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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Remarks:
combined repeated dose and reproduction / developmental screening
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP compliant, OECD Guideline study performed without deviations

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2002
Report date:
2002

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
GLP compliance:
yes
Remarks:
US EPA GLP (40 CFR, Part 792) and OECD GLP
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder
Details on test material:
- Name of test material (as cited in study report): Dimethyl cyclohexyl bisphenol (DMBPC; CAS No. 2362-14-3)
- Synonyms: Dimethyl bisphenolcyclohexane; 4,4’-cyclohexylidene di-o-cresol; 1,1-Bis(4-hydroxy-3-ethyl)cyclohexane; Bis-OC-Z
- Appearance: fine white powder

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
Sixty virgin male and 50 virgin female Crl:CD®(SD) rats were received from the supplier on May 14, 2001. Males and females came from separate rooms at the breeding facility to avoid sibling mating. The animals were approximately 63 days old upon receipt and 10-11 weeks old at initiation of test article administration. The range of F0 male body weights at the start of the prebreed exposure period was 315.0 to 361.7 g. The range for F0 females was 213.2 to 248.5 g. During the one-week acclimation the animals were examined by a veterinarian, weighed, and representative animals were subjected to faecal examination and serum viral antibody analysis. In addition, one rat per sex was selected as a sentinel which remained in the study room under the identical conditions of the study animals and was sacrificed and subjected to faecal examination and serum viral antibody analysis and the end of the study. All evaluations were negative and the animals assigned to study were deemed healthy and appropriate for use.

Each rat was uniquely identified by an eartag displaying the animal number. Following receipt, all F0 parental test animals were housed individually, except during the mating period when they were house two per cage, in clean, solid-bottom polycarbonate cages with stainless-steel wire lids. All animals were housed throughout the acclimation period and during the study in an environmentally controlled room. The animal room was on a 12-hour light cycle with a temperature range of 68.0 to 73.6 °F and a relative humidity range of 45.8 to 66.6 % throughout the study. Certified rodent chow and city tap water were available ad libitum.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: 0.5 % aqueous methyl cellulose (CAS No. 9004-67-5; 4000 centipoises, Fisher Scientific)
Details on oral exposure:
DMBPC was weighed into colour-coded glass beakers for each concentration. The formulations were not corrected for the purity of the test substance. Approximately 400 mL of vehicle was added to 2-litre calibrated beakers to a 1-litre mark. With the vehicle in the 2-litre beakers being stirred on magnetic stir plates, DMBPC was slowly added and the suspensions were stirred for at least 15 minutes. Additional vehicle was added to the calibration line. All test article formulations were then sonicated for 30 minutes, then stirred at least 5 minutes, allowed to rest for 2.5 hours, then stirred for an additional time (30 minutes to 2.5 hours), depending on the formulation, prior to analytical and archival sampling.

Prior to and during the study, dose formulations encompassing the range of dose concentrations employed in the study (2 and 200 mg/mL) were found to be homogeneous, stable for four hours under room temperature (to simulate daily dosing periods), and stable for at least 32 days in amber bottles under refrigerated conditions (approximately 4 °C). Based on these stability results, formulations were used within the stability limits established and were stored under refrigeration. Dose formulations were originally analysed as 91.3 - 110 % of nominal concentrations, although an error was subsequently detected after the formulations were presented to the animals, which indicated that the top dose formulated on June 28, 2001, was not 91.3 % of nominal but 86.7 % of nominal. The use of this formulation was unavoidable and had no effect on the study. No DMBPC was detected in the vehicle control formulations, with an estimated limit of detection of 0.4 mg/mL.

Male and female CD (Sprague-Dawley) rats (the F0 generation) were administered DMBPC (CAS No. 2362-14-3) orally by gavage at 0, 50, 200, or 1000 mg/kg/day at a dose volume of 5 mL/kg/day.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples from each dose formulation prepared for use on study were analysed by single injection using high performance liquid chromatography (HPLC) with a Model 680 Automated Gradient Controller (Waters Corporation), a Model 510 pump and a Model 710B WISP autosampler. The column was a Zorbax SB-C18 4.6 x 50 mm; 3.5 µm (Agilent), and the guard column was a Zorbax SB-C18 (Agilent) 4.6 x 12.5mm; 5 µm. The detector was a Model 757 absorbance detector (Applied Biosystems). The regression equation for the vehicle standard data was calculated, and the data were plotted for a visual evaluation of linearity. The concentration of DMBPC was calculated in the dose formulation samples (mg/mL) from the peak area ratio for each sample and the linear regression equation.

Standards for acceptable accuracy of formulations were the mean of the analysed samples was within ± 10 % of nominal, and the % RSD (Relative Standard Deviation) for triplicate samples did not exceed 10 %. If one or more of these standards were not met, the dosing formulations were not administered to the animals until the problem was resolved by analysis of the archived sample of the dosing formulations and/or after reformulation and reanalysis. All dose formulations used in the study had analytical values of 91.4 to 110 % of target concentrations with one dose of 86.7 %. Vehicle control formulations contained no DMBPC, with an estimated detection limit of 0.4 mg/mL.

Prior to and during the performance of this study, aliquots of doses, encompassing the range of concentrations that were to be used in the study (2 and 200 mg/mL), were used to assess stability of the dose suspensions. Triplicate one-mL aliquots were collected from the top, middle, and bottom of the prepared concentrations and analysed for homogeneity by HPLC.

For stability studies, the doses mixed for the low and high homogeneity study were removed from the refrigerator on the day of sampling (3, 9-10, 21, and 32 days) and brought to ambient conditions. The formulations were stirred for two hours prior to sampling. Triplicate 1-g aliquots were removed and analysed by high performance liquid chromatography. Dose formulations at 2 and 200 mg/mL were stable for 32 days when stored in the refrigerator.
Duration of treatment / exposure:
Males: Two weeks prior to mating and during the two week mating period (for a total of 28 doses)
Females: Two weeks prior to mating, during the two week mating period, through three weeks of gestation and through lactation day 3 (the day prior to necropsy)
Frequency of treatment:
once daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 50, 200, and 1000 mg/kg/day
Basis:
other: nominal (gavage dose)
No. of animals per sex per dose:
10/sex/group; 5 additional males in the control and high concentration (recovery)
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The doses were chosen based on a range-finding study, employing doses of 0, 50, 200, and 1000 mg/kg/day, administered by oral gavage at 5 mL/kg for 14 days.

- Details on study schedule: Males received a total of 14 or 15 doses prior to mating (one dose per day). Males were dosed throughout the mating period through the day prior to euthanasia for a total of 28 doses. Females received 14 doses prior to pairing (one dose per day) and were dosed through lactation day 3 (the day prior to necropsy). After the two-week prebreed exposure period, animals were randomly mated within treatment groups for a two-week mating period to produce the F1 generation, with exposure continuing. Five additional males per group in the control and high dose (1000 mg/kg/day) groups were retained as recovery animals for two weeks after the end of the dosing period to evaluate recovery from any possible treatment-related effects identified in the high dose group.
Positive control:
none

Examinations

Observations and examinations performed and frequency:
Parental animals: Observations and examinations: Observations for mortality were made twice daily (a.m. and p.m.), and the general condition of all animals was checked daily. Clinical examinations were conducted and recorded daily throughout the course of the study. This record included the time of onset and degree and duration of symptoms. These cage-side observations included, but were not limited to, changes in skin and fur, eyes, mucous membranes, respiratory and circulatory system, autonomic and central nervous system, somatomotor activity, and behaviour pattern.

The body weights of the F0 male rats were determined and recorded initially and weekly through mating. The body weights of F0 female rats were recorded in the same manner until confirmation of mating. During gestation, F0 females were weighed on gestational day (GD) 0, 7, 14, and 20. Dams producing litters were weighed on PND 0 and 4, and body weight gains were computed.

Feed consumption measurements were recorded weekly for all F0 parental study animals during the prebreed treatment period. During pregnancy of F0 females, feed consumption was recorded for GD 0-7, 7-14, and 14-20. During lactation of the F1 litters, maternal feed consumption was measured for PND 0-4. Feed consumption was not measured during the cohabitation period, since two adult animals (breeding pair) were in the same cage. Feed consumption collection periods corresponded to the collection of the animals' body weight data.

A Functional Observational Battery (FOB), including home cage observations, handling observations, and open field observations, was performed on all animals at least once per week during prebreed, mating (both sexes), gestation and lactation (females) treatment periods.
Five F0 males and five females per dose group were evaluated for auditory function, motor activity, and assessment of grip strength prior to necropsy.
In addition, haematology, clinical biochemistry, and urinalysis (males only) assays were performed at necropsy for five randomly selected parental F0 males and females per dose group.
- Haematology Parameters Examined: Red blood cell (nucleated RBC), Red cell distribution width, RBC Morphology, Mean platelet volume, White blood cell (Total/differential), Mean corpuscular volume, Mean corpuscular haemoglobin, Platelet counts, Mean corpuscular haemoglobin concentration , Haemoglobin concentration and Haematocrit.
- Clinical Chemistry Parameters Examined: Albumin, Creatinine, Aspartate aminotransferase, Glucose, Alanine aminotransferase, Total protein and sodium, Urea nitrogen, Potassium, Total cholesterol and Chloride.


Litter observations: Beginning on GD 20, each female was observed twice daily (a.m. and p.m.) for evidence of littering. On the day of birth (PND 0), anogenital distance was measured and body weight recorded for all live F1 pups in all litters. Body weight was recorded for all live pups on PND 4 prior to euthanasia. Any female which did not show evidence of successful mating after 14 days of cohabitation was weighed weekly, and treatment continued until GD 26 or delivery occurred. If a female without a confirmed GD 0 date was, in fact, pregnant and delivered a litter, her lactational information was collected as described below.

All F1 pups were sexed and examined as soon as possible after birth (PND 0) to determine the number of viable and stillborn from each litter. Thereafter, litters were evaluated for survival through PND 4. Individual anogenital distance and body weight were recorded on PND 0 for all F1 offspring. All live pups were counted, sexed, weighed individually, and examined grossly at birth and on PND 4. The body weights and sexes were recorded on an individual basis, but the pups were not uniquely identified. All pups were examined for physical abnormalities at birth and on PND 4. All pups dying during the early lactation period were necropsied, when possible, to investigate the cause of death.
Sacrifice and pathology:
Postmortem examinations (Parental animals): A complete necropsy was conducted on all F0 animals, including recovery males, at termination following euthanasia by carbon dioxide inhalation. The necropsy included examination of the external surface, all orifices, the cranial cavity, the external surfaces of the brain and spinal cord, and the thoracic, abdominal and pelvic cavities, including viscera. The number of nidation scars and corpora lutea were recorded for all F0 females. The fixed (buffered neutral 10 % formalin) uteri from any females of the F0 generation failing to produce a litter were stained with potassium ferricyanide for confirmation of pregnancy. This staining procedure did not interfere with subsequent histopathologic evaluation. The ovaries, uterus (with cervix and vagina), prostate, epididymides, testes and seminal vesicles (with coagulating glands and their fluids) were weighed and retained for all F0 animals. The liver, heart, kidneys, adrenals, brain, spleen and thymus were weighed and retained from 5 selected male and female animals/group. In addition, the spinal cord, thyroid, stomach, urinary bladder, sciatic nerve, femur, small and large intestines (including Peyer’s patches), trachea and lungs, lymph nodes and all gross lesions were retained from 5 F0 adult males and females/group including all recovery males. Full histopathology of the retained organs was performed on five high dose and control F0 animals.

Postmortem examinations (Offspring): All F1 pups were examined externally for gross abnormalities, euthanised on PND 4 and examined viscerally.
Other examinations:
Reproductive indices: The following reproductive indices were calculated: Male Mating Index (%); Male Fertility Index (%); Male Pregnancy Index (%); Female Mating Index (%); Female Fertility Index (%): and Female Gestational Index (%).
 
Offspring viability indices: The following litter parameters were calculated: Live birth index (%); Day 4 Survival Index (%, survival between PND 0 and 4); and Mean Live Litter Size.
Statistics:
The unit of comparison was the male, the female, the pregnant female, or the litter, as appropriate. Treatment groups were compared to the concurrent control group using either parametric ANOVA under the standard assumptions or robust regression method. The homogeneity of variance assumption was examined via Levene's Test. If Levene's Test indicated lack of homogeneity of variance (p<0.05), robust regression methods were used to test all treatment effects. The presence of linear trends was analysed by GLM procedures for homogenous data or by robust regression methods for nonhomogenous data. If Levene's Test did not reject the hypothesis of homogeneous variances, standard ANOVA techniques were applied for comparing the treatment groups. The GLM procedure in SAS 6.12 was used to evaluate the overall effect of treatment and when a significant treatment effect was present, to compare each exposed group to control via Dunnett's Test. For the litter-derived percentage data (e.g., PND 0-4 pup survival indices), the ANOVA was weighted according to litter size. A one-tailed test (i.e., Dunnett's Test) was used for all pairwise comparisons to the vehicle control group, except that a two-tailed test was used for parental and pup body weights, parental organ weight parameters and feed consumption, percent F1 males per litter, and F1 anogenital distance. For any endpoints which involved only two groups (e.g., for F0 recovery males, etc.), Student’s t-test was used for the two-group comparisons.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
- but determined to be incidental and not treatment related
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
- paired testes weight, relative to terminal body weight, was significantly increased at 1000 mg/kg/day
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
There were no treatment-related histopathologic findings.
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
There were no treatment-related histopathologic findings.
Details on results:
Mortality: No parental animals died during the test.

Body weight and weight gain: At 1000 mg/kg/day, F0 male body weights were significantly reduced on study day (SD) 14 and 21 and male body weight changes were significantly reduced for SD 7 to 14 and SD 0 to 28. Absolute body weights for recovery males at 1000 mg/kg/day remained lower throughout the two week recovery period; however, body weight gain was comparable to the recovery control males. F0 female body weight for SD 14 and body weight changes for SD 0-14 were significantly reduced at 1000 mg/kg/day. F0 maternal body weights during gestation were significantly reduced at 200 and 1000 mg/kg/day for gestation day (GD) 7 and 14, whereas body weight change showed no effect of treatment among groups. During lactation, F0 maternal body weights were significantly reduced on post natal day (PND) 0 and 4 at 1000 mg/kg/day. Maternal body weight change was not affected during lactation.

Food consumption: Feed consumption expressed as g/day was significantly reduced for the F0 females at 200 and 1000 mg/kg/day for SD 0-7. When expressed as g/kg/day, feed consumption was significantly reduced at 200 mg/kg/day for SD 0-7. During gestation, maternal feed consumption was significantly reduced when expressed as g/day for GD 0-7 and GD 7-14 at 1000 mg/kg/day.

Organ weights: At necropsy, paired testes weight, relative to terminal body weight, was significantly increased at 1000 mg/kg/day; however, organ weights, relative to terminal brain weights, were unaffected across groups.

Clinical chemistry: The F0 males’ sodium level was significantly lower at 200 mg/kg/day, and chloride was significantly higher at 200 and 1000 mg/kg/day. Clinical chemistry values for F0 females were unaffected, except alanine aminotransferase was significantly increased at 1000 mg/kg/day.

Haematology: Haemoglobin was significantly reduced at 50, 200, and 1000 mg/kg/day, the haematocrit was reduced at 50 and 200 (but not 1000) mg/kg/day, and there was a reduced red blood cell count at 50 (but not 200 or 1000) mg/kg/day. Red blood cell distribution width (a measure of variation in red blood cell size) was significantly increased at 50, 200, and 1000 mg/kg/day, but there was no change in mean corpuscular volume (the size of the red blood cell) at any dose, and there was no evidence of extramedullary haematopoiesis in the livers or spleens (expected if there were decreases in circulating erythrocytes) of females (or males) at 1000 mg/kg/day. Due to the lack of dose-related, meaningful, or consistent findings in the haematologic assessments in either sex, the observed changes in these parameters are considered incidental, due to biologic variation, and not treatment related.

There was no evidence of F1 offspring toxicity at any dose, either pre- or postnatally, with no effects on offspring survival, anogenital distance, sex ratio (% males) per litter, or body weights per litter. The one exception is reduced body weight per litter at 1000 mg/kg/day on PND 4 for males only, with no effects on body weights per litter of females or all pups combined.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Remarks:
for F0 generation
Effect level:
200 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Reduced body weight (males and females) and food consumption at (females only) 1000 mg/kg/day
Dose descriptor:
NOAEL
Remarks:
for F1 generation
Effect level:
>= 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects at the maximum dose tested
Dose descriptor:
NOAEL
Remarks:
for risk assessments
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Body weight and body weight gain reductions lower than 10 %

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Table 1: Body Weights/Body Weight Changes - Males (g)

Dose (mg/kg/day)

0

50

200

1000

Body Weights

Day 14

  Mean

419.2

411.2

401.9

393.7**

  S.D.

6.1

6.6

5.1

5.0

  N

10

10

10

10

Day 21

  Mean

439.2

431.0

417.7

412.6*

  S.D.

6.8

8.6

5.6

5.8

  N

10

10

10

10

Body Weight Changes

Days 7 to 14

  Mean

36.2

31.1

28.2

20.6**

  S.D.

2.5

2.7

1.8

4.4

  N

10

10

10

10

Days 0 to 28

  Mean

125.9

117.1

104.1

97.4*

  S.D.

6.1

9.6

5.2

4.8

  N

10

10

10

10

* Significantly different from the control group at 0.05 using Dunnett’s test

** Significantly different from the control group at 0.01 using Dunnett’s test 

Table 2: Body Weights and Body Weight Changes – Females (g)

Dose (mg/kg/day)

0

50

200

1000

Body Weights (Prebreed)

Day 14

  Mean

257.4

257.8

247.3

239.4*

  S.D.

4.1

6.4

4.8

4.4

  N

10

10

10

10

Body Weight Changes (prebreed)

Days 0-14

  Mean

25.4

23.5

16.4

10.1*

  S.D.

2.1

5.0

3.1

4.0

  N

10

10

10

10

Body Weights (Gestation)

GD 7

  Mean

297.4

297.2

275.0*

273.7*

  S.D.

3.1

7.6

7.1

5.0

  N

10

9

7

10

GD 14

  Mean

333.4

334.6

307.3*

307.1*

  S.D.

3.5

8.8

9.9

4.4

  N

10

9

7

10

Body Weights (Lactation)

Lactation day 0

  Mean

320.3

317.3

297.9

297.1*

  S.D.

5.5

5.8

8.8

5.9

  N

10

9

7

10

Lactation day 4

  Mean

334.5

339.5

316.3

309.1*

  S.D.

4.9

9.0

9.5

5.8

  N

10

9

7

10

* Significantly different from the control group at 0.05 using Dunnett’s test

Table 3: Food Consumption – Females

Group (mg/kg/day)

0

50

200

1000

Prebreed

Days 0-7

  Mean

21.1

21.4

18.9*

19.1*

  S.D.

0.5

0.4

0.7

0.6

  N

10

10

10

10

Gestation

GD 0 to 7

  Mean

23.6

25.7

21.4

21.0*

  S.D.

0.6

0.7

1.1

0.7

  N

10

9

7

10

GD 7 to 14

  Mean

25.3

27.5

23.8

21.9*

  S.D.

0.7

1.0

1.2

0.8

  N

10

9

7

10

* Significantly different from the control group at 0.05 using Dunnett’s test

** Significantly different from the control group at 0.01 using Dunnett’s test

Applicant's summary and conclusion

Conclusions:
Under the conditions of this study, the NOAEL for systemic parental toxicity was 200 mg/kg/day; for reproductive and offspring toxicity, the NOAEL was at least 1000 mg/kg/day.
Executive summary:

The toxicity of the test material was assessed in a combined repeated dose and reproduction / developmental screening study conducted in accordance with the standardised guideline OECD 422 under GLP conditions.

Male and female CD (Sprague-Dawley) rats (the F0 generation) were administered DMBPC orally by gavage at 0, 50, 200, or 1000 mg/kg/day at a dose volume of 5 mL/kg/day in 0.5 % aqueous methyl cellulose.

Ten/animals/sex/dose were treated for two weeks pre-breeding (males and females), two weeks of mating (males and females), and three weeks of gestation and lactation each (females). Five additional males per group from the control and 1000 mg/kg/day groups were designated as recovery animals and held without dosing for two weeks after the male dosing period was completed, to evaluate recovery from any possible treatment-related effects identified in the high dose group.

Body weights and feed consumption were recorded at least weekly during the pre-breed period for both sexes and for females during gestation and lactation; clinical signs were recorded at least once daily. A Functional Observational Battery (FOB) was performed on all animals at least once per week during pre-breed, mating (both sexes), gestation, and lactation (females) treatment periods. Five F0 males and five females per dose group were evaluated for auditory function, motor activity, and assessment of grip strength prior to necropsy. F0 males were necropsied after the mating period with complete histologic evaluation of five males in the 0 and 1000 mg/kg/day groups. On the day of birth, F0 females were necropsied with complete histologic evaluation of five females in the 0 and 1000 mg/kg/day groups. In addition, haematology, clinical biochemistry, and urinalysis (males only) assays were performed at necropsy for five randomly selected parental F0 males and females per dose group.

No parental animals died during the test. No test substance-related clinical observations were noted throughout the study. In F0 males, a statistically significant decrease in body weight was found at the highest dose on study day 14 (p<0.01) and study day 21 (p<0.05); however, there was not a statistically significant difference in body weight between the controls and the high dose on study day 28. Similarly while the body weight change in F0 males was statistically significant between the control and 1000 mg/kg bw/d dose group from day 7 to day 14 and from day 0 to day 28, there was not a statistically significant difference from day 0 to 7, 14 to 21, or from day 21 to 28. In addition, no statistically significant effects in body weight or body weight change were observed between controls and 1000 mg/kg bw/d dose groups used for recovery animals at any point of the study. Alterations in haematology parameters were observed during the study, but due to the lack of dose-related, meaningful, or consistent findings in the haematologic assessments in either sex, the observed changes in these parameters were considered incidental, due to biologic variation, and not treatment related. There were no significant alterations in clinical chemistry parameters. At necropsy, paired testes weight, relative to terminal body weight, was significantly increased at 1000 mg/kg bw/d in parental males; however, organ weights, relative to terminal brain weights, were unaffected across parental groups. All other absolute organ weights and organ weights relative to terminal body weight were not affected by treatment. There were no treatment-related gross or histopathological findings in parental animals and no neurobehavioral alterations or significant effects on reproductive success at any dose.

There was no evidence of F1 offspring toxicity at any dose.

Under the conditions of this study, the no observed adverse effect level (NOAEL) for systemic parental toxicity was 200 mg/kg/day; for reproductive and offspring toxicity, the NOAEL was at least 1000 mg/kg/day.