
1970

Exposure during
laundry or dry cleaning
to percholroethylene

Significant
increase in
pancreas cancer
incidence in men
and women
combined

Lynge and
Thygesen
1990

Low

23


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

Target Organ/ System

Outcome/
Endpoint

Study Population

Exposure

Results

Reference

Data
Quality
Evaluation

Cancer

Incident cancers
of the esophagus,
gastric cardia,
pancreas, cervix
uteri, bladder,
and kidney,
primary liver
cancer, non-
Hodgkin
lymphoma

Laundry and dry

cleaning
workers identified
from the 1970
censuses in
Denmark, Norway,
Sweden, and Finland
(1,616 case, 2,398
controls)

Occupation (laundry
and dry cleaning);
mean
perchloroethylene for
dry cleaners 160
mg/m3

Non-significant
increased risk of
kidney cancer
incidence among
assistants in dry
cleaning shops;
Non-significant
decrease in risk of
kidney cancer for
dry cleaners. No
elevations in risk
of kidney cancer
were observed
with length of
employment.

Lynge et al.
2006

Medium

24


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

Target Organ/ System

Outcome/
Endpoint

Study Population

Exposure

Results

Reference

Data
Quality
Evaluation

Cancer

Kidney/renal
cancer, all cancer
discharges (with
and without skin
cancer) ICD9
189.0 and
189.1

All residents of New
York City from 1993
to 2004, at least 45
years old, who were

admitted as
inpatients to a state
regulated hospital

(N=10,916
kidney/renal cancer
discharges)

Dry cleaning facilities

using
perchloroethylene in

New York City (5
exposure levels based
on the distribution of
density of Perc dry
cleaners per squared

kilometer): 0-0.47;
0.47- 1.90, 1.90- 1.50;
1.50-2.70; 2.70-16.43

Significant
association
between the
density of
perchloroethylene
dry cleaning
establishments
and the rate of

hospital
discharges that
include a
diagnosis of
kidney cancer
among
persons 45 years
of age and older
living in New York
City

Ma et al.
2009

Medium

Cancer

Renal cell
carcinoma
diagnosis

Renal cell carcinoma
cases (n= 1732) and
population controls
(n=2309), complete
occupational history
collected 1989-1991,
Australia, Denmark,
Germany, Sweden,
USA

Renal cell carcinoma
diagnosis

Significantly
increased risk for

renal cell
carcinoma with
exposure to dry
cleaning solvents

Mandel et al.
1995

High

25


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

Target Organ/ System

Outcome/
Endpoint

Study Population

Exposure

Results

Reference

Data
Quality
Evaluation

Cancer

Lung cancer

Investigation of
occupational
exposure and
environmental
causes of respiratory
cancers (ICARE)
study subjects,
population-based
case-control study in
France 2001-2007
(2274 men cases and
2780 men controls)

Cumulative Exposure
Index (CEI) based on
self-reported job
histories and
probability, intensity,
and frequency of
exposure to Perc
based on jobs

Perc was not
significantly
associated with
lung cancer in
men.

Mattei et al.
2014

Medium

Cancer

Kidney cancer
(renal cell
carcinoma), renal
pelvic carcinoma

489 cases of kidney
cancer, 147 cases of
pelvic cancer and
523 controls in New
South Wales

Occupation in dry
cleaning industry

Significantly
elevated risk of
renal pelvic
carcinoma
associated with
working in the dry
cleaning industry
compared to
population
controls

McCredie
and Stewart
1993

Medium

Cancer

Kidney cancer
(renal cell
carcinoma)

368 cases and 396
controls in Denmark,
interviewed between
1989-1992

Occupational
exposure in dry
cleaning industry

Non-significant
elevations in risk

of renal cell
carcinoma in men
and in women
employed in the
dry cleaning
industry 10 or
more years before
the interview

Mellemgaard
et al 1994

Medium

26


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

Target Organ/ System

Outcome/
Endpoint

Study Population

Exposure

Results

Reference

Data
Quality
Evaluation

Cancer

All Non-Hodgkin
lymphoma and by
non-Hodgkin
lymphoma
subtype (i.e,.

small
lymphocytic,
follicular, diffuse,
other),

All newly diagnosed
cases of
non-Hodkin
lymphomas, chronic
lymphocytic leukemia
(CLL) during 1991-

1993 among men
and women age 20 to
74 years in 11 areas
in Italy

Perc exposure based

on job-specific
questionnaires and
industrial hygiene
experts for level of
probability (i.e,. low,
medium, high) and
intensity of exposure
(i.e., very low, low,
medium, and high)
with durations of less
than 15 years and 15
or more years.

Perc was not
significantly
associated with

non-Hodgkin
lymphoma either
by intensity or
duration of
exposure.

Miligi et al.
2006

High

Cancer

Mycosis
fungoides (MF)

100 patients with
Mycosis Fungoides
and 2846 controls,
35-69 years of age,
from Denmark,
Sweden, France,
Germany, Italy, and
Spain, 1995-1997

Occupational
exposure to Perc
assessed with job
exposure matrix

A positive, non-
significant
association was
observed between
Mycosis
Fungoides and
male subjects with
exposure to Perc

>= median of
control exposure
vs. unexposed
male subjects

Morales-
Suarez-
Varela et al.
2013

High

27


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

Target Organ/ System

Outcome/
Endpoint

Study Population

Exposure

Results

Reference

Data
Quality
Evaluation

Cancer

Brain cancer:
glioma and
meningioma
cases

489 glioma cases,
197 meningioma
cases, and 799
controls from three
USA hospitals in
Arizona,
Massachusetts and
Pennsylvania

Occupational
exposure to Perc via

self-reported
occupational history

and industrial
hygienist assigned
level of exposure

Perc was not
significantly
associated with
glioma or
meningioma

Neta et al.
2012

High

Cancer

Mortality from all
cancer (SMR)

1690 workers
employed in facilities

that used perc as
their primary solvent
in Oakland, Detroit,
Chicago, or New
York City, workers
employed at least
one year prior to
1960

Years of employment
in a perc facility

A positive trend of
increasing risk of
all cancer
mortality was
observed with an
increase in both
years of exposure
and latency (time

since first
employment in a
perc facility)

NIOSH 1985

High

Cancer

Excess risk of
renal cell
carcinoma (RCC)

Multi-center
population level case-
control study of 935
patients diagnosed
with RCC between
1991 and 1995 and
4298 controls
matched by
geographical region,
sex and age (-1:4
ratio of cases to
controls).

Exposure was
categorized as
medium, high or
substantial based on a
job exposure matrix

(JEM or a job-
exposure-task matrix
(JETM).

Odds ratios
showed low to no

significant
increased risk of
renal cell
carcinoma for
Perc exposure, no
dose response
trends.

Pesch et al.
2000

Medium

28


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

Target Organ/ System

Outcome/
Endpoint

Study Population

Exposure

Results

Reference

Data
Quality
Evaluation

Cancer

Cancer of the
liver

15 million people
participating in a
decennial census in
Denmark, Finland,
Iceland, Norway, and
Sweden. Aged 30-64
in years 1960-1990.

Employment in dry
cleaning and/or
laundering during time
period of predominant
Perc use

Significantly
elevated SIRs
were observed in
women for
stomach, liver,
cervical, oral
cavity, and lung

cancers. No
association was
found for kidney,
bladder, and non-

Hodgkin's
lymphoma cancer
incidence in
women.

Pukkala et
al. 2009

Medium

Cancer

Diagnosis of
kidney cancer

General population
case-control study of
kidney cancer (1217
cases; 1235
controls). Detroit
(2002 - 2007) and
Chicago (2003).

Job exposure matrix
was used to determine
years exposed,
average weekly
exposure and
cumulative hours
exposed, to perc

Increased risk of
kidney cancer for

high intensity
exposure group;
OR 3.0(1.3-7.4)

for 3rd fertile
(>1820 hours) vs.

unexposed for
cumulative hours
exposed. No
significant
associations
observed in for
other levels of
perc exposure.

Purdue et al.
2016

High

29


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

Target Organ/ System

Outcome/
Endpoint

Study Population

Exposure

Results

Reference

Data
Quality
Evaluation

Cancer

Mortality from
multiple myeloma

Aircraft maintenance
workers (n = 14,457;

10,730 men and
3725 women) at Hill
Air Force Base (Utah,
USA), for at least one
year from 1952-1956,
and followed up
through 2000

Occupational
exposure to Perc
(yes/no) based on job-
exposure matrix; no

quantitative
assessment available

Positive
association
between mortality
from multiple
myeloma and
occupational
exposure to Perc
compared to no
exposure
(statistically
significant for
females, non-
statistically
significant for
males)

Radican et
al. 2008

Medium

Cancer

Childhood
cancers, neural
tube defects, oral
clefts,

Children born to
mothers with
exposure to
contaminated
drinking water at
Camp Lejeune : 51
cases and 526
controls

Perchloroethylene
(perc) in drinking
water during 1st
trimester of
pregnancy; modelled
exposure high (>=44
ppb), low (<44 ppb)

Positive, non-
significant
associations
observed
between
childhood cancers
and any, high or
low 1st trimester
exposure to perc
compared to
unexposed).

Ruckart et al.
2013

High

30


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

Target Organ/ System

Outcome/
Endpoint

Study Population

Exposure

Results

Reference

Data
Quality
Evaluation

Cancer

Age of diagnosis
of breast cancer
(male only).

Case-control, male
Marines born before
1969, diagnosed
1995-2013, with
identifiable tour
dates/locations

Perc, residential
drinking water at
Camp Lejeune ,
cumulative exposure
>159 ppb

Non-significant
positive
association
between Perc
exposure and
breast cancer
diagnosis and age
of diagnosis

Ruckart et al.
2015

High

Cancer

Glioma

Non-farm workers
from the Upper
Midwest Health Study
(798 cases and 1141
controls from lawa,
Michigan, Minnesota,
and Wisconsin 1995-
1997)

Perc

(perchloroethylene)
use (self-reported
occupational history
through 1992,
bibliographic database
of published exposure)

Perc was
associated with a
significant
decrease in
gliomas.

Ruder et al.
2013

High

Cancer

Total lymphoma,
HL, B-NHL, T-
NHL, B-NHL
subentities
(DLBCL, FL, CLL,
multiple
myeloma,
marginal zone
lymphoma)

710 participating
cases (matched to
710 controls) with
malignant lymphoma

among men and
women aged 18 to 80
years in 6 regions in
Germany

Cumulative
occupational exposure

to Perc [ppm*years]
based on intensity, the
frequency, and
duration of Perc
exposure (0 to >78.8
ppm*years)

Perc was not
significantly
associated with

malignant
lymphoma or any
specific type of

lymphoma;
however, there
was an increase
(non-significant) in

risk of total
lymphoma in the
highest exposure
group (>78.8
ppm*years).

Seidler et al.
2007

High

31


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

Target Organ/ System

Outcome/
Endpoint

Study Population

Exposure

Results

Reference

Data
Quality
Evaluation

Cancer

Kidney, bladder,
liver, NHL, overall
cancer incidence

Swedish national
cohort of dry-cleaning

and laundry
workers (n = 10,389)
assembled in 1984
followed up for new
cases of cancer by
matching with the
Swedish cancer
register from 1985 to
2006

Occupation as dry
cleaners ans laundry
workers exposed to
perchloroethylene;
exposure levels in the
1970s were of the
order of 100-200
mg/m3 (15-30 ppm)

Non-significant
elevated risk of
Hodgkin's
lymphoma, kidney
and liver cancer,

significantly
elevated risk of
Non-Hodgkin's
lymphoma and
lung cancer; no
elevated risk of
bladder cancer

Selden and
Ahlborg
2011

Medium

Cancer

Kidney cancer
incidence

Greater Montreal
metropolitan area.

Case-control study of

occupationally-
exposed men aged
35 to 70 year old
(4263 cases, 533
population controls;
also hospital and
cancer controls).

Any or substantial
exposure

ORs were not
significantly
elevated for PCE

exposure and
kidney cancer (no
quantitative data
were provided).

Siemiatycki
1991

Medium

Cancer

Bladder and other
urinary cancer
mortality

National Institute for
Occupational Safety
and Health (NIOSH)
Cohort, 34494
workers at NY
microelectronics and
business machine
facility, 2009, 52-
65yrs

Cumulative Perc
exposure score based
on department-
exposure matrix

Perc was not
significantly
associated with
bladder and other
urinary cancers
mortality.

Silver et al.
2014

Medium

32


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

Target Organ/ System

Outcome/
Endpoint

Study Population

Exposure

Results

Reference

Data
Quality
Evaluation

Cancer

Testicular cancer

National Institute for
Occupational Safety
and Health (NIOSH)
Cohort, 34494
workers at NY
microelectronics and
business machine
facility, 2009, 52-
65yrs

Cumulative Perc
exposure score based
on department-
exposure matrix

Perc was not
significantly
associated with
testicular cancer
incidence.

Silver et al.
2014

Medium

Cancer

Acute myeloid
lymphoma

Cases of acute
myeloid leukemia

(n=14,337)
diagnosed between
1961 and 2005, and
controls (n=71,027)
matched by age, sex,
and country identified

from the Nordic
Occupational Cancer
Study cohort

Cumulative Perc
exposure estimated
using job exposure
matrix, Median (ppm-
yr) 12.1

No significant
increase in acute
myeloid leukemia
risk was observed

with low,
moderate, or high
exposure to Perc,
compared to
referent group
when hazard
ratios were
calculated using a
10-year lag (p-
value = 0.39).
Findings for
analysis stratified

by sex or age
were not reported

Talibov et al.
2014

High

33


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

Target Organ/ System

Outcome/
Endpoint

Study Population

Exposure

Results

Reference

Data
Quality
Evaluation

Cancer

Cancer
diagnosis:
liver/biliary,
kidney, bladder,
pancreas, lung,
cervix, Hodgkin's
lymphoma, and
non-Hodgkin's
lymphoma

Adults working in the
Sweden during the

1960 and 1970
census, including
31,418 women and
15,515 men working
as launderers, dry
cleaners, or pressers

Occupation as a dry
cleaner, launderer, or
presser served as
surrogate for Perc
exposure

Increased
incidence of
Hodgkin's disease
(significant), lung
(significant), cervix
(significant),
liver/biliary
passages, kidney,

and bladder
cancer, all other
outcomes were
non-significant

Travier et al
2002

High

Cancer

Lung cancer

Lung cancer cases

and randomly
selected population-

based controls
frequency matched
by sex and age in
Montreal Canada

Perc exposure (any or

substantial) was
assessed by a team of

industrial chemists
and hygienists based
on self-reported job
histories

Increase in OR for
any exposure or

substantial
exposure to Perc,
results were only
significant for any
exposure in Study
I and in the pooled
analysis

Vizcaya et
al. 2013

Medium

Cancer

Liver and kidney
cancer, non-
Hodgkin's
lymphoma (NHL)

and multiple
myeloma (MM)

All subjects aged 30-
64 years
who participated in
1960 through 1990
censuses in Finland,
Iceland, Norway and

Sweden ; five
matched control sper
case

Job-exposure matrix,
intensity x prevalence
of perchloroethylene

exposure (90th
percentile:: 0.05 units)

A positive, non-
significant
association was
observed between
high cumulative
perchloroethylene
exposure
(intensity x
prevalence) and
kidney cancer in
men and women.

Vlaanderen
et al. 2013

High

34


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

Target Organ/ System

Outcome/
Endpoint

Study Population

Exposure

Results

Reference

Data
Quality
Evaluation

Cancer

Renal pelvis
cancer, bladder
cancer

Employed Swedish
residents (1,014 and

360 renal
pelvis cancers and
18,244 and 3,347
bladder cancers

among
men and women,
respectively)

Occupation type
(workers in laundry,
ironing , dyeing) or
industry

Non-significant
excess risk of
renal pelvis
cancer among
men working in
laundry, ironing ,
dyeing industry.

Wilson et al.
2008

Medium

Cardiovascular

Major cardiac
birth defects

1,090 live births in
the TCE study area
and 3.6 million births
in the comparison
group (NY State
without NYC) (1978-
2002).

Maternal exposure to

Perc through soil
vapor intrusion (4.1-
9.5 ug/m3 indoor air
sampling) associated
with a 1979 spill from

a semiconductor
manufacturing facility
in Endicott, New York

Adjusted rate
ratios for low birth
weight (LBW),

small for
gestational age
(SGA), term LBW,
cardiac defects
and conotruncal
defects were
significantly
elevated in the
Perc study area.

Forand et al.
2012

Medium

Cardiovascular

Blood pressure
and heart rate

21 year old male
employee

Accidental
occupational exposure
with estimated mean

perchloroethylene
concentration of 393
ppm

No effects
observed for
Cardiovascular
outcomes.

Stewart et al.
1961

Medium

35


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

Target Organ/ System

Outcome/
Endpoint

Study Population

Exposure

Results

Reference

Data
Quality
Evaluation

Clinical
Chemistry/Biochemical

Urinalysis

Five researchers,
1930s, sex and age
not reported

One to two hour
inhalation chamber

exposures at
approximately 500,
1000, 1500, and 2000
PPm

perchloroethylene

No effects
observed for
Clinical
Chemistry/Bioche
mical outcomes.

Carpenter
1937

Low

Clinical
Chemistry/Biochemical

Clinical chemistry
panel and
urinalysis

21 year old male
employee

Accidental
occupational exposure
with estimated mean

perchloroethylene
concentration of 393
ppm

Minor, transient
elevations of
alkaline
phosphatase and
SGP-T

Stewart et al.
1961

Medium

Clinical
Chemistry/Biochemical

Clinical chemistry
panel and
urinalysis

Sixteen healthy male
technical employees
ranging in age from
24 to 64 years; five

subjects were
selected for repeated
exposure

7-hour inhalation
chamber exposure to
approximately 100
ppm

perchloroethylene for
1-5 days

No effects
observed for
Clinical
Chemistry/Bioche
mical outcomes.

Stewart et al.
1970

Medium

Clinical Symptoms

Ears, nose,
throat,
ophthalmological,
cutaneous,
respiratory,
digestive signs,
neurological
symptoms,
Epworth test>8,
pre-narcotic
syndrome

50 exposed workers
from 22 dry-cleaning

establishments in
France , 95 matched
unexposed controls

Ambient
perchloroethylene
levels , blood perc
levels; years of
employment; median
value of atmospheric

perc was 7 ppm
(0.22-33), the median
blood level of perc
was 73.6 |jg/l (118—
144).

Perchloroethylene
exposure was not
associated with
significant
increase in clinical
symptoms among
dry-cleaning
employees
compared to
unexposed
controls.

Lucas et al.
2015

Medium

36


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

Target Organ/ System

Outcome/
Endpoint

Study Population

Exposure

Results

Reference

Data
Quality
Evaluation

Growth (early life) and
Development

Childhood
cancers, neural
tube defects, oral
clefts,

Children born during

1968-1985 to
mothers exposed to
contaminated
drinking water at
Camp Lejeune during
pregnancy: 51 cases
and 651 controls

Perchloroethylene
(perc) in drinking
water during 1st
trimester of
pregnancy; modelled
exposure above MCL
(>=5 ppb), below MCL
(< 5 ppb)

Positive non-
significant
association
observed
between neural
tube defects and
exposure to perc
<= 5 ppb
compared to
unexposed.
Negative, non-
significant
association
observed
between neural
tube defects and
any exposure to
perc, or exposure
> 5 ppb compared
to unexposed.

Ruckart et al.
2013

High

Hematological and
Immune

Primary Sjogren
syndrome

Cases (n= 175)
followed up in
departments of
Internal Medicine of
three University
Hospitals and
matched controls
(n=350) (2010-2013)

Occupational Perc
exposure based on
self-reported
occupational histories,
expert judgement of
industrial hygienists
and occupational
practitioners, as well
as the French JEM
(used more for the
chlorinated solvents)

Significant
increase in risk for
Sjogren'
syndrome with
occupational Perc

exposure;
increase OR with
high final
cumulative
exposure, but was
not significant

Chaigne et al
2015

Medium

37


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

Target Organ/ System

Outcome/
Endpoint

Study Population

Exposure

Results

Reference

Data
Quality
Evaluation

Hematological and
Immune

Systemic
Sclerosis

Meta-analysis of 14
case-control studies
(6 with TCE and/or

PCE exposure
analysis). The perc
studies included 714

cases and 2479
controls. The TCE
studies included 1029
cases and 2884
controls.

Proportion of subjects
exposed to solvents
occupational^

A positive, non-
significant
association was
observed between
risk of SSc and
perc exposure

Zhao et al.
2016

Medium

Mortality

Mortality from all
causes

5,369 dry cleaners
members of a dry
cleaning union in St.
Louis, men and
women, follow-up
1948-1993

Dry cleaner
occupation,
perchloroethylene the
dominant solvent

Significant
elevations in all-
cause cancer
mortality for the
entire follow-up
period, and for the
first and second
follow-up periods;
and for men and
women, and for
blacks and whites

Blair et al.
2003

Medium















38


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

Neurological/Behavior

Risky behavior
endpoints
measured/analyz

ed: smoking
usage as a teen,
smoking usage

as an adult,
alcohol usage as
a teen, alcohol
usage as an
adult, drug usage
as a teen, drug
usage as an
adult, multiple
risky behaviors

as a teen,
multiple risky
behaviors as an
adult, selected
risky behaviors
as a teen among
subjects without
prenatal
exposure to

smoking,
selected risky
behaviors
(smoking,
alcohol, drug
usage) as an
adult among
subjects without
prenatal
exposure to
smoking

585 exposed and 562
unexposed born
1969-1983 in Cape
Cod, MA and 365
older siblings

EPA's water
distribution system
modeling software
modeled cumulative
prenatal and childhood
Perc exposure

Among subjects in
the >=67th
exposure
percentile group,
a higher risk of
multiple risky
behaviors as a
teen (significant)

or adult (not
significant) was

observed in
comparison to
unexposed
subjects

Medium

39


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

Neurological/Behavior

Drinking
frequently as a
teenager

1378 men and
women in Cape Cod,

MA, 1969-1983,
Mean age 29 years

Perchloroethylene,
Cumulative exposure
levels in drinking water
prenatally and during

childhood 9age 5
years). Mean 142 g,
median 34g, range
11mg - 4668g.

A positive,
significant
association was

observed
between initiating
smoking at a
young age,
drinking frequently
as a teenager at a
young age, use of
more than 1 drug
as teenager, use
of more than 1
major drug as an

adult and
cumulative Perc
exposure in
drinking water
when comparing
highest fertile with

lowest fertile.
A positive, non-
significant
association was

observed
between heavy
smoking at a
young age,
drinking heavily in
the past 30 days
at a young age
and cumulative
Perc exposure in

drinking water
when comparing

Medium

40


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

Target Organ/ System

Outcome/
Endpoint

Study Population

Exposure

Results

Reference

Data
Quality
Evaluation









highest fertile with
lowest fertile.





Neurological/Behavior

Cause-specific
mortality: kidney
cancer, Hodgkin

lymphoma,
Leukemias, ALS

Camp Lejeune, North
Carolina cohort;
n=154,932
median age, start of

follow-up: 20
median age, end of

follow-up: 49
Camp Pendleton,
California cohort
n=154,969
median age, start of

follow-up: 20
median age, end of

follow-up: 49
exposure period:

1975-1985;
mortality follow-up
period: 1979-2008

Chemical name:
Perchloroethylene
(PCE); exposure
matrix: estimated
monthly average PCE

concentration in
Tarawa Terrace water
system (1975-1985)
Mean: 75.7 ug/L,
Median: 84.9 ug/L,
Range: 0-158.1 ug/L;
estimated monthly
average PCE
concentration in
Hadnot Point water
system (1975-1985)
Mean: 15.7 ug/L,
Median: 15.4 ug/L,
Range: 0-38.7 ug/L);
Duration: On average

an individual in the
Camp Lejeune cohort
resided at the base for
18 months.

Positive, non-
significant
associations
observed between

cumulative
exposure to PCE
and mortality due
to ALS

Bove et al.
2014

High

41


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

Target Organ/ System

Outcome/
Endpoint

Study Population

Exposure

Results

Reference

Data
Quality
Evaluation







Percholroethylene.
Cumulative lifetime
exposure levels based
on complete
work histories,
hobbies, and
industrial hygiene
evaluations of subjects
in participating shops:.
Categories: low (n=24,
average 3.4 years at
shop), moderate
(n=18,average 8.1
years at shop), and
high (n=23, average
20.2 years at shop).

Significant
decrease (6.7%)
was observed in





Neurological/Behavior

Pattern memory
(Number correct)

'Dry Cleaner Study
Population' (n=65).
men and women;
Detroit, USA

the adjusted mean
performance on

the pattern
memory (number
correct) between
the low and high
Perc exposure
categories.

Echeverria et
al. 1995

Medium

Neurological/Behavior

Parkinson's
Disease (PD)

99 male twin pairs
35-84 years of age
from US National

Academy of
Sciences/National
Research Council
World War II Veteran
Twins Registry, 1993-
1995

Self-reported
exposure to Perc

A positive, non-
significant
association was
observed between

Parkinson
Disease and ever
exposure to Perc

Goldman et
al. 2012

High

42


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

Target Organ/ System

Outcome/
Endpoint

Study Population

Exposure

Results

Reference

Data
Quality
Evaluation

Neurological/Behavior

Autism spectrum
disorders

3,137 children in
North Carolina (1,931
total, 201 cases) and
West Virginia (1,246
total, 173 cases),
2000-2004, 8 years
old

1996 modeled perc in
ambient air, geometric
mean concentration:
227.0 (NC) and 172.2
(WV) ng/mA3

A positive, non-
significant
association
between ambient
perc (80th vs.
20th percentile)

and autism
spectrum disorder

Kalkbrenner
et al. 2010

High

Neurological/Behavior

Autism Spectrum
Disorder

Nurses' Health Study
II children 3-18 years
(US; 325
cases/22101
controls).

Perc air
concentrations at
mother's location at
birth

Perc exposure
was significantly
associated with
Autism Spectrum
Disorder based on

a significant
increase in odds
ratio comparing
the highest to the
lowest
concentration
quintile.

Roberts et
al. 2013

High

Neurological/Behavior

Diseases of the
nervous system
mortality

National Institute for
Occupational Safety
and Health (NIOSH)
Cohort, 34494
workers at NY
microelectronics and
business machine
facility, 2009, 52-
65yrs

Cumulative Perc
exposure score based
on department-
exposure matrix

Perc exposure
was significantly
associated with
increased risk of
mortality from
diseases of the
nervous system.

Silver et al.
2014

Medium

43


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

Target Organ/ System

Outcome/
Endpoint

Study Population

Exposure

Results

Reference

Data
Quality
Evaluation

Neurological/Behavior

Neurological
examination
including the
Romberg test,
Crawford manual
dexterity tests,
and Flannagan
coordination,
arithmetic, and
inspection tests

Sixteen healthy male
technical employees
ranging in age from
24 to 64 years; five

subjects were
selected for repeated
exposure

7-hour inhalation
chamber exposure to
approximately 100
PPm

perchloroethylene for
1-5 days

Slightly impaired
performance on
the Romberg test,
no other effects
observed

Stewart et al.
1970

Medium



Michigan eye-

hand
coordination,
rotary pursuit,

Flanagan
coordination,
saccade eye
velocity, dual-
attention tasks,

Lorr-McNair
mood evaluation
test,

electroencephalo
gram











Neurological/Behavior

12 subjects,
Wisconsin, 1975, 19-
42 years of age

Perchloroethylene,
controlled exposure of
0, 25, 100 ppm for 5.5
hrs

Perchloroethylene
(100 ppm) had
statistically
significant
negative
correlation with

Flanagan
coordination in

Stewart et al.
1977

Medium







some sessions, no

other significant
effects were found





44


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

Target Organ/ System

Outcome/
Endpoint

Study Population

Exposure

Results

Reference

Data
Quality
Evaluation

Neurological/Behavior

Failure to meet

test-based
standards for
English language
arts in 3rd grade
standardized
tests.

Children (n=201,559
) born 1994-1998 in

New York City ,
enrolled in 3rd grade
public schools before
2008.

Perchloroethylene in
ambient air estimated
from

EPA's National Air
Toxics Assessment
(NATA) from 1996
(prenatal exposure).
High

perchloroethylene
category: median 1.13
mg/m3, range 0.84 -
9.2 mg/m3.

Low

perchloroethylene
category: median 0.63
mg/m3, range 0.28 -
0.84 mg/m3.

A positive, not
statistically
significant
association
(borderline) was
observed between
English language

arts test and
highest quartile of
Perc exposure
compared to
lowest 3 quartiles.

Stingone et
al. 2016

Medium

Neurological/Behavior

Autism spectrum
disorder
diagnosis with

Social
Communication
Questionnaire
score of 15+

217 cases, 224
interview controls,
4856 birth certificate

controls, children
born from 2005-2009
in 6 counties of
Pennsylvania

Perc exposure (94-
267 ng/m3) during
gestation estimated

with National Air
Toxics Assessment
2005 model from
addresses at birth

Perc showed non-
significant positive
association with
Autism Spectrum
Disorder diagnosis

relative to birth
certificate controls
across all quartiles
of exposure

Talbott et al
2015

Medium

45


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

Target Organ/ System

Outcome/
Endpoint

Study Population

Exposure

Results

Reference

Data
Quality
Evaluation

Neurological/Behavior

Autism diagnosis

Children (n=619
cases) born to
mothers living within
5 km of air pollutant
monitoring stations in
Los Angeles County
during pregnancy,
1995-2006,
monitored until age 6

Maternal ambient Perc
exposure during entire
pregnancy

A positive,
significant
association was
observed between
autistic disorder
by age 6 years
and maternal
ambient Perc
exposure

von
Ehrenstein et
al. 2014

High

Neurological/Behavior

Autism Spectrum
Disorder

Children born 1994
followed for 9 years,
284 cases and 657
birth month- and sex-

matched control
births from the San
Francisco area

1996 EPA estimated

annual average
concentrations of Perc
on the census tract
level, mean (SD)
exposure for cases:
0.61 (0.33 ug/m3)

Non significant
positive
association
observed for 3rd
and 4th quartile of
Perc exposure
compared to
those exposed to

the median
exposure level or
less.

Windham et
al. 2006

Medium

Renal

Chronic renal
disease (chronic
and unspecified
nephritis, renal
failure, and other
renal sclerosis)
mortality

National Institute for
Occupational Safety
and Health (NIOSH)
Cohort, 34494
workers at NY
microelectronics and
business machine
facility, 2009, 52-
65yrs

Cumulative Perc
exposure score based
on department-
exposure matrix

Perc was not
significantly
associated with
mortality from
chronic renal
diseases.

Silver et al.
2014

Medium

46


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

Target Organ/ System

Outcome/
Endpoint

Study Population

Exposure

Results

Reference

Data
Quality
Evaluation

Reproductive

Polycystic ovary

syndrome,
endometriosis,
infertility (i.e.,
trouble getting
pregnant), and
miscarriage

828 women, Cape
Cod, MA, 1969-1983,
24-38 years

Early life Perc
exposure with water
modeling software
(mean cumulative
exposure 121.7 g)

Perc was not
significantly
associated with
polycystic ovary

syndrome,
endometriosis,
trouble getting
pregnant, or
miscarriage.

Mahalingaia
h et al. 2016

High

Reproductive

Mean birth weight
difference (g)

11,896 singleton
births, Camp
Lejeune, North
Carolina

Perchloroethylene,
median (of exposed

average monthly
concentrations during
pregnancy) 35.8 ppb

Significant
negative
associations
between exposure
to perc and mean
birth weight
(quartiles
compared to
unexposed): Q2 -
28.5 g (-55.1, -
1.9); non-
significant
associations for
Q1 4.4 g (-17.4,
26.1), Q3 3.8 g (-
28.3, 36.0), and
Q4 8.2 g (-29.5,
46.0)

Ruckart et al.
2014

High

47


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

Target Organ/ System

Outcome/
Endpoint

Study Population

Exposure

Results

Reference

Data
Quality
Evaluation









Positive,













statistically
significant,
association









Aircraft maintenance



between mortality
from
nonmalignant
respiratory
disease in males
and occupational
exposure to Perc
compared to no

exposure
(negative, non-
statistically
significant
association for
females)





Respiratory

Mortality from
nonmalignant
respiratory
disease

workers (n = 14,457;

10,730 men and
3725 women) at Hill
Air Force Base (Utah,
USA), for at least one
year from 1952-1956,
and followed up
through 2000

Occupational
exposure to Perc
(yes/no) based on job-
exposure matrix; no

quantitative
assessment available

Radican et
al. 2008

Medium

48


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

Table 2.2 Summary of the Animal Toxicological Database for Perchloroethylene not considered for
dose-response

Target Organ/
System1

Study
Type

Species/
Strain/ Sex
(Number/
group)2

Exposure
Route

Doses/
Concentrations

3

Duration4

NOAEL/
LOAEL/
LC50 5i(mg/
m3 or mg/
kg-day)
(Sex)

Effect6

Reference7

Data
Quality
Evaluation

8

Body Weight

Short-term (1-
30 days)

Rat Sprague-
Dawley - [rat]
Female (8 )

Inhalation

0 , 686 , 2058 ,
6860 mg/ m3 (
0 , 100,300 ,
1000 ppm)

6 hours/ day 5
days/ week for 4

weeks (20
exposure days)

Not
Reported

Decreased
body weight

Boverhof et al
(2013)

High

Body Weight

Reproductive

Rat Other
Both (24/ sex/
group in F0
parents )

Inhalation

0 , 686 , 2058 ,
6860 mg/ m3 (
0 , 100,300 ,
1000 ppm)

6 hours/ day 5
days / week in
multi-generation
study (including
prior to mating
through 2nd
generation)

Not
Reported

No body
weight
decrease
greater than
10% from
control; liver

weights
increased at
1000 ppm in
F0 males and
F1 females
but no
histopathology
changes seen.

Hajogenated

Solvents
.)

Medium

Body Weight

Chronic (> 90
days)

Rat Osborne-
Mendel - [rat]

Male ( 50
(treated), 20
(untreated and
vehicle
controls))

Oral

0 , 471 , 941
mg/ kg-bw/ day

5 days/week
for 78 weeks

Not
Reported

decreased
survival,
decreased
body weight
gain, toxic
nephropathy,

hunched
appearance

National
Institute of

Heal-

Medium

Body Weight

Chronic (> 90
days)

Rat Osborne-
Mendel - [rat]
Female (50
(treated), 20
(untreated and
vehicle
controls))

Oral

0 , 474 , 949
mg/ kg-bw/ day

5 days/week
for 78 weeks

Not
Reported

decreased
survival,
decreased
body weight
gain, toxic
nephropathy,

National
Institute of

Heal-

Medium

49


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

Target Organ/
System1

Study
Type

Species/
Strain/ Sex
(Number/
group)2

Exposure
Route

Doses/
Concentrations

3

Duration4

NOAEL/
LOAEL/
LC50 5i(mg/
m3 or mg/
kg-day)
(Sex)

Effect6

Reference7

Data
Quality
Evaluation

8















hunched
appearance





Body Weight

Chronic (> 90
days)

Mouse
B6C3F1-
[mouse] Male
(50 (treated),
20 (untreated
and vehicle
controls))

Oral

0 , 536 , 1072
mg/ kg-bw/ day

5 days/week
for 78 weeks

Not
Reported

decreased
survival,
decreased
body weight
gain, hunched
appearance,
hepatocellular
carcinoma,

toxic
nephropathy

National
Institute of

Heal-

Medium

Body Weight

Chronic (> 90
days)

Mouse
B6C3F1-
[mouse]
Female (50
(treated), 20
(untreated and
vehicle
controls))

Oral

0 , 386 , 772
mg/ kg-bw/ day

5 days/week
for 78 weeks

Not
Reported

decreased
survival,
decreased
body weight
gain, hunched
appearance,
hepatocellular
carcinoma,

toxic
nephropathy

National
Institute of

Heal-

Medium

Cancer

Chronic (> 90
days)

Rat Osborne-
Mendel - [rat]

Male ( 50
(treated), 20
(untreated and
vehicle
controls))

Oral

0 , 471 , 941
mg/ kg-bw/ day

5 days/week
for 78 weeks

Not
Reported

No effects
were observed
on incidences
of neoplastic
or non-
neoplastic
lesions based
on necropsy
and

histopathology
examination
for these
organs/
systems.

National
Institute of
Hear

Medium

50


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

Target Organ/
System1

Study
Type

Species/
Strain/ Sex
(Number/
group)2

Exposure
Route

Doses/
Concentrations

3

Duration4

NOAEL/
LOAEL/
LC50 5i(mg/
m3 or mg/
kg-day)
(Sex)

Effect6

Reference7

Data
Quality
Evaluation

8

Cancer

Chronic (> 90
days)

Mouse
B6C3F1-
[mouse] Male
(50 (treated),
20 (untreated
and vehicle
controls))

Oral

0 , 536 , 1072
mg/ kg-bw/ day

5 days/week
for 78 weeks

Not
Reported

decreased
survival,
decreased
body weight
gain, hunched
appearance,
hepatocellular
carcinoma,

toxic
nephropathy

National
Institute of

Heal-

Medium

Cancer

Chronic (> 90
days)

Mouse
B6C3F1-
[mouse]
Female (50
(treated), 20
(untreated and
vehicle
controls))

Oral

0 , 386 , 772
mg/ kg-bw/ day

5 days/week
for 78 weeks

Not
Reported

decreased
survival,
decreased
body weight
gain, hunched
appearance,
hepatocellular
carcinoma,

toxic
nephropathy

National

MMituteof
Heal;

Medium

Cancer

Chronic (> 90
days)

Rat Osborne-
Mendel - [rat]
Female (50
(treated), 20
(untreated and
vehicle
controls))

Oral

0 , 474 , 949
mg/ kg-bw/ day

5 days/week
for 78 weeks

Not
Reported

No effects
were observed
on incidences
of neoplastic
or non-
neoplastic
lesions based
on necropsy
and

histopathology
examination
for these
organs/
systems.

National
Institute of

Heal-

Medium

Cardiovascul
ar

Chronic (> 90
days)

Rat Osborne-
Mendel - [rat]
Male ( 50

Oral

0 , 471 , 941
mg/ kg-bw/ day

5 days/week
for 78 weeks

Not
Reported

No effects
were observed
on incidences

National
Institute of
Hear

Medium

51


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

Target Organ/
System1

Study
Type

Species/
Strain/ Sex
(Number/
group)2

Exposure
Route

Doses/
Concentrations

3

Duration4

NOAEL/
LOAEL/
LC50 5i(mg/
m3 or mg/
kg-day)
(Sex)

Effect6

Reference7

Data
Quality
Evaluation

8





(treated), 20
(untreated and
vehicle
controls))









of neoplastic
or non-
neoplastic
lesions based
on necropsy
and

histopathology
examination
for these
organs/
systems.





Cardiovascul
ar

Chronic (> 90
days)

Rat Osborne-
Mendel - [rat]
Female (50
(treated), 20
(untreated and
vehicle
controls))

Oral

0 , 474 , 949
mg/ kg-bw/ day

5 days/week
for 78 weeks

Not
Reported

No effects
were observed
on incidences
of neoplastic
or non-
neoplastic
lesions based
on necropsy
and

histopathology
examination
for these
organs/
systems.

National
Institute of

Heal-

Medium

Cardiovascul
ar

Chronic (> 90
days)

Mouse
B6C3F1-
[mouse] Male
(50 (treated),
20 (untreated
and vehicle
controls))

Oral

0 , 536 , 1072
mg/ kg-bw/ day

5 days/week
for 78 weeks

Not
Reported

No effects
were observed
on incidences
of neoplastic
or non-
neoplastic
lesions based
on necropsy
and

histopathology
examination
for these

National
Institute of

Heal-

Medium

52


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

Target Organ/
System1

Study
Type

Species/
Strain/ Sex
(Number/
group)2

Exposure
Route

Doses/
Concentrations

3

Duration4

NOAEL/
LOAEL/
LC50 5i(mg/
m3 or mg/
kg-day)
(Sex)

Effect6

Reference7

Data
Quality
Evaluation

8















organs/
systems.





Cardiovascul
ar

Chronic (> 90
days)

Mouse
B6C3F1-
[mouse]
Female (50
(treated), 20
(untreated and
vehicle
controls))

Oral

0 , 386 , 772
mg/ kg-bw/ day

5 days/week
for 78 weeks

Not
Reported

No effects
were observed
on incidences
of neoplastic
or non-
neoplastic
lesions based
on necropsy
and

histopathology
examination
for these
organs/
systems.

National
Institute of

Heal-

Medium

Endocrine

Chronic (> 90
days)

Rat Osborne-
Mendel - [rat]

Male ( 50
(treated), 20
(untreated and
vehicle
controls))

Oral

0 , 471 , 941
mg/ kg-bw/ day

5 days/week
for 78 weeks

Not
Reported

No effects
were observed
on incidences
of neoplastic
or non-
neoplastic
lesions based
on necropsy
and

histopathology
examination
for these
organs/
systems.

National
Institute of

Heal-

Medium

Endocrine

Chronic (> 90
days)

Rat Osborne-
Mendel - [rat]
Female (50
(treated), 20
(untreated and
vehicle
controls))

Oral

0 , 474 , 949
mg/ kg-bw/ day

5 days/week
for 78 weeks

Not
Reported

No effects
were observed
on incidences
of neoplastic
or non-
neoplastic
lesions based

National
Institute of
Hear

Medium

53


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

Target Organ/
System1

Study
Type

Species/
Strain/ Sex
(Number/
group)2

Exposure
Route

Doses/
Concentrations

3

Duration4

NOAEL/
LOAEL/
LC50 5i(mg/
m3 or mg/
kg-day)
(Sex)

Effect6

Reference7

Data
Quality
Evaluation

8















on necropsy
and

histopathology
examination
for these
organs/
systems.





Endocrine

Chronic (> 90
days)

Mouse
B6C3F1-
[mouse] Male
(50 (treated),
20 (untreated
and vehicle
controls))

Oral

0 , 536 , 1072
mg/ kg-bw/ day

5 days/week
for 78 weeks

Not
Reported

No effects
were observed
on incidences
of neoplastic
or non-
neoplastic
lesions based
on necropsy
and

histopathology
examination
for these
organs/
systems.

National
Institute of

Heal-

Medium

Endocrine

Chronic (> 90
days)

Mouse
B6C3F1-
[mouse]
Female ( 50
(treated), 20
(untreated and
vehicle
controls))

Oral

0 , 386 , 772
mg/ kg-bw/ day

5 days/week
for 78 weeks

Not
Reported

No effects
were observed
on incidences
of neoplastic
or non-
neoplastic
lesions based
on necropsy
and

histopathology
examination
for these
organs/
systems.

National
Institute of

Heal-

Medium

54


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

Target Organ/
System1

Study
Type

Species/
Strain/ Sex
(Number/
group)2

Exposure
Route

Doses/
Concentrations

3

Duration4

NOAEL/
LOAEL/
LC50 5i(mg/
m3 or mg/
kg-day)
(Sex)

Effect6

Reference7

Data
Quality
Evaluation

8

Gastrointestin
al

Chronic (> 90
days)

Rat Osborne-
Mendel - [rat]

Male ( 50
(treated), 20
(untreated and
vehicle
controls))

Oral

0 , 471 , 941
mg/ kg-bw/ day

5 days/week
for 78 weeks

Not
Reported

No effects
were observed
on incidences
of neoplastic
or non-
neoplastic
lesions based
on necropsy
and

histopathology
examination
for these
organs/
systems.

National
Institute of

Heal-

Medium

Gastrointestin
al

Chronic (> 90
days)

Rat Osborne-
Mendel - [rat]
Female (50
(treated), 20
(untreated and
vehicle
controls))

Oral

0 , 474 , 949
mg/ kg-bw/ day

5 days/week
for 78 weeks

Not
Reported

No effects
were observed
on incidences
of neoplastic
or non-
neoplastic
lesions based
on necropsy
and

histopathology
examination
for these
organs/
systems.

National
Institute of

Heal-

Medium

Gastrointestin
al

Chronic (> 90
days)

Mouse
B6C3F1-
[mouse] Male
(50 (treated),
20 (untreated
and vehicle
controls))

Oral

0 , 536 , 1072
mg/ kg-bw/ day

5 days/week
for 78 weeks

Not
Reported

No effects
were observed
on incidences
of neoplastic
or non-
neoplastic
lesions based
on necropsy
and

histopathology

National
Institute of
Hear

Medium

55


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

Target Organ/
System1

Study
Type

Species/
Strain/ Sex
(Number/
group)2

Exposure
Route

Doses/
Concentrations

3

Duration4

NOAEL/
LOAEL/
LC50 5i(mg/
m3 or mg/
kg-day)
(Sex)

Effect6

Reference7

Data
Quality
Evaluation

8















examination
for these
organs/
systems.





Gastrointestin
al

Chronic (> 90
days)

Mouse
B6C3F1-
[mouse]
Female (50
(treated), 20
(untreated and
vehicle
controls))

Oral

0 , 386 , 772
mg/ kg-bw/ day

5 days/week
for 78 weeks

Not
Reported

No effects
were observed
on incidences
of neoplastic
or non-
neoplastic
lesions based
on necropsy
and

histopathology
examination
for these
organs/
systems.

National
Institute of

Heal-

Medium

Growth (early

life) and
Development

Reproductive

Rat Other
Both (24/ sex/
group in F0
parents )

Inhalation

0 , 686 , 2058 ,
6860 mg/ m3 (
0 , 100,300 ,
1000 ppm)

6 hours/ day in
multi-generation
study (including
prior to mating
through 2nd
generation)

Not
Reported

Decreased F1
male and
female pup
weights from
PNDs 5 to 29

Haloaenated
Solvents

.)

Medium

Hematologica
I and Immune

Short-term (1-
30 days)

Rat Sprague-
Dawley - [rat]
Female (8 )

Inhalation

0 , 686 , 2058 ,
6860 mg/ m3 (
0 , 100,300 ,
1000 ppm)

6 hours/ day 5
days/ week for 4

weeks (20
exposure days)

Not
Reported

No effects on

survival,
hematology,

antibody
responses to
sheep red
blood cells,
bronchoalveol

ar lavage
parameters,

spleen,
thymus, or
kidney

Boverhof et al
(2013)

High

56


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

Target Organ/
System1

Study
Type

Species/
Strain/ Sex
(Number/
group)2

Exposure
Route

Doses/
Concentrations

3

Duration4

NOAEL/
LOAEL/
LC50 5i(mg/
m3 or mg/
kg-day)
(Sex)

Effect6

Reference7

Data
Quality
Evaluation

8















weights, or
spleen,
thymus, lung,
nasal, trachea,
or bone
marrow
histopathology





Hematologica
I and Immune

Chronic (> 90
days)

Rat Osborne-
Mendel - [rat]

Male ( 50
(treated), 20
(untreated and
vehicle
controls))

Oral

0 , 471 , 941
mg/ kg-bw/ day

5 days/week
for 78 weeks

Not
Reported

No effects
were observed
on incidences
of neoplastic
or non-
neoplastic
lesions based
on necropsy
and

histopathology
examination
for these
organs/
systems.

National
Institute of

Heal-

Medium

Hematologica
I and Immune

Chronic (> 90
days)

Rat Osborne-
Mendel - [rat]
Female (50
(treated), 20
(untreated and
vehicle
controls))

Oral

0 , 474 , 949
mg/ kg-bw/ day

5 days/week
for 78 weeks

Not
Reported

No effects
were observed
on incidences
of neoplastic
or non-
neoplastic
lesions based
on necropsy
and

histopathology
examination
for these
organs/
systems.

National
Institute of

Heal-

Medium

57


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

Target Organ/
System1

Study
Type

Species/
Strain/ Sex
(Number/
group)2

Exposure
Route

Doses/
Concentrations

3

Duration4

NOAEL/
LOAEL/
LC50 5i(mg/
m3 or mg/
kg-day)
(Sex)

Effect6

Reference7

Data
Quality
Evaluation

8

Hematologica
I and Immune

Chronic (> 90
days)

Mouse
B6C3F1-
[mouse] Male
(50 (treated),
20 (untreated
and vehicle
controls))

Oral

0 , 536 , 1072
mg/ kg-bw/ day

5 days/week
for 78 weeks

Not
Reported

No effects
were observed
on incidences
of neoplastic
or non-
neoplastic
lesions based
on necropsy
and

histopathology
examination
for these
organs/
systems.

National
Institute of

Heal-

Medium

Hematologica
I and Immune

Chronic (> 90
days)

Mouse
B6C3F1-
[mouse]
Female (50
(treated), 20
(untreated and
vehicle
controls))

Oral

0 , 386 , 772
mg/ kg-bw/ day

5 days/week
for 78 weeks

Not
Reported

No effects
were observed
on incidences
of neoplastic
or non-
neoplastic
lesions based
on necropsy
and

histopathology
examination
for these
organs/
systems.

National
Institute of

Heal-

Medium

Hepatic

Short-term (1-
30 days)

Rat Sprague-
Dawley - [rat]
Female (8 )

Inhalation

0 , 686 , 2058 ,
6860 mg/ m3 (
0 , 100,300 ,
1000 ppm)

6 hours/ day 5
days/ week for 4

weeks (20
exposure days)

Not
Reported

Increased liver
weight

Boverhof et al
(2013)

High

Hepatic

Reproductive

Rat Other
Both (24/ sex/
group in F0
parents )

Inhalation

0 , 686 , 2058 ,
6860 mg/ m3 (
0 , 100,300 ,
1000 ppm)

6 hours/ day in
multi-generation
study (including
prior to mating

Not
Reported

No body
weight
decrease
greater than
10% from

Haloaenated
Solvents
Q

Medium

58


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

Target Organ/
System1

Study
Type

Species/
Strain/ Sex
(Number/
group)2

Exposure
Route

Doses/
Concentrations

3

Duration4

NOAEL/
LOAEL/
LC50 5i(mg/
m3 or mg/
kg-day)
(Sex)

Effect6

Reference7

Data
Quality
Evaluation

8











through 2nd
generation)



control; liver

weights
increased at
1000 ppm in
F0 males and
F1 females
but no
histopathology
changes seen.





Hepatic

Chronic (> 90
days)

Rat Osborne-
Mendel - [rat]

Male ( 50
(treated), 20
(untreated and
vehicle
controls))

Oral

0 , 471 , 941
mg/ kg-bw/ day

5 days/week
for 78 weeks

Not
Reported

No effects
were observed
on incidences
of neoplastic
or non-
neoplastic
lesions based
on necropsy
and

histopathology
examination
for these
organs/
systems.

National
Institute of

Heal-

Medium

Hepatic

Chronic (> 90
days)

Mouse
B6C3F1-
[mouse] Male
(50 (treated),
20 (untreated
and vehicle
controls))

Oral

0 , 536 , 1072
mg/ kg-bw/ day

5 days/week
for 78 weeks

Not
Reported

decreased
survival,
decreased
body weight
gain, hunched
appearance,
hepatocellular
carcinoma,

toxic
nephropathy

National

MMituteof
Heal;

Medium

Hepatic

Chronic (> 90
days)

Mouse
B6C3F1-
[mouse]
Female (50

Oral

0 , 386 , 772
mg/ kg-bw/ day

5 days/week
for 78 weeks

Not
Reported

decreased
survival,
decreased
body weight

National
Institute of

Heal-

Medium

59


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

Target Organ/
System1

Study
Type

Species/
Strain/ Sex
(Number/
group)2

Exposure
Route

Doses/
Concentrations

3

Duration4

NOAEL/
LOAEL/
LC50 5i(mg/
m3 or mg/
kg-day)
(Sex)

Effect6

Reference7

Data
Quality
Evaluation

8





(treated), 20
(untreated and
vehicle
controls))









gain, hunched
appearance,
hepatocellular
carcinoma,

toxic
nephropathy





Hepatic

Chronic (> 90
days)

Rat Osborne-
Mendel - [rat]
Female (50
(treated), 20
(untreated and
vehicle
controls))

Oral

0 , 474 , 949
mg/ kg-bw/ day

5 days/week
for 78 weeks

Not
Reported

No effects
were observed
on incidences
of neoplastic
or non-
neoplastic
lesions based
on necropsy
and

histopathology
examination
for these
organs/
systems.

National
Institute of

Heal-

Medium

Mortality

Acute (< 24hr)

Fischer 344-
[rat] Both ( 6 )

Oral

0 , 1300,2500
, 3200 , 4000 ,
5000 mg/ kg-
bw/ day

1 day

Not
Reported

Not reported

Dow
Chemical

i)

Low

Mortality

Short-term (1-
30 days)

Rat Sprague-
Dawley - [rat]
Female (8 )

Inhalation

0 , 686 , 2058 ,
6860 mg/ m3 (
0 , 100,300 ,
1000 ppm)

6 hours/ day 5
days/ week for 4

weeks (20
exposure days)

Not
Reported

No effects on

survival,
hematology,

antibody
responses to
sheep red
blood cells,
bronchoalveol

ar lavage
parameters,

spleen,
thymus, or
kidney

Boverhof et al
(2013)

High

60


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

Target Organ/
System1

Study
Type

Species/
Strain/ Sex
(Number/
group)2

Exposure
Route

Doses/
Concentrations

3

Duration4

NOAEL/
LOAEL/
LC50 5i(mg/
m3 or mg/
kg-day)
(Sex)

Effect6

Reference7

Data
Quality
Evaluation

8















weights, or
spleen,
thymus, lung,
nasal, trachea,
or bone
marrow
histopathology





Mortality

Chronic (> 90
days)

Rat Osborne-
Mendel - [rat]

Male ( 50
(treated), 20
(untreated and
vehicle
controls))

Oral

0 , 471 , 941
mg/ kg-bw/ day

5 days/week
for 78 weeks

Not
Reported

decreased
survival,
decreased
body weight
gain, toxic
nephropathy,

hunched
appearance

National
Institute of

Heal-

Medium

Mortality

Chronic (> 90
days)

Rat Osborne-
Mendel - [rat]
Female (50
(treated), 20
(untreated and
vehicle
controls))

Oral

0 , 474 , 949
mg/ kg-bw/ day

5 days/week
for 78 weeks

Not
Reported

decreased
survival,
decreased
body weight
gain, toxic
nephropathy,

hunched
appearance

National
Institute of

Heal-

Medium

Mortality

Chronic (> 90
days)

Mouse
B6C3F1-
[mouse] Male
(50 (treated),
20 (untreated
and vehicle
controls))

Oral

0 , 536 , 1072
mg/ kg-bw/ day

5 days/week
for 78 weeks

Not
Reported

decreased
survival,
decreased
body weight
gain, hunched
appearance,
hepatocellular
carcinoma,

toxic
nephropathy

National
Institute of
Hear

Medium

Mortality

Chronic (> 90
days)

Mouse
B6C3F1-
[mouse]

Oral

0 , 386 , 772
mg/ kg-bw/ day

5 days/week
for 78 weeks

Not
Reported

decreased
survival,
decreased

National
Institute of
Hear

Medium

61


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

Target Organ/
System1

Study
Type

Species/
Strain/ Sex
(Number/
group)2

Exposure
Route

Doses/
Concentrations

3

Duration4

NOAEL/
LOAEL/
LC50 5i(mg/
m3 or mg/
kg-day)
(Sex)

Effect6

Reference7

Data
Quality
Evaluation

8





Female (50
(treated), 20
(untreated and
vehicle
controls))









body weight
gain, hunched
appearance,
hepatocellular
carcinoma,

toxic
nephropathy





Neurological/
Behavior

Reproductive

Rat Other
Both (24/ sex/
group in F0
parents )

Inhalation

0 , 686 , 2058 ,
6860 mg/ m3 (
0 , 100,300 ,
1000 ppm)

6 hours/ day in
multi-generation
study (including
prior to mating
through 2nd
generation)

Not
Reported

Neurological:
clinical signs
(decreased
activity and
response to
sound).
Renal:
Increased
kidney weight;
increased
incidence of
minimal
chronic
progressive
glomerulonep
hropathy;
increased
pleomorphism
within the
proximal
tubular nuclei.
Effects seen in
F0 and F1
parents.

Haloaenated
Solvents
Q

Medium

Neurological/
Behavior

Chronic (> 90
days)

Rat Osborne-
Mendel - [rat]

Male ( 50
(treated), 20
(untreated and
vehicle
controls))

Oral

0 , 471 , 941
mg/ kg-bw/ day

5 days/week
for 78 weeks

Not
Reported

decreased
survival,
decreased
body weight
gain, toxic
nephropathy,

National
Institute of

Heal-

Medium

62


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

Target Organ/
System1

Study
Type

Species/
Strain/ Sex
(Number/
group)2

Exposure
Route

Doses/
Concentrations

3

Duration4

NOAEL/
LOAEL/
LC50 5i(mg/
m3 or mg/
kg-day)
(Sex)

Effect6

Reference7

Data
Quality
Evaluation

8















hunched



















appearance





Neurological/

Chronic (> 90

Rat Osborne-

Oral

0 , 474 , 949

5 days/week

Not

decreased

National

Medium

Behavior

days)

Mendel - [rat]
Female (50
(treated), 20
(untreated and
vehicle
controls))



mg/ kg-bw/ day

for 78 weeks

Reported

survival,
decreased
body weight
gain, toxic
nephropathy,

hunched
appearance

Institute of

Heal-



Neurological/

Chronic (> 90

Mouse

Oral

0 , 536 , 1072

5 days/week

Not

decreased

National

Medium

Behavior

days)

B6C3F1-
[mouse] Male
(50 (treated),
20 (untreated
and vehicle
controls))



mg/ kg-bw/ day

for 78 weeks

Reported

survival,
decreased
body weight
gain, hunched
appearance,
hepatocellular
carcinoma,

toxic
nephropathy

Institute of

Heal-



Neurological/

Chronic (> 90

Mouse

Oral

0 , 386 , 772

5 days/week

Not

decreased

National

Medium

Behavior

days)

B6C3F1-
[mouse]
Female (50
(treated), 20
(untreated and
vehicle
controls))



mg/ kg-bw/ day

for 78 weeks

Reported

survival,
decreased
body weight
gain, hunched
appearance,
hepatocellular
carcinoma,

toxic
nephropathy

Institute of
Hear



Renal

Reproductive

Rat Other
Both (24/ sex/
group in F0
parents )

Inhalation

0 , 686 , 2058 ,
6860 mg/ m3 (
0 , 100,300 ,
1000 ppm)

6 hours/ day in
multi-generation
study (including
prior to mating
through 2nd
generation)

Not
Reported

Neurological:
clinical signs
(decreased
activity and
response to
sound).

Renal:

Hajogenated

Solvents
.)

Medium

63


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

Target Organ/
System1

Study
Type

Species/
Strain/ Sex
(Number/
group)2

Exposure
Route

Doses/
Concentrations

3

Duration4

NOAEL/
LOAEL/
LC50 5i(mg/
m3 or mg/
kg-day)
(Sex)

Effect6

Reference7

Data
Quality
Evaluation

8















Increased
kidney weight;
increased
incidence of
minimal
chronic
progressive
glomerulonep
hropathy;
increased
pleomorphism
within the
proximal
tubular nuclei.
Effects seen in
F0 and F1
parents.





Renal

Chronic (> 90
days)

Rat Osborne-
Mendel - [rat]

Male ( 50
(treated), 20
(untreated and
vehicle
controls))

Oral

0 , 471 , 941
mg/ kg-bw/ day

5 days/week
for 78 weeks

Not
Reported

decreased
survival,
decreased
body weight
gain, toxic
nephropathy,

hunched
appearance

National
Institute of

Heal-

Medium

Renal

Chronic (> 90
days)

Rat Osborne-
Mendel - [rat]
Female (50
(treated), 20
(untreated and
vehicle
controls))

Oral

0 , 474 , 949
mg/ kg-bw/ day

5 days/week
for 78 weeks

Not
Reported

decreased
survival,
decreased
body weight
gain, toxic
nephropathy,

hunched
appearance

National
Institute of

Heal-

Medium

Renal

Chronic (> 90
days)

Mouse
B6C3F1-
[mouse] Male
(50 (treated),

Oral

0 , 536 , 1072
mg/ kg-bw/ day

5 days/week
for 78 weeks

Not
Reported

decreased
survival,
decreased
body weight

National
Institute of
Hear

Medium

64


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

Target Organ/
System1

Study
Type

Species/
Strain/ Sex
(Number/
group)2

Exposure
Route

Doses/
Concentrations

3

Duration4

NOAEL/
LOAEL/
LC50 5i(mg/
m3 or mg/
kg-day)
(Sex)

Effect6

Reference7

Data
Quality
Evaluation

8





20 (untreated
and vehicle
controls))









gain, hunched
appearance,
hepatocellular
carcinoma,

toxic
nephropathy





Renal

Chronic (> 90
days)

Mouse
B6C3F1-
[mouse]
Female (50
(treated), 20
(untreated and
vehicle
controls))

Oral

0 , 386 , 772
mg/ kg-bw/ day

5 days/week
for 78 weeks

Not
Reported

decreased
survival,
decreased
body weight
gain, hunched
appearance,
hepatocellular
carcinoma,

toxic
nephropathy

National
Institute of

Heal-

Medium

Reproductive
 

Reproductive

Rat Other
Both (24/ sex/
group in F0
parents )

Inhalation

0 , 686 , 2058 ,
6860 mg/ m3 (
0 , 100,300 ,
1000 ppm)

6 hours/ day in
multi-generation
study (including
prior to mating
through 2nd
generation)

NOAEL =
2058 mg/ m3

At the 1000
ppm, there

were
reductions in
percentage of

pups born
alive (F1, F2a,
and F2b
litters) and
decreased
pup survival
PND 1-5 (F1
,F2a, and F2c

litters) and
PND 5-22 (F1
and F2a).
Decreased
testes weights
observed at
300 and 1000
ppm of F1
parents, but

Haloaenated
Solvents
Q

Medium

65


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

Target Organ/
System1

Study
Type

Species/
Strain/ Sex
(Number/
group)2

Exposure
Route

Doses/
Concentrations

3

Duration4

NOAEL/
LOAEL/
LC50 5i(mg/
m3 or mg/
kg-day)
(Sex)

Effect6

Reference7

Data
Quality
Evaluation

8















there was no
associated
histopathology
, no male-
dependent
effects on
fertility, and no

change in
testes weights
in F0 males.





Reproductive
 

Chronic (> 90
days)

Rat Osborne-
Mendel - [rat]

Male ( 50
(treated), 20
(untreated and
vehicle
controls))

Oral

0 , 471 , 941
mg/ kg-bw/ day

5 days/week
for 78 weeks

Not
Reported

No effects
were observed
on incidences
of neoplastic
or non-
neoplastic
lesions based
on necropsy
and

histopathology
examination
for these
organs/
systems.

National
Institute of

Heal-

Medium

Reproductive
 

Chronic (> 90
days)

Rat Osborne-
Mendel - [rat]
Female (50
(treated), 20
(untreated and
vehicle
controls))

Oral

0 , 474 , 949
mg/ kg-bw/ day

5 days/week
for 78 weeks

Not
Reported

No effects
were observed
on incidences
of neoplastic
or non-
neoplastic
lesions based
on necropsy
and

histopathology
examination
for these
organs/
systems.

National
Institute of

Heal-

Medium

66


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

Target Organ/
System1

Study
Type

Species/
Strain/ Sex
(Number/
group)2

Exposure
Route

Doses/
Concentrations

3

Duration4

NOAEL/
LOAEL/
LC50 5i(mg/
m3 or mg/
kg-day)
(Sex)

Effect6

Reference7

Data
Quality
Evaluation

8

Reproductive
 

Chronic (> 90
days)

Mouse
B6C3F1-
[mouse] Male
(50 (treated),
20 (untreated
and vehicle
controls))

Oral

0 , 536 , 1072
mg/ kg-bw/ day

5 days/week
for 78 weeks

Not
Reported

No effects
were observed
on incidences
of neoplastic
or non-
neoplastic
lesions based
on necropsy
and

histopathology
examination
for these
organs/
systems.

National
Institute of

Heal-

Medium

Reproductive
 

Chronic (> 90
days)

Mouse
B6C3F1-
[mouse]
Female (50
(treated), 20
(untreated and
vehicle
controls))

Oral

0 , 386 , 772
mg/ kg-bw/ day

5 days/week
for 78 weeks

Not
Reported

No effects
were observed
on incidences
of neoplastic
or non-
neoplastic
lesions based
on necropsy
and

histopathology
examination
for these
organs/
systems.

National
Institute of

Heal-

Medium

Respiratory

Short-term (1-
30 days)

Rat Sprague-
Dawley - [rat]
Female (8 )

Inhalation

0 , 686 , 2058 ,
6860 mg/ m3 (
0 , 100,300 ,
1000 ppm)

6 hours/ day 5
days/ week for 4

weeks (20
exposure days)

Not
Reported

No effects on

survival,
hematology,

antibody
responses to
sheep red
blood cells,
bronchoalveol

ar lavage
parameters,

Boverhof et al
(2013)

High

67


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

Target Organ/
System1

Study
Type

Species/
Strain/ Sex
(Number/
group)2

Exposure
Route

Doses/
Concentrations

3

Duration4

NOAEL/
LOAEL/
LC50 5i(mg/
m3 or mg/
kg-day)
(Sex)

Effect6

Reference7

Data
Quality
Evaluation

8















spleen,
thymus, or

kidney
weights, or
spleen,
thymus, lung,
nasal, trachea,
or bone
marrow
histopathology





Respiratory

Chronic (> 90
days)

Rat Osborne-
Mendel - [rat]

Male ( 50
(treated), 20
(untreated and
vehicle
controls))

Oral

0 , 471 , 941
mg/ kg-bw/ day

5 days/week
for 78 weeks

Not
Reported

No effects
were observed
on incidences
of neoplastic
or non-
neoplastic
lesions based
on necropsy
and

histopathology
examination
for these
organs/
systems.

National
Institute of

Heal-

Medium

Respiratory

Chronic (> 90
days)

Rat Osborne-
Mendel - [rat]
Female (50
(treated), 20
(untreated and
vehicle
controls))

Oral

0 , 474 , 949
mg/ kg-bw/ day

5 days/week
for 78 weeks

Not
Reported

No effects
were observed
on incidences
of neoplastic
or non-
neoplastic
lesions based
on necropsy
and

histopathology
examination
for these

National
Institute of

Heal-

Medium

68


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

Target Organ/
System1

Study
Type

Species/
Strain/ Sex
(Number/
group)2

Exposure
Route

Doses/
Concentrations

3

Duration4

NOAEL/
LOAEL/
LC50 5i(mg/
m3 or mg/
kg-day)
(Sex)

Effect6

Reference7

Data
Quality
Evaluation

8















organs/
systems.





Respiratory

Chronic (> 90
days)

Mouse
B6C3F1-
[mouse] Male
(50 (treated),
20 (untreated
and vehicle
controls))

Oral

0 , 536 , 1072
mg/ kg-bw/ day

5 days/week
for 78 weeks

Not
Reported

No effects
were observed
on incidences
of neoplastic
or non-
neoplastic
lesions based
on necropsy
and

histopathology
examination
for these
organs/
systems.

National
Institute of

Heal-

Medium

Respiratory

Chronic (> 90
days)

Mouse
B6C3F1-
[mouse]
Female ( 50
(treated), 20
(untreated and
vehicle
controls))

Oral

0 , 386 , 772
mg/ kg-bw/ day

5 days/week
for 78 weeks

Not
Reported

No effects
were observed
on incidences
of neoplastic
or non-
neoplastic
lesions based
on necropsy
and

histopathology
examination
for these
organs/
systems.

National
Institute of

Heal-

Medium

Skin and
Connective
Tissue

Chronic (> 90
days)

Rat Osborne-
Mendel - [rat]

Male ( 50
(treated), 20
(untreated and
vehicle
controls))

Oral

0 , 471 , 941
mg/ kg-bw/ day

5 days/week
for 78 weeks

Not
Reported

No effects
were observed
on incidences
of neoplastic
or non-
neoplastic
lesions based

National
Institute of
Hear

Medium

69


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

Target Organ/
System1

Study
Type

Species/
Strain/ Sex
(Number/
group)2

Exposure
Route

Doses/
Concentrations

3

Duration4

NOAEL/
LOAEL/
LC50 5i(mg/
m3 or mg/
kg-day)
(Sex)

Effect6

Reference7

Data
Quality
Evaluation

8















on necropsy
and

histopathology
examination
for these
organs/
systems.





Skin and
Connective
Tissue

Chronic (> 90
days)

Rat Osborne-
Mendel - [rat]
Female (50
(treated), 20
(untreated and
vehicle
controls))

Oral

0 , 474 , 949
mg/ kg-bw/ day

5 days/week
for 78 weeks

Not
Reported

No effects
were observed
on incidences
of neoplastic
or non-
neoplastic
lesions based
on necropsy
and

histopathology
examination
for these
organs/
systems.

National
Institute of

Heal-

Medium

Skin and
Connective
Tissue

Chronic (> 90
days)

Mouse
B6C3F1-
[mouse] Male
(50 (treated),
20 (untreated
and vehicle
controls))

Oral

0 , 536 , 1072
mg/ kg-bw/ day

5 days/week
for 78 weeks

Not
Reported

No effects
were observed
on incidences
of neoplastic
or non-
neoplastic
lesions based
on necropsy
and

histopathology
examination
for these
organs/
systems.

National
Institute of

Heal-

Medium

70


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

Target Organ/

Study

Species/

Exposure

Doses/

Duration4

NOAEL/

Effect6

Reference7

Data

System1

Type

Strain/ Sex
(Number/
group)2

Route

Concentrations

3



LOAEL/
LC50 5i(mg/
m3 or mg/
kg-day)
(Sex)





Quality
Evaluation

8

Skin and

Chronic (> 90

Mouse

Oral

0 , 386 , 772

5 days/week

Not

No effects

National

Medium

Connective

days)

B6C3F1-



mg/ kg-bw/ day

for 78 weeks

Reported

were observed

Institute of



Tissue



[mouse]
Female (50
(treated), 20
(untreated and
vehicle
controls))









on incidences
of neoplastic
or non-
neoplastic
lesions based
on necropsy
and

histopathology
examination
for these
organs/
systems.

Heal-



Thyroid

Chronic (> 90

Rat Osborne-

Oral

0 , 471 , 941

5 days/week

Not

No effects

National

Medium



days)

Mendel - [rat]

Male ( 50
(treated), 20
(untreated and
vehicle
controls))



mg/ kg-bw/ day

for 78 weeks

Reported

were observed
on incidences
of neoplastic
or non-
neoplastic
lesions based
on necropsy
and

histopathology
examination
for these
organs/
systems.

Institute of

Heal-



Thyroid

Chronic (> 90

Rat Osborne-

Oral

0 , 474 , 949

5 days/week

Not

No effects

National

Medium

days)

Mendel - [rat]
Female (50
(treated), 20
(untreated and
vehicle
controls))



mg/ kg-bw/ day

for 78 weeks

Reported

were observed
on incidences
of neoplastic
or non-
neoplastic
lesions based
on necropsy
and

histopathology

Institute of
Hear



71


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

Target Organ/
System1

Study
Type

Species/
Strain/ Sex
(Number/
group)2

Exposure
Route

Doses/
Concentrations

3

Duration4

NOAEL/
LOAEL/
LC50 5i(mg/
m3 or mg/
kg-day)
(Sex)

Effect6

Reference7

Data
Quality
Evaluation

8















examination
for these
organs/
systems.





Thyroid

Chronic (> 90
days)

Mouse
B6C3F1-
[mouse] Male
(50 (treated),
20 (untreated
and vehicle
controls))

Oral

0 , 536 , 1072
mg/ kg-bw/ day

5 days/week
for 78 weeks

Not
Reported

No effects
were observed
on incidences
of neoplastic
or non-
neoplastic
lesions based
on necropsy
and

histopathology
examination
for these
organs/
systems.

National
Institute of

Heal-

Medium

Thyroid

Chronic (> 90
days)

Mouse
B6C3F1-
[mouse]
Female (50
(treated), 20
(untreated and
vehicle
controls))

Oral

0 , 386 , 772
mg/ kg-bw/ day

5 days/week
for 78 weeks

Not
Reported

No effects
were observed
on incidences
of neoplastic
or non-
neoplastic
lesions based
on necropsy
and

histopathology
examination
for these
organs/
systems.

National
Institute of

Heal-

Medium















"Unacceptable
studies not
included in
table





72


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

Target Organ/
System1

Study
Type

Species/
Strain/ Sex
(Number/
group)2

Exposure
Route

Doses/
Concentrations

3

Duration4

NOAEL/
LOAEL/
LC50 5i(mg/
m3 or mg/
kg-day)
(Sex)

Effect6

Reference7

Data
Quality
Evaluation

8

Developmental

Effects
(Neurotoxicity)

Developmental

Mouse, NMRI,
M, n = 36-48/
group

Oral, gavage

0, 5, or 320 mg/
kg-day

PNDs 10-16, for
exposure days
and PND 60 was
last day of study

LOAEL = 5
mg/ kg-day

Spontaneous

activity
(locomotion,
rearing, and
total activity

(Fredriksson et
aL 1993)



73


-------