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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
2003
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
assessment report
Reference
Endpoint:
one-generation reproductive toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1983-03-08 through 1983-05-19
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Reason / purpose for cross-reference:
assessment report
Reason / purpose for cross-reference:
assessment report
Qualifier:
no guideline followed
Principles of method if other than guideline:
"Screening for potential reproductive hazards":
1) Minimum effective dose (MED) was determined in a preliminary test (10 virgin females per dose. Dose levels: 1000, 1525, 2330, 3560, 5435, and8300 mg/kg/day)
2) timed- pregnant females (n=50) received 0 and 1525 mg/kg/day by oral gavage. Subsequent examinations were similar to OECD TG 415
GLP compliance:
not specified
Species:
mouse
Strain:
Swiss
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Kingston, NY
- Weight at study initiation: (P) Females: 29-30 g
- Housing: individually in plastic cages
- Diet: Purina certified Rodent Chow # 5002; ad libitum
- Water: ad libitum
- Acclimation period: 4-5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 72°F +/- 3°
- Humidity (%): 50 +/-20
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
Concentration in vehicle: 1525 mg 2-EH/10 mL
- Amount of vehicle (if gavage): constant dose volume of 10 mL/kg bw during the preliminary and the definitive study
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
during days 7 through 14 of gestation (GD 7 - GD14)
- 8 exposures on consecutive days
Frequency of treatment:
8 exposures on consecutive days
Remarks:
1525 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
50
Control animals:
yes, concurrent vehicle
Dose descriptor:
NOAEL
Effect level:
1 525 mg/kg bw/day (actual dose received)
Sex:
female
Basis for effect level:
other: Reproduction index in treated females reduced to 55% compared to 97% in controls
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
1 525 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: Only one dose tested. Reduction of pup viability and body weight on days 1 and 3 post partum
Reproductive effects observed:
not specified
Conclusions:
In a screening test carried out under GLP mice (Charles River CD-1) were given 1525 mg 2-ethylhexanol/kg body weight/day by gavage from days 7 to14 of pregnancy. The dams and pups were observed until day 3 of lactation. The treatment and control groups each comprised 50 animals. The dose used was in the maternally toxic range, the signs of toxicity in the dams including reduced movement, ataxia,hypothermia, unkempt coats and blood in the urine. The body weight of the dams was significantly reduced. Of the 50 mice treated, 18 died during the study, the investigators attributing the deaths of 17 of these animals to 2-ethylhexanol. None of the control mice died. The fertility index in the treated mice was 40 % (controls 68 %), the pregnancy index 55 % (controls 97 %). There were significant reductions in the number of live pups and in their weight compared with the controls. No further parameters were considered in this study (Hazleton, 1983; Hardin et al., 1987).
Reason / purpose for cross-reference:
assessment report
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
19 Aug 2014 - 01 Dec 2014
Reliability:
1 (reliable without restriction)
Reason / purpose for cross-reference:
assessment report
Reason / purpose for cross-reference:
assessment report
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
not specified
Specific details on test material used for the study:
Colour/ appearance : Liquid, colourless to yellow
Molecular formula1 : C8H16O2
Molecular weight1 : 144.21
Storage conditions1 : ambient temperature
Purity1 : 99.8%
Batch number1 : 15667956P0
Species:
rat
Strain:
Wistar
Sex:
male/female
Route of administration:
oral: feed
Details on exposure:
The test substance was administered to the animals at constant concentrations in the diet, which remained the same for each group during the study.
Male animals received the test item via the diet during a 2-week premating period, during mating and up to and including day 30. Female animals were fed the diets during a 2-week premating period, and during mating, gestation and lactation up to and including the day of sacrifice (day 4 to 7 of lactation). Animals that were fasted before sacrifice were kept on the diets until the overnight fasting period started.
Details on mating procedure:
At the end of the premating period, each female was caged together with one male from the same group until mating occurred. Every consecutive morning during the mating period, vaginal smears were made for determination of the presence of sperm. The day on which sperm was detected in the vaginal smear was considered as gestation day 0. Upon evidence of copulation the females were caged individually. Mating pairs were clearly
identified.
Sperm positive females that turn out to be non-pregnant were killed not earlier than 28 days after copulation. Dams were allowed to raise their litter
until sacrifice 4 to 7 days after giving birth.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The test item in the diets was analyzed by Gas Chromatography – Flame Ionization Detection (GC-FID) after extraction from the diet.
Duration of treatment / exposure:
Male animals received the test item via the diet during a 2-week premating period, during mating and up to and including day 30.
Female animals were fed the diets during a 2-week premating period, and during mating, gestation and lactation up to and including the day of sacrifice (day 4 to 7 of lactation).
Remarks:
1538, 4615 and 15385 ppm
Basis:
nominal in diet
Remarks:
males: 82-86, 248-253 and 761-797 mg/kg body weight/day
Basis:
actual ingested
Remarks:
females: 107-116, 308-351 and 809-1146 mg/kg bw; PND0-4: 190, 530 and 1371 mg/kg bw
Basis:
actual ingested
No. of animals per sex per dose:
10
Control animals:
yes, plain diet
Parental animals: Observations and examinations:
Each animal was observed daily in the morning hours by cage-side observations and, if necessary, handled to detect signs of toxicity. All cages were checked again in the afternoon for dead or moribund animals to minimize loss of animals from the study.
In addition to the above daily general clinical observations, detailed clinical examinations outside the home cage were performed on all rats of all groups prior to the first exposure and then once weekly throughout the study (during the conduct of the Functional Observational Battery tests (FOB, see below), detailed clinical examination formed part of the FOB in the animals concerned). Signs noted included but were not limited to changes in skin and fur, piloerection, changes in the eyes, gait (including posture), and presence of clonic or tonic movements, stereotypies and bizarre behaviour.

FOB and motor activity assessment
Shortly prior to sacrifice, Functional Observational Battery (FOB) tests and spontaneous Motor Activity Assessment (MAA) were performed in 5 males/group on day 28 of the study and in 5 females with a litter/group on PN day 4 (see section 4.6). For females, FOB and MAA was performed after weaning of their pups on PN day 4. Weaned pups were sacrificed.
During neuro-behavioural testing, the observer was unaware of the treatment of the animals.

Body weight
Body weights of male and female animals were recorded on the start of the treatment (to enable allocation, see § 4.6) (day 0). Males were weighed weekly until sacrifice. Females were weighed once per week during the premating period. Mated females were weighed on days 0,7, 14 and 21 during presumed gestation and on day 0 and 4 of lactation. Mated females that
were sacrificed on GD 20 were weighed on GD 0, 7 and 14.
In addition, all animals were weighed on their scheduled necropsy date in order to calculate
the correct organ to body weight ratios.

Food consumption
The food in the feeders was replaced twice per week with fresh food from the freezer. Except
for during the mating period, the food consumption was measured per cage over the same
periods as the body weight was measured. The results are expressed in g per animal per day
and g per kg body weight per day.

Intake of test item
The intake of the test item per kg body weight per day was calculated from the nominal dietary
concentration, the feed consumption and the body weight at the end of the pertaining period.

Parturition and litter evaluation
At the end of the gestation period (GD 21), all remaining females were examined twice daily
for signs of parturition. To keep nest disturbance to a minimum the litters were examined only
once daily for dead pups.

Litter size, sexes and weight
The total litter size and numbers of each sex as well as the number of stillbirths, live- and dead
pups and grossly malformed pups was evaluated on days 0 and 4 of lactation. The pups were
individually weighed on days 0 and 4 of lactation. Mean pup weight was calculated per sex
and for both sexes combined.

Signs and pathology of pups
Any abnormal behaviour of pups was recorded on day 0 and 4 of lactation. Grossly malformed
pups were examined macroscopically. A necropsy was performed on stillborn pups and pups
dying during the study; macroscopic abnormalities were recorded. At necropsy of the surviving
dams, pups were examined externally for gross abnormalities and killed by hypothermia whilst
under CO2/O2 anaesthesia. Pups were stored in a freezer for possible skeletal analyses until
finalisation of the report.

Gross necropsy and histology of parental animals
Males were killed after the mating period on day 30. Dams were
sacrificed on PN day 5 to 7.
Two sperm positive females that turned out to be non-pregnant (low-dose female 43 and middose
female 75 were sacrificed together with the last lot of pregnant females.
All surviving male and female parent animals were sacrificed by exsanguination from the
abdominal aorta whilst under CO2/O2 anaesthesia at necropsy and then examined grossly for
pathological changes.

Samples of the following tissues and organs of all parental animals were preserved in a
neutral aqueous phosphate-buffered 4% solution of formaldehyde; except for the testes which
were preserved in Bouin's fixative:
- ovaries (after counting the corpora lutea)
- uterus (after counting of the implantation sites)
- testes
- epididymides
seminal vesicles (with coagulating glands)
- prostate
- all gross lesions.
In addition the following organs of five animals/sex/group were
preserved (animals were fasted overnight):
adrenals
bone marrow (femur)
brain (including sections of cerebrum, cerebellum, medulla/pons)**
caecum
cervix
clitoral gland
colon
coagulation glands
duodenum
eyes
femur including joint
heart
ileum
jejunum (including Peyer’s patches)
kidneys
liver
lungs
mesenterial and axillary lymph nodes
peripheral nerve (sciatic or tibial)
pituitary gland
preputial gland
prostate
rectum
seminal vesicles (including coagulation glands)
skeletal muscle (thigh)
spinal cord (cervical, mid-thoracic and lumbar)
spleen
stomach1
thymus
thyroid (including parathyroid)
trachea
urinary bladder
uterus
vagina

Haematology
Haematology was conducted in 5 selected male animals/group on day 30 of the study and in 5
selected female animals/group on PN day 4-7 (see section 4.6).
Before sacrifice, the rats were fasted overnight (water was freely available) and blood was
taken from the aorta whilst under CO2/O2 anaesthesia. K3-EDTA was used as anticoagulant
and for APTT measurement blood was collected in citrate buffer.
In each plasma sample the following determinations were carried out according to the
methods listed in Annex 3 to the study plan (see Annex 10 of this report):
haemoglobin
packed cell volume
red blood cell count
reticulocytes
total white blood cell count
differential white blood cell counts (neutrophils, lymphocytes, eosinophils, basophils, monocytes)
prothrombin time
thrombocyte count
mean corpuscular volume (MCV; calculated)
mean corpuscular haemoglobin (MCH; calculated)
mean corpuscular haemoglobin concentration (MCHC; calculated).
activated partial thromboplastin time (APTT)
red blood cell distribution width (RDW).

Clinical chemistry
Clinical chemistry was conducted in 5 selected male animals/group on day 30 of the study and
in 5 selected female animals/group on PN day 4-7 (see section 4.6).
Before sacrifice, the rats were fasted overnight (water was freely available) and blood was
taken from the aorta whilst under CO2/O2 anaesthesia. Blood was collected in heparinized
plastic tubes and plasma was prepared by centrifugation.
The following measurements were made according to the methods listed in Annex 4 to the
study plan (see Annex 10 of this report):
alkaline phosphatase activity (ALP) bilirubin (total)
aspartate aminotransferase activity (ASAT) cholesterol (total)
alanine aminotransferase activity (ALAT) triglycerides
gamma glutamyl transferase activity (GGT) phospholipids
total protein calcium (Ca)
albumin sodium (Na)
ratio albumin to globulin (calculated) potassium (K)
urea chloride (Cl)
creatinine inorganic phosphate (PO4).
glucose (fasting)
bile acids

Peroxisome proliferation
Peroxisome proliferation was measured in the liver of all non-fasted male and female animals
that were not used for haematology, clinical chemistry and possible hormone determinations
(same animals as used for zinc and metallothioneins determinations).
Sperm parameters (parental animals):
Sperm analysis
From all male animals, epididymal sperm analysis and testicular sperm count was performed.

Epididymal sperm motility, count and morphology
At scheduled necropsy, epididymal sperm was derived from the left cauda epididymis of the
males of each group. For this purpose, the cauda epididymis was dissected, weighed and then
minced in M199 medium containing 0.5% Bovine Serum Albumin. Sperm motility and, after
sonification and DNA-staining, the cauda epididymal sperm reserves (sperm count) were
measured for males of all groups, using the Hamilton Thorne Integrated Visual Optical System
(IVOS).
In addition, a smear of the sperm solution was prepared and stained for males of all groups,
but only the smears of the control and the high-dose males were examined microscopically for
morphology.

Testicular sperm count
At scheduled necropsy, the left testis of the male animals of each group was placed on dry ice
and subsequently stored in a freezer (<-70°C) for later determination of the number of
homogenization-resistant spermatids. The testes to be analysed was thawed just before
further processing. Following removal of the tunica albuginea, the testicular parenchyma was
weighed, minced and homogenized in Saline Triton X-100 solution. Following DNA-staining,
the homogenization-resistant sperm heads were enumerated using the IVOS. The daily sperm
production was calculated. Sperm counts was only be conducted on the control and the highdose
males.
Reproductive indices:
The following parameters were calculated:
- pre-coital time = time between the start of mating and successful copulation
- duration of gestation = time between gestation day 0 and day of delivery
- female mating index = (number of females inseminated/number of females placed with males) x 100
- female fertility index = number of pregnant females*100/number of inseminated females
- gestation index = (number of females with live pups / number of females pregnant) x 100
- live birth index = (number of pups born alive/number of pups born) x 100
- viability index day 0 - 4 = (number of pup surviving 4 days/number of liveborn on day 0) x100
- pup mortality day 0 or 4 = (number of dead pups on day 0 or 4/ total number of pups on day 0 or 4) x 100
- sex ratio day 0 or 4 = (number of live male fetuses or pups on day 0 or 4/ number of live fetuses or pups on day 0 or 4) x 100
- pre-implantation loss = [(number of corpora lutea – number of implantation sites)/number of corpora lutea] x 100
- number of lost implantations = number of implantations sites - number of pups
Dose descriptor:
NOAEL
Effect level:
4 615 mg/kg diet
Sex:
male/female
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
15 385 mg/L drinking water
Sex:
male/female
Basis for effect level:
other: Fertility
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
4 615 mg/kg diet
Sex:
male/female
Basis for effect level:
other: cevelopmental toxicity
Reproductive effects observed:
not specified
Conclusions:
As a dose-range finding study for a planned extended one-generation reproduction toxicity study (OECD guideline 443) an oral repeated dose toxicity study and reproduction/developmental toxicity screening test with 2-Ethylhexanoic acid (based on OECD guideline 422) was performed. The objective of this study was to provide initial data on the possible effects of the test item on general toxicity, reproductive performance and development of pups after daily oral administration of various concentrations (0, 1538, 4615 and 15385 mg/kg diet) of the test item 2-Ethylhexanoic acid to male and female rats during a premating period of 2 weeks and during mating (1 week), gestation and lactation until postnatal day 4 to 7 (PN day 4 to 7).

The content, homogeneity and stability of the test item in the diets were confirmed by analysis.

No mortalities occurred and no treatment-related clinical signs were observed during the study. Functional observations and Motor Activity Assessment performed at the end of the study did not show effects that were considered to be related to treatment. Incidental effects were observed on body weight and food intake in the mid-dose group whereas during a major part of the study the body weight and food consumption of the male and female animals of the high-dose group were decreased (up to 10% decreased body weight in females at the end of gestation). The observed effects on body weights and food consumption in the high-dose group were considered to be related to treatment.

No effect was observed on fertility and reproductive performance of the male and female animals. No effects were observed on the incidences of liveborn and stillborn pups, viability indices of pups, sex-ratio’s and pup observations. The weight of the pups of the high-dose group was decreased on PN day 4 (14%) which was considered to be related to treatment.

Haematology conducted in 5 females/group on PN days 4-7 showed lower values for mean corpuscular volume (MCV), mean corpuscular haemoglobin concentration (MCH) and reticulocytes in the high-dose group compared to controls. Total white blood cells, monocytes and the absolute number of neutrophils were higher than in controls in females of the high-dose group. Haematology conducted in 5 males/group on day 30 did not reveal any treatment related changes in red- and white blood cell variables or

clotting potential. Clinical chemistry conducted in 5 females/group on PN days 4-7, showed lower total protein concentration and albumin concentration than in controls in females of the high-dose group while the albumin/globulin ratio was higher. Clinical chemistry conducted in 5 males/group on day 30 showed an increase in bile acids in high-dose males. Terminal body weights at necropsy were decreased in both males and females of the highdose group. The relative weight of the liver was increased in the high dose group in both sexes. The absolute and relative weights of the thymus were lower in high dose females than in controls. The relative weight of the kidney was increased in high-dose males. Macroscopic examination at necropsy did not reveal any treatment-related findings. Microscopic examination of 5 rats/sex in the control and high dose group, showed and increased incidence of proteinaceous droplets in the kidney renal tubuli of the males. The incidence of extramedullary hematopoiesis in the spleen was reduced in high-dose females.

Based on measurements of Palmitoyl-CoA oxidase, there was no evidence of peroxisome proliferation in livers of male and female parental animals.

In conclusion, there were no effects of the test item on fertility and reproductive performance at any dose level. Based on lower pup weights as observed in the high-dose group, the NOAEL for developmental toxicity was placed at the mid-dose concentration of 4615 mg test item per kg diet (corresponding to at least 248 mg/kg body weight/day for males and at least 308 mg/kg body weight/day for female animals). Based on the effects on body weights, food consumption, organ weights, haematology

and clinical chemistry, the NOAEL for parental effects was placed at the mid-dose concentration of 4615 mg test item per kg diet (corresponding to at least 248 mg/kg body weight/day for males and at least 308 mg/kg body weight/day for female animals).

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
2003

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes

Test material

1
Chemical structure
Reference substance name:
Fatty acids, C18-unsatd., dimers
EC Number:
500-148-0
EC Name:
Fatty acids, C18-unsatd., dimers
Cas Number:
61788-89-4
Molecular formula:
Not applicable, UVCB substance
IUPAC Name:
61788-89-4

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female

Administration / exposure

Route of administration:
oral: feed
Details on exposure:
Four groups of 10 male and 10 female Sprague-Dawley rats received distilled dimer via the diet at concentrations of 0, 200, 2000 and 20,000 ppm. The males were dosed for at least 4 weeks, starting from 2 weeks prior to mating while the females were dosed from 2 weeks prior to mating until at least Day 6 of lactation. The animals were monitored for clinical signs, body weight, food consumption, mating and litter performance.
Duration of treatment / exposure:
The males were dosed for at least 4 weeks, starting from 2 weeks prior to mating while the females were dosed from 2 weeks prior to mating until at least Day 6 of lactation.
Doses / concentrations
Remarks:
0, 200, 2000 and 20,000 ppm
No. of animals per sex per dose:
Four groups of 10 male and 10 female Sprague-Dawley rats
Control animals:
yes
Details on study design:
Four groups of 10 male and 10 female Sprague-Dawley rats received distilled dimer via the diet at concentrations of 0, 200, 2000 and 20,000 ppm. The males were dosed for at least 4 weeks, starting from 2 weeks prior to mating while the females were dosed from 2 weeks prior to mating until at least Day 6 of lactation. The animals were monitored for clinical signs, body weight, food consumption, mating and litter performance.

All animals were submitted for necropsy, which included weighing male reproductive organs. Histopathology was conducted on the epididymides and testes of all control and high dose males and on the ovaries of all control and high dose females.

Examinations

Parental animals: Observations and examinations:
The males were dosed for at least 4 weeks, starting from 2 weeks prior to mating while the females were dosed from 2 weeks prior to mating until at least Day 6 of lactation. The animals were monitored for clinical signs, body weight, food consumption, mating and litter performance.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed

Details on results (P0)

Paternal toxicity was exhibited at 20000 ppm as a slight decrease in weight gain and an increase in piloerection. There were no obvious maternal effects at this level.

There were no obvious parental effects at 200 or 2000 ppm, nor were there any effects of treatment on the reproductive parameters at any dose level applied. The testes and epididymides weights were essentially similar in all groups.

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
2 000 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: The animals were monitored for clinical signs, body weight, food consumption, mating and litter performance.

Results: P1 (second parental generation)

General toxicity (P1)

Clinical signs:
no effects observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed

Reproductive function / performance (P1)

Reproductive performance:
no effects observed

Effect levels (P1)

Dose descriptor:
NOAEL
Effect level:
20 000 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: The animals were monitored for clinical signs, body weight, food consumption, mating and litter performance.

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Body weight and weight changes:
no effects observed
Food efficiency:
no effects observed

Details on results (F1)

There were no obvious effects of treatment on litter size, litter survival, or pup weights at any dose level and no abnormalities noted among pups.
The mean number of implants per pregnancy was higher in all the treated groups compared to controls. However, historical data shows that the findings in the treated groups were within background ranges for animals of this age and strain. Rather, it was considered most likely that the control value was at the lower end of the background range.

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
20 000 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: There were no obvious effects of treatment on litter size, litter survival, or pup weights at any dose level and no abnormalities noted among pups.

Overall reproductive toxicity

Reproductive effects observed:
no
Lowest effective dose / conc.:
20 000 ppm

Any other information on results incl. tables

  Paternal toxicity was exhibited at 20000 ppm as a slight decrease in weight gain and an increase in piloerection. There were no obvious maternal effects at this level.

There were no obvious parental effects at 200 or 2000 ppm, nor were there any effects of treatment on the reproductive parameters at any dose level applied. The testes and epididymides weights were essentially similar in all groups.

The mean number of implants per pregnancy was higher in all the treated groups compared to controls. However, historical data shows that the findings in the treated groups were within background ranges for animals of this age and strain. Rather, it was considered most likely that the control value was at the lower end of the background range. There were no obvious effects of treatment on litter size, litter survival, or pup weights at any dose level and no abnormalities noted among pups.

Under the conditions of this study, the parental NOAEL was considered to be 2000 ppm (approximately 175 mg/kg/day) and for reproductive parameters the NOAEL was considered to be 20,000 ppm (approximately 1738 mg/kg/day).  

Applicant's summary and conclusion

Conclusions:
Under the conditions of this study, the parental NOAEL was considered to be 2000 ppm (approximately 175 mg/kg/day) and for reproductive parameters the NOAEL was considered to be 20,000 ppm (approximately 1738 mg/kg/day).