4-(α,α-dimethylbenzyl)phenol

Repeated dose toxicity: oral

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

Study period:

2002-07-12 to 2005-03-21

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP study conducted according to OECD Test Guideline 422.

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

reference to same study

Cross-reference 2

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2005

Report date:

2005

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:

yes

Remarks:

the study exceeds the guideline by following the F1 offspring to adulthood and includes assessment of neurologic function.

Principles of method if other than guideline:

N/A

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

4-(α,α-dimethylbenzyl)phenol

EC Number:

209-968-0

EC Name:

4-(α,α-dimethylbenzyl)phenol

Cas Number:

599-64-4

Molecular formula:

C15H16O

IUPAC Name:

4-(2-phenylpropan-2-yl)phenol

Details on test material:

- Name of test material (as cited in study report): p-cumylphenol
- Substance type: active
- Physical state: white crystals
- Analytical purity: 99.9 %
- Storage condition of test material: Ambient (cool, dry)

Test animals

Species:

rat

Strain:

other: CD® (Sprague-Dawley) rats (Crl:CD[SD] IGS BR

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories, Raleigh, NC
- Age at study initiation: P generation - approximately 10 weeks; F1 generation - Treatment began on postnatal day 22, the day after weaning.
- Weight at study initiation: (P) Males: 270.9-355.4 g; Females: 215.7-248.5 g
- Housing: The animals were individually housed upon arrival, during the acclimation period and upon the initiation of the treatment period in solid-bottom polycarbonate cages (8”x19”x10.5” high) with stainless-steel wire lids, with Sani-Chip cage litter. Study animals were housed 2/cage (1 male:1 female from the same dose level) during the mating period. Females were caged individually once they were successfully mated (or at the end of the mating period) and throughout gestation. Females were housed with their litters throughout the lactation period. Selected F1 weanlings, males, and females were singly housed during the post weaning exposure period.
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: approximately 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22+/-3
- Humidity (%):30-70 (3 relative humidity deviations occurred outside this range during the conduct of the study, but they were very brief, minor, rare and did not affect the design, performance or conclusions of the study)
- Photoperiod (hrs dark / hrs light):12/12

IN-LIFE DATES: From: 2002-07-08 (date of arrival), 2002-07-15 (date of first treatment) To: 2002-11-15

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS: The purity of the test substance was assumed to be 100% for dose formulation purposes (i.e., all measurements of the test substance were made by weight and not corrected for purity). Dosing formulations were prepared by suspending the test substance in corn oil. Dose formulations were stirred for at least 30 minutes prior to use.


VEHICLE
- Amount of vehicle (if gavage): 5 ml/kg/day

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Prior to dosing, studies of homogeneity and storage stability under refrigeration and at ambient temperatures of the test substance in corn oil at 1.0 and 60.0 mg/ml were conducted. In addition, stability tests under conditions simulating dosing in the animal room(s) were conducted.
Dose formulations were prepared and concentration verifications were performed monthly. All dose formulations used in the study had analytical values of 95.3 to 110% of target concentrations. Vehicle control formulations contained no test substance, with a detection limit of 0.03 mg/ml. The storage stability studies showed the test substance to be stable at least for 32 days when stored in amber bottles either at ambient temperature or in a refrigerator. The simulated dosing stability studies showed formulation of the test substance to be stable under conditions that simulated dosing (in corn oil in a beaker open to light and air at ambient temperature) for 4 hours in dose formations prepared at 1.0 and 60.0 mg/g.

Duration of treatment / exposure:

Dosing for the parental animals began on study day 0 and continued until the day before scheduled necropsy [at least 4-week duration for males (2 week prebreed and 2 week mating period) and 8 to 10 week duration for females (2 week prebreed through mating, gestation and lactation)]. For the P generation recovery males, dosing began on study day 0 and continued until the end of the dosing period of the P generation males (at least 4 weeks). The recovery males were then held with no dosing for 2 weeks to evaluate recovery. F1 selected pups were treated directly for at least 7 weeks (from weaning (post natal day 22) to scheduled sacrifice).

Frequency of treatment:

once daily

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 5, 50, and 300 mg/kg/day
Basis:

No. of animals per sex per dose:

10 per sex per group were designated as parental animals and 5 additional males in the control and high-dose groups were designated as recovery males.

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Target doses were selected based on the results of a 10-day range-finding study.
- Rationale for selecting satellite groups: random
- Post-exposure recovery period in satellite groups: 14 days

Positive control:

N/A

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily for mortality and once daily for general condition
- Observations included, but were not limited to, change in skin and fur, eyes, mucous membranes, respiratory and circulatory systems, autonomic and central nervous systems, somatomotor activity and behaviour pattern.

BODY WEIGHT: Yes
- Time schedule for examinations: body weights for males were determined and recorded initially and then weekly until termination. The body weights of females were recorded in the same manner until confirmation of mating. During gestation, females were weighed on gestation days 0, 7, 14 and 20. Dams producing litters were weighed on lactation days 0, 4, 7, 14 and 21; body weight gains were computed.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal was determined weekly during the prebreed treatment period. During pregnancy of females, feed consumption was recorded on gd 0-7, 7-14 and 14-20. During lactation of the litters, maternal feed consumption was measured on lactation days 0-4, 4-7, 7-14 and 14-21, although maternal feed consumption after day 14 was confounded by the contribution from the pups since the pups were self-feeding by this time. Feed consumption was not measured during the cohabitation period since 2 adult animals were in the same cage.


HAEMATOLOGY: Yes
Hematology parameters were evaluated during the study from randomly selected males and females (5/sex/group). Prior to mating, blood was collected from the tail vein of 5 selected females per group for hematology evaluation. In addition, blood was collected via cardiac puncture at necropsy from randomly selected rats (5 males fasted overnight) for hematology evaluation. The hematology parameters measured included: red blood cell count; total, corrected and differential leukocyte counts; platelet count; hemoglobin concentration; hematocrit; red cell distribution width; mean platelet volume; mean corpuscular volume; mean corpuscular hemoglobin; mean corpuscular hemoglobin concentration; and prothrombin time. Blood smears were prepared for microscopic differentiation of white blood cells and assessment of red blood cell morphology.

CLINICAL CHEMISTRY: Yes
Clinical chemistry parameters were evaluated during the study from randomly selected males and females (5/sex/group). Blood was collected via cardiac puncture at necropsy from randomly selected rats (5 males and 5 females per group, fasted overnight) for clinical biochemistry evaluation. Clinical chemistry assays for albumin, aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, total cholesterol, creatinine, glucose, total protein, and for the electrolytes sodium, potassium, and chloride were performed.

URINALYSIS: Yes
At the end of the mating period, 5 randomly selected males per group were housed in metabolism cages overnight and the urine was collected. The urine samples were observed visually for color, appearance and total volume. The presence of glucose, bilirubin, ketones, specific gravity, blood, pH, protein, urobilinogen, nitrite and leukocytes in urine were evaluated.

NEUROBEHAVIOURAL EXAMINATION: Yes
A Functional Observational Battery (FOB), including home cage observations, handling observations, open field observations, sensory and neuromuscular observations, and physiological observations, was performed on all animals once before exposure and at least once per week during prebreed, mating (both sexes), gestation and lactation (females). Five males and five females per dose group were evaluated for auditory function, motor activity and assessment of grip strength prior to necropsy.

Sacrifice and pathology:

All parental animals (including recovery animals) in all groups were subjected to a complete gross necropsy, where selected organs were weighed and/or retained in fixative for possible subsequent histopathologic evaluation. Uterine nidation scars were also recorded for the females. The organs weighed and retained from all animals were: epididymides (pair), ovaries (pair), prostate, seminal vesicles with coagulating glands and the fluids (pair), testes (pair), uterus with cervix and vagina. In addition, the following organs were weighed and saved from 5 randomly selected males and females per group: adrenal (pair), brain (including cerebrum, cerebellum and pons) heart, kidneys (pair), liver, spleen, thymus. In addition to the organs listed above, the organs listed below were also saved from the same randomly selected animals: all gross lesions, bone marrow (femur), lymph nodes (1 cervical near route of administration, and 1 mesenteric distant from the route of administration), peripheral nerve (sciatic nerve), small and large intestines (including Peyer’s patches), spinal cord, stomach, thyroid, trachea and lungs (preserved by inflation with fixative and them immersion fixed), urinary bladder.

Full histopathology of the organs listed above was performed for the selected high dose and control males and females (with special emphasis on stages of spermatogenesis in the male gonads and histopathology of interstitial testicular cell structure). In addition, based on histopathology findings in the kidneys from the high dose males, histopathology was performed on the kidneys from the low and mid dose males (5/group), as well as the control and high dose recovery males (5/group).

The fixed uteri from any females failing to produce a litter were stained for confirmation of pregnancy. This staining procedure did not interfere with subsequent histopathologic evaluation.

Organ weights were reported as absolute and relative to terminal body weight and brain weight.

Other examinations:

N/A

Statistics:

See below.

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

effects observed, treatment-related

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

no effects observed

Details on results:

PARENTAL OBSERVATIONS:
CLINICAL SIGNS AND MORTALITY: No males (including recovery) or females died on study. Treatment related clinical observations included: rooting in the bedding post dosing which occurred in 3, 3, and 10 males at 0, 50, and 300 mg/kg/day, respectively: and 1 male in the control group, and 6 males in the high dose group exhibited salivation predosing.
Clinical signs in the recovery males included rooting postdosing in all males at 300 mg/kg/day and efflux of the dosing formulation, and/or salivating prior to and/or postdosing in 1 male each at 300 mg/kg/day during the dosing period. No other treatment related signs were recorded during the dosing or recovery periods.
Clinical signs related to treatment in the females included rooting in the bedding postdosing in 3 of 10 females at 50 mg/kg/day and 9 of 10 females at 300 mg/kg/day. Salivation predosing and/or postdosing occurred in 4/10 females at 300 mg/kg/day.
Clinical observation of females during gestation included rooting in the bedding postdosing that occurred in 2, 1, 5 and 8 females at 0, 5, 50 and 300 mg/kg/day, respectively. Salivation prior to dosing occurred in 1 female at 50 mg/kg/day and 4 females at 300 mg/kg/day. No other clinical signs were considered to be related to treatment.
Maternal clinical observations during lactation included rooting in the bedding postdosing (6 females) and salivation prior to dosing (4 females) at 300 mg/kg/day.

BODY WEIGHT AND WEIGHT GAIN: There were no statistically significant differences among groups for male body weight. However, body weight changes for sd 0-7, 14-21, and 0-28 were significantly decreased at 300 mg/kg/day. Body weight change was also significantly reduced at 50 mg/kg/day but only for sd 14-21. At scheduled sacrifice mean body weights showed a dose related decreasing trend, but no pairwise comparisons were statistically significant.
High dose recovery males exhibited significantly reduced body weight during the 4-week treatment period (sd 7, 14, 21 and 28) and during the 2-week recovery period (sd 35 and 42). Body weight gain was significantly reduced in the high dose recovery males for sd 0-7, 7-14 and 0-28 during the 28-day dosing period, and was unaffected during the 2-week recovery period. Sacrifice weight was significantly reduced in the high dose group compared to the control value.
There was a significant reduction in female body weight on sd 14 at 50 mg/kg/day and significantly reduced body weight changes at 50 and 300 mg/kg/day for sd 0-7 and for the premating period (sd 0-14). None of these changes showed a dose response, however. In addition, body weight was significantly decreased at the time of FOB measurement at 50 and 300 mg/kg/day in weeks 3, 4 and 5 (although again without a dose response), and at 300 mg/kg/day in week 6.
There was a significant decrease in the maternal body weight on gd 7 and 20 (but not on gd 14) at 300 mg/kg/day. Significant decrease in body weight change occurred at 300 mg/kg/day for gd 14-20.
There were no significant differences in maternal lactation body weights at 0, 5, 50 or 300 mg/kg/day.
At scheduled sacrifice mean body weights of the females were equivalent across all groups.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): In males, there were no significant effects on feed consumption expressed as g/day. However, there was a significant reduction in male food consumption expressed in g/kg/day for sd 0-7 at 300 mg/kg/day.
In females, feed consumption, expressed as g/day for the first week of prebreed and for the entire prebreed period (sd 0-14), was significantly decreased at 300 mg/kg/day. When feed consumption was expressed as g/kg/day, there were significant reductions at 50 and 300 mg/kg/day for sd 0-7 and a significant reduction at 300 mg/kg/day for sd 0-14. There were no significant effects on feed consumption (expressed as g/day or g/kg/day) in any group during the second week of the prebreeding period (sd 7-14).
There were no treatment related effects across groups for maternal feed consumption when expressed as g/day or g/kg/day of gd 0-7, 7-14, 14-20 or 0-20.
Maternal lactational feed consumption (g/day and g/kg/day) was unaffected at 0, 5, 50 and 300 mg/kg/day for pnd 0, 4, 7, 14 and 21.

HAEMATOLOGY: Hematology performed prior to mating in the females indicated that red blood cell distribution width and percent of segmented neutrophils were significantly reduced at 300 mg/kg/day. These were not considered related to treatment because of the lack of effects in associated blood parameters. All other hematology and prothrombin time values in females were unaffected across all dose groups.
No effects were observed in males prior to sacrifice.

CLINICAL CHEMISTRY: No effects were observed in males or females prior to sacrifice.

URINALYSIS: No effects were observed in males prior to sacrifice.

NEUROBEHAVIOUR: FOB was performed once during quarantine for all animals as a base line. There were no significant differences for home-cage observations, handling observations, sensory and neuromuscular observations, or open field observations in males or females assigned to any dose group.
There were no treatment-related changes in any of the FOB tests conducted weekly through prebreeding and breeding in the males. Statistically significant differences were not dose related, showed no pattern consistent with a toxic effect, and were not considered treatment related. There was no effects of treatment on motor activity, auditory startle, or grip strength which were performed in week 4.
There was no effect of treatment on FOB in the females during the prebreed period or during weeks 3 and 4 (2-week mating period). Average hindlimb grip strength was significantly reduced at 300 mg/kg/day for weeks 5, 7 and 8. No other statistically significant differences were considered to be related to treatment based upon a lack of correlation with other observations/measurements, lack of dose response, consistency across measurement period, and/or inconsistency with toxicologically relevant effects.
Five females per group that littered were selected for auditory startle, motor activity, and grip strength testing during the last week of lactation (pnd 14-21). No effect of treatment was seen on average force of jump or average duration of jump on any blocks tested during auditory startle. No effects were seen for motor activity or for average forelimb or hindlimb grip strength.

ORGAN WEIGHTS: In the males, absolute paired kidney weights and kidney weights, relative to body and brain weights, were significantly increased at 300 mg/kg/day. Relative (to body weight) paired testes weight at 50 and 300 mg/kg/day, paired epididymis weight at 300 mg/kg/day and prostate weight at 50 mg/kg/day were significantly increased. These differences were considered to be related to the slightly reduced body weights because there was no effect on the absolute weights. There were no other differences in absolute or relative organ weights that were considered treatment related.
In the recovery males, there were no differences found for absolute organ weights between the control and high dose animals. Brain and paired testes weights, relative to terminal body weight, were significantly increased at 300 mg/kg/day (most likely due to reduced body weights at this dose). Liver weight, relative to terminal brain weight, was significantly decreased at 300 mg/kg/day, but this was not considered to be a result of the earlier treatment because the liver weights were not affected following the dosing period.
In the females, absolute spleen weight, as well as spleen weight relative to terminal body weight and brain weight, was significantly decreased at 50 and 300 mg/kg/day. Absolute (but not relative to body or brain weight) paired kidney weights were significantly decreased at 50 and 300 mg/kg/day. Due to the lack of effect on kidney weight relative to body weight, the lack of histopathological effects, and the lack of effects in F1 adult females, the kidney weight decreases were not considered to be a result of test substance toxicity and were likely statistical anomalies resulting from the slightly high control group value and the small group size. All other absolute organ weights , organ weights relative to body weight and relative to brain weight, were unaffected across all dose groups.

GROSS PATHOLOGY: In the males there were no gross necropsy findings that exhibited treatment or dose related pattern of incidence or severity at scheduled sacrifice.
In the recovery males, there were no treatment related observations at the scheduled necropsy.
In the females there were no treatment related gross necropsy findings. Recorded findings occurred in the control and treatment groups and/or were not dose related and, therefore, were not considered a result of test substance toxicity.
HISTOPATHOLOGY: NON-NEOPLASTIC: Treatment related histopathological findings in males included 4 of 5 males with renal tubular necrosis and 5 of 5 males with diffuse renal tubule regeneration at 300 mg/kg/day. Other histological findings were considered to be typical for this age and strain of rat. Since the renal tubular necrosis and tubular regeneration were considered treatment related at 300 mg/kg/day, kidneys for the parental and F1 generation in the mid and low dose groups and the kidneys from the recovery males were also submitted for histopathological evaluation. No findings considered related to treatment were observed in the mid and low dose groups.
In the recovery males, of the 5 males each in the control and high dose groups for which kidneys were submitted, 3 males at 300 mg/kg/day had diffuse tubular regeneration, considered to be associated with the treatment related lesions observed in the animals sacrificed following dosing. The incidence and severity of these lesions were reduced from those following treatment. Tubular necrosis was not evident by the end of the recovery period. No other lesions were considered to be related to the earlier treatment.
In the females there were no treatment related histopatholigcal lesions. Recorded findings occurred in the control and treatment groups and/or were not dose related and, therefore, were not considered a result of test substance toxicity.

Effect levels

1

Dose descriptor:

NOAEL

Remarks:

parental

Effect level:

50 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

2

Dose descriptor:

LOAEL

Remarks:

parental

Effect level:

300 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: Based on reduced body weight, increased kidney effects and renal tubular effects at 300 mg/kg/day

3

Dose descriptor:

NOAEL

Remarks:

parental

Effect level:

50 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

female

4

Dose descriptor:

LOEL

Remarks:

parental

Effect level:

300 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: see 'Remark'

5

Dose descriptor:

NOAEL

Remarks:

F1 generation

Effect level:

300 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No significant effects were seen in the F1 generation.

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Summary of F0 Adult Systemic Toxicity – Key Parameters and Statistically Significant Differences

p-Cumylphenol (mg/kg/day)	F0
	0	5	50	300
F0 MALES
Weight Change	---	---	---	d
Feed Consumption:       g/day	---	---	---	---
g/kg/day	---	---	---	d^a
Mating Exposure
Weight Change	---	---	d^a	dd^a
Neurobehavioral Assessments Prebreed (Week 2):
Sensory and Neuromuscular Observations:
Average Hindlimb Grip Strength	---	u	u	---
Average Hindlimb Foot Splay	---	d	---	---
Hematology
Platelet Count	---	---	dd	---
Necropsy Organ Weights:
Liver                                         A	---	---	d	---
R - Body	---	---	---	---
R - Brain	---	---	d	---
Paired Kidneys             A	---	---	---	u
R - Body	---	---	---	uu
R - Brain	---	u	---	u
Paired Testes                                        A	---	---	---	---
R - Body	---	---	u	uu
R - Brain	---	u	---	---
Paired Epididymides                 A	---	---	---	---
R - Body	---	---	---	u
R - Brain	---	---	---	---
Prostate                                                A	---	---	---	---
R - Body	---	---	u	---
R - Brain	---	---	---	---
Gross Findings:
Seminal Vesicle: Reduced in size, right	---	---	---	1
Histopathology:^a
Renal Necrosis	---	---	---	u
Diffuse Renal Tubule Regeneration	---	---	---	u
F0 FEMALES
Prebreed/Mating/Postmating (sd 0-42) Exposure
Body Weights	---	---	d^a	---
Weight Change	---	---	d^a	d^a
Feed Consumption:                   g/day	---	---	---	dd^a
g/kg/day	---	---	d^a	ddd^a
Hematology
Red Blood Cell Distribution Width	---	---	---	dd
Segmented Neutrophil	---	---	---	d
Gestation
Body Weights	---	---	---	d^a
Weight Change	---	---	---	d^a
Lactation (pnd 0-21)
Weight Change	---	---	---	uu^a
Neurobehavioral Assessments Mating and Gestation (Week 3):
Body Weights	---	---	d	d
Mating and Gestation (Week 4):
Body Weights	---	---	dd	dd
Gestation (Week 5):
Body Weights	---	---	dd	dd
Sensory and Neuromuscular Observations
Hindlimb Grip Strength	---	---	---	d
Gestation and Lactation (Week 6):
Body Weights	---	---	---	d
Prior to Necropsy (Week 7):
Sensory and Neuromuscular Observations	---	---	---	---
Average Forelimb Grip Strength	---	dd	---	---
Average Hindlimb Grip Strength	---	---	---	d
Average Hindlimb Footsplay	---	---	---	d
Necropsy (Week 8):
Sensory and Neuromuscular Observations	---	---	---	---
Necropsy Organ Weights
Spleen                                          A	---	---	ddd	ddd
R - Body	---	---	ddd	ddd
R - Brain	---	---	ddd	ddd
Paired Kidneys                              A	---	---	dd	d
R - Body	---	---	---	---
R - Brain	---	---	---	---

^a Different levels of significance for different intervals during this period.

^b Histopathology was performed on control and high dose F0 males and females and for F0 males only at 5 and 50 mg/kg/day.

u, uu, uuu = statistically significant increase; 1 symbol – p is less than 0.05; 2 symbols – p is less than 0.01; 3 symbols – p is less than 0.001

d, dd, ddd = statistically significant decrease; 1 symbol – p is less than 0.05; 2 symbols – p is less than 0.01; 3 symbols – p is less than 0.001

--- = no statistically significant difference

A = absolute organ weight

- Body = organ weight relative to terminal body weight (%)

R - Brain = organ weight relative to terminal brain weight (%)

Applicant's summary and conclusion

Conclusions:

P-cumylphenol, administered by gavage once daily at 0-300 mg/kg/day to parental rats (10/sex/group) through prebreed, mating , gestation and lactation and direct dosing to F1 offspring from weaning to scheduled sacrifice, resulted in systemic toxicity (manifested as renal tubular necrosis) at 300 mg/kg/day in the parental males. The LOAEL was determined to be 300 mg/kg/day for parental males. A slight decrease in uterine implantations at 300 mg/kg/day in the parental females was noted, however, based on the lack of other associated effects on reproductive parameters and the screening nature of this study a LOEL for females was established at 300 mg/kg/day. No toxicity in the F1 offspring from birth through 7 weeks of postweaning dosing were observed. The NOAEL for the Parental rats was determined to be 50 mg/kg/day and the NOAEL for the F1 genration was determined to be 300 mg/kg/day.

Executive summary:

N/A