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EC number: 602-997-3 | CAS number: 124495-18-7
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Toxicity to reproduction
Administrative data
- Endpoint:
- two-generation reproductive toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 995
- Report date:
- 1995
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EPA OPP 83-4 (Reproduction and Fertility Effects)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: EEC Directive 87/302/EEC: Two-Generation Reproduction Toxicity test
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: MAFF Toxicity Testing Guidelines for Reproduction Studies
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Reference substance 001
- Cas Number:
- 124495-18-7
- Test material form:
- solid: particulate/powder
Constituent 1
- Specific details on test material used for the study:
- Test substance name: XDE-795
Lot Number: TSN 100097
Purity: 97.4 ± 0.2%
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on species / strain selection:
- This strain of rat was selected because of its general acceptance and suitability for toxicity testing, and the availability of a reliable commercial source.
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Breeding Laboratory, Kingston, New York
- Age at study initiation: Approximately 6 weeks
- Weight at study initiation: P1: Males: 170.2 - 171.4 g, Females: 175.8 - 177.5 g
- Housing: Rats were housed singly in wire mesh, stainless steel cages in racks provided with deotized cage board to minimize odor and aid in maintaining a clean environment. During the gestation/lactation phases of the study, P1 females were housed in plastic cages provided with ground corn cob nesting material. The sperm-positive P2 adult females were transferred from the males breeding cage back to the wire mesh, stainless steel cages on gestation day 0. Sperm positive P2 females were then transferred to plastic nesting cages on or prior to gestation day 19. P2 females which failed to mate were transferred to nesting cages at the completion of the three week mating period.
- Diet: Purina Certified Rodent Chow No.5002, ad libitum
- Water: Municipal drinking water, ad libitum
- Acclimation period: Approximately 2 weeks
ENVIRONMENTAL CONDITIONS
- Temperature: Approximately 22°C
- Humidity: Approximately 40-60%
- Air changes (per hr):12-15
- Photoperiod (hrs dark / hrs light): 12
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- other: Feed
- Details on exposure:
- Diets were prepared by serially diluting a test material/ feed concentrate (premix). The premix was ball-milled for approximately 20 minutes in order to ensure a homogeneous mixture. Premixes were prepared as necessary based on available stability data. The homogeneity of the test diets was confirmed during the course of the study.
The target concentration of test substance in the diets fed during the first two weeks of study was calculated using body weight and feed consumption data collected approximately one week prior to the study start. Thereafter, the concentration of the test material in the diets was calculated using weekly body weights and feed consumption data in order to maintain the targeted dose levels on a mg/kg/day basis. Test animals were maintained on the appropriate test diets for approximately 10 and 12 weeks of treatment prior to breeding of the first parental (P1) and second parental (P2) generations, respectively. - Details on mating procedure:
- - M/F ratio per cage: 1:1
- Length of cohabitation: 3 week period
- Proof of pregnancy: Vaginal plug referred to as Day 0 of gestation
- After successful mating each pregnant female was caged: During the gestation/lactation phases of the study, P1 females were housed in plastic cages provided with ground com cob nesting material. The sperm-positive P2 adult females were transferred from the males breeding cage back to the wire mesh, stainless steel cages on gestation day 0. Sperm positive P2 females were then transferred to plastic nesting cages on or prior to gestation Day 19. P2 females which failed to mate were transferred to nesting cages at the completion of the three week mating period. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Analyses of the test diets to determine the concentration of the test substance were performed at least three times per generation. Analyses of the test diets showed that the average concentration of test substance present in the diets ranged from 98 to 101% of the targeted concentrations. Analysis of diet samples dispensed from the top and bottom of the storage packs confirmed that the diets were homogeneous.
- Duration of treatment / exposure:
- Approximately 6 weeks of age to scheduled necropsy
- Frequency of treatment:
- Daily
- Details on study schedule:
- Treatment of the P1 rats began at approximately 6 weeks of age. After approximately 10 weeks on test diets, P1 rats were mated (one male to one female of the respective treatment group) to produce the F1a litters. Following weaning (3 weeks of age) of the F1a litters, 30 males and 30 females (one/sex/litter whenever possible) from each treatment group were randomly selected to become the parents for the next generation (P2 adults). Approximately one week after weaning of the last F1a litter, the P1 adults were again mated, to produce the F1b litters. After approximately 12 weeks of treatment following weaning of the last F1a litter, the P2 adults were bred to produce the F2 litters.
Doses / concentrationsopen allclose all
- Dose / conc.:
- 5 mg/kg bw/day
- Dose / conc.:
- 20 mg/kg bw/day
- Dose / conc.:
- 100 mg/kg bw/day
- No. of animals per sex per dose:
- 30
- Control animals:
- yes, plain diet
- Details on study design:
- - Dose selection rationale: These dose levels were selected based upon the results of the 4- and 13-week dietary toxicity studies. The high dose was expected to produce decreases in body weights and histopathologic alterations in the liver. Intermediate and low doses were chosen to provide dose-response data for any treatment-related effects observed in the high-dose group and to ensure definition of a NOEL for the test substance.
- Rationale for animal assignment: These rats were randomly assigned by weight to the treatment groups inorder to increase the probability of uniform group mean weights and standard deviations at the initiation of the study.
Examinations
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Each rat on study was observed daily for changes in behavior or demeanor. An additional observation for moribundity, mortality and the availability of feed and water was made at least once daily throughout the duration of the study.
BODY WEIGHT: Yes
- Time schedule for examinations: Body weights was recorded weekly for all P1 adults during the pre-breeding treatment period, beginning on or before the first day of
the study. Male body weights were recorded weekly throughout the course of the study. Sperm-positive females and females observed with in situ vaginal plugs were weighed on days 0, 7, 14 and 21 of presumed gestation. Females that delivered litters were weighed on days 1, 4, 7, 14, and 21 of lactation.
FOOD CONSUMPTION AND COMPOUND INTAKE:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: During breeding, feed consumption of males and females was not measured due to cohousing. Following completion of the breeding periods, weekly feed consumption was again measured in males and dietary concentrations were adjusted accordingly. During gestation, feed consumption was measured at weekly intervals for presumed pregnant females. After parturition, feed consumption was measured twice a week through the first 2 weeks of lactation, and at 2 - 3 day intervals during the last week of lactation. A similar schedule was followed for the P2 generation.
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes
- Litter observations:
- STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: No
PARAMETERS EXAMINED
The following parameters were examined in F1 / F2 offspring:
The parameters that were recorded on each litter includes, the date of parturition, litter size on the day of parturition (day 0), the number of live and dead pups on days 0, 1, 4, 7, 14, and 21 postpartum, and the sex and the weight of each pup on days 1, 4, 7, 14, and 21 of lactation. Any visible physical abnormalities or demeanor changes in the neonates were recorded during the lactation period.
GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities; possible cause of death was/was not determined for pups born or found dead and discarded - Postmortem examinations (parental animals):
- SACRIFICE
The scheduled necropsy was performed after the majority of the litters from the respective generation had been weaned.
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.
HISTOPATHOLOGY
The tissues that were prepared for microscopic examination were cervix, coagulating glands, epididymides, kidneys, liver, mammary gland, ovaries, oviducts, pitutary glands, prostate gland, seminal vesicles, testes, uterus and vagina. - Postmortem examinations (offspring):
- SACRIFICE
- The F1 offspring which were not selected as P2 adults and all F2 offspring were sacrificed at 21 days of age.
- These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination) as follows: At the time of weaning, 10 pups/sex/dose level from the F1a, F1b and F2 litters were randomly selected for a complete necropsy under the supervision of a veterinary pathologist. The pups were anesthetized with methoxyflurane and euthanized. Gross pathologic examination and preservation of tissue samples was performed for adults, except that testes and epididymides were preserved in neutral, phosphate-buffered 10% formalin. Histologic examination of tissues was not performed.
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera. - Statistics:
- Descriptive statistics (means and standard deviations) were reported for feed consumption. Body weights and body weight gains were first evaluated by Bartlett's test for equality of variances. Based upon the outcome of Bartlett's test, either a parametric or nonparametric analysis of variance (ANOVA) was performed. If the ANOVA was significant, a Dunnett's test or the Wilcoxon Rank-Sum test with Bonferroni's correction was performed. Since litters were not culled, an analysis of covariance was used to test the effects of dose on pup weights with litter size as the covariate.
Gestation length, average time to mating and litter size were analyzed using a nonparametric ANOVA. If the ANOVA was significant, the Wilcoxon Rank-Sum test with Bonferroni's correction was performed. Statistical outliers were identified by the method of Grubbs (1969) and were routinely excluded from analysis for feed consumption only. Outliers for body weight, gestation length, litter size and average time to mating were only excluded from analysis for documented, scientifically sound reasons. The fertility indices were analyzed by the Fisher exact probability test and Bonferroni's correction was used for multiple testing of groups in comparison to a single control. Evaluation of the neonatal sex ratio was performed by the binomial distribution test. Survival indices and other incidence data among neonates was analyzed using the litter as the experimental unit by the Wilcoxon test as modified by Haseman and Hoel (1974).
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- - Excessive chromodacryorrhea of eyes was observed in one animal at all doses including control animals. Abrasion of skin, fur and mucous memebrane was observed at all doses in rats except in 20 mg/kg bw/d female. Perineal soiling was observed in one control female.
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- Two control male animals and one 5 mg/kg bw/d male died during study. one control animal which was found dead on Day 181, Upon histopathologic examination showed severe microscopic hemorrhages involving the skin/subcutis, esophageal wall, mesenteric, mandibular, and thoracic lymph nodes were noted. These observations were consistent with trauma, however, no clinical observations were made on this animal prior to its death. Another control male, and a 5 mg/kg/day male, died on test days 192 and 42, respectively. Histopathologically, each had spontaneous lymphosarcoma and died as a result of this neoplastic disease. The lymphosarcoma noted in each rat was accompanied by inflammation (very slight to severe) in one or more organs, probably the result of impairment or damage to the immune system caused by lymphosarcoma.
- Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No significant treatment-related effects on body weights were observed at any dose level in males throughout the entire test period or in females during the premating, gestation or lactation periods. Similarly, no treatment related effects were observed on the body weight gain of females during the F1a or F1b gestation or lactation periods. However, a statistically significant increase in body weight gain was noted in females given 100 mg/kg/day over the duration of the F1a lactation period when compared to control values. This increase in weight gain was not considered to be toxicologically significant as no dose response relationship was observed, test material effects would be expected to produce decreases in body weight gain rather than increases, and a similar increase was not observed during the F1b or F2 lactation periods.
- Food consumption and compound intake (if feeding study):
- effects observed, non-treatment-related
- Description (incidence and severity):
- No significant effects were observed on feed consumption of males throughout the entire test period or females during pre-mating or gestation at any dose level. Slight decreases in feed consumption were noted during the final week of the F1a and F1b lactation periods, however, concomitant decreases in dam body weights were not observed. As rat pups begin consuming feed during the final week of lactation, this decrease may have been due to decreased feed consumption by the high-dose pups, rather than the maternal animals.
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- A treatment-related increased incidence of slight or very slight hypertropy of the hepatocytes in the centrilobular region occurred in the livers of 24 male rats given 100 mg/kg/day test substance. The alteration was characterized by increased size of hepatocytes as a result of an apparent increase of agranular eosinophilic cytoplasm similar to that seen with agents that produce proliferation of smooth endoplasmic reticulum and metabolic enzyme induction. No treatment-related effects were observed on any reproductive parameter or histopathology of the reproductive organs for P1 adult animals at any dose level tested.
Reproductive function / performance (P0)
- Reproductive performance:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No treatment-related effects were observed on male or female reproductive indices, gestation survival index, gestation length or time to mating at any dose level for the F1a or F1b matings/litters.
Effect levels (P0)
open allclose all
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- 20 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- histopathology: non-neoplastic
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- 100 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: systemic toxicity
- Remarks on result:
- other: no systemic effects at highest dose tested
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- 100 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Reproductive Toxicity
- Remarks on result:
- other: no repro effects at highest dose tested
Results: P1 (second parental generation)
General toxicity (P1)
- Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No treatment-related effects on behavior or demeanor were observed in P2 adult males or females at any dose level during the pre-mating, gestation or lactation periods.
- Mortality:
- no mortality observed
- Description (incidence):
- All P2 adults survived the test period and were necropsied on the scheduled date of termination.
- Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No significant treatment-related effects on body weights were observed at any dose level in males throughout the entire test period or in females during the premating, gestation or lactation periods. However, statistically significant increases in body weight were noted sporadically in females given 5 and 20 mg/kg/day during the premating period. These increases were interpreted to be unrelated to treatment as there was no dose-response relationship observed. No treatment related effects were observed on the body weight gain of females during the gestation or lactation periods. A non-statistically identified decrease (~11 %) in body weight gain was, however, observed in females given 100 mg/kg/day over the entire gestation period. This decrease in weight gain was not considered to be toxicologically significant as no dose-response relationship was observed and similar decreases were not observed during the P1 female gestation periods.
- Food consumption and compound intake (if feeding study):
- effects observed, non-treatment-related
- Description (incidence and severity):
- No significant effects were observed on feed consumption of males throughout the entire test period or females during pre-mating or gestation at any dose level. However, a decrease in feed consumption was noted during the final week of the F2 lactation period. This decrease was consistent with slight decreases observed during the final week of the P1 lactation periods. As in the F1a and F1b lactation periods, no correlate between decreased feed consumption and maternal weight gain was observed, suggesting decreases may have been due to decreased feed consumption by the high-dose pups.
- Gross pathological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No treatment-related gross pathologic changes were observed in the P2 adults at any dose leveL The observations made for the P2 adults were similar to those of the P1 adults with no gross lesions attributed to test substance treatment. Generally, gross observations occured in only a single rat per dose level except for dilated renal pelvis, pale foci noted at the juncture of the right and left portions of the middle lobes of the liver, and the dark foci in the uterus associated with previous implantation sites.
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Effects related to test substance treatment were similar to those in the first parental generation and involved the liver of male rats given 100 mg/kg/day. Slight or very slight hepatocellular hypertrophy was associated with treatment at 100 mg/kg/day in 28 of 30 males. The alteration was again characterized by increased size of hepatocytes as a result of an apparent increase of agranular eosinophilic cytoplasm. No treatment-related effects were observed on any reproductive parameter or histopathology of the reproductive organs for P2 adult animals at any dose level tested.
Reproductive function / performance (P1)
- Reproductive performance:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No treatment-related effects were observed on the male or female reproductive indices, gestation, gestation length or time to mating at any dose level for the F2 matings/litters. Statistically identified decreases in male and female conception and fertility indexes noted at 20 mg/kg/day were considered spurious and unrelated to treatment as no decreases were noted in these indexes at 100 mg/kg/day, no dose-response relationship was observed for the apparent change in these parameters, and similar effects were not noted for the F1a or F1b matings.
Effect levels (P1)
open allclose all
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- 20 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- histopathology: non-neoplastic
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- 100 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: systemic toxicity
- Remarks on result:
- other: no effects at highest dose tested
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- 100 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Reproductive toxicity
- Remarks on result:
- other: Highest dose tested
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No treatment-related clinical observations or physical alterations were observed in any F1a or F1b pups from any dose group during the lactation period. An increased incidence of F1b pups observed to have staining, lacerations or scaling in the perianal region was noted in all treatment groups. These observations were not attributed to treatment as these observations were noted in control as well as treated litters, no dose response relationship was observed and perianal staining/ scaling did not occur in any F1a pups from any dose group.
- Mortality / viability:
- mortality observed, non-treatment-related
- Description (incidence and severity):
- No effects on litter size were observed at 5 or 20 mg/kg/day at any time during the F1a or F1b lactation periods. The size of F1a litters from dams given 100 mg/kg/day was not significantly different from control litters, however, a statistically significant increase in litter size was noted in the 100 mg/kg/day F1b litters on lactation Days 1, 4 and 7. This increase was not considered to be treatment-related as this effect was not observed in the F1a or F2 litters. Neonatal survival was not adversely affected at any dose level in either generation.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Minimal neonatal effects were also observed at 100 mg/kg bw/d in F1a and F1b litters. Statistically decrease in mean body weights of both male and female pups on Day 21 of lactation period was observed. These transient decreases were attributed, in part, to the decreased feed consumption noted during the final week of the P1 and P2 lactation periods. No adverse effects were observed on pup body weights at doses of 5 or 20 mg/kg/day in either generation.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Minimal neonatal effects were also observed at 100 mg/kg bw/d in F1a and F1b litters. Although pup feed consumption was slightly decreased, the higher concentration of test material in the maternal diet they consumed would have resulted in a dose on a mg/kg/day basis greater than that targeted for the adults.
- Sexual maturation:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The statistically significant deviation from a normal distribution in the sex ratio of F1b pups from dams given 100 mg/kg/day was not attributed to treatment as the sex ratio of pups in this dose group was similar to the control, and no significant effects were observed on the sex ratios of pups in the F1a litters at any dose level.
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- No treatment-related gross pathologic observations were observed at any dose level in the F1a or F1b weanlings.
- Other effects:
- no effects observed
- Description (incidence and severity):
- No treatment-related effects were observed on pup survival indices, pup sex ratios at any dose level for the F1a or F1b matings/litters.
Effect levels (F1)
- Key result
- Dose descriptor:
- NOEL
- Generation:
- other: F1a & F1b
- Effect level:
- 20 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- food consumption and compound intake
- Remarks on result:
- other: The effect observed on pup body weight is transient
Results: F2 generation
General toxicity (F2)
- Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No treatment-related clinical observations or physical alterations were observed in any F2 pups from any dose group during the F2 lactation period. Three pups from a single 100 mg/kg/day litter were noted as having yellow skin as well as being cold to the touch. This skin discoloration was not felt to be treatment related as the observation did not occur in any other high-dose litters.
- Mortality / viability:
- mortality observed, non-treatment-related
- Description (incidence and severity):
- Neonatal survival was not adversely affected at any dose level in F2 generation.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Minimal neonatal effects were also observed at 100 mg/kg bw/d in F2 litters. Statistically decrease in mean body weights of both male and female pups on Day 21 of lactation period was observed. These transient decreases were attributed, in part, to the decreased feed consumption noted during the final week of the P1 and P2 lactation periods. No adverse effects were observed on pup body weights at doses of 5 or 20 mg/kg/day in either generation.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Minimal neonatal effects were also observed at 100 mg/kg bw/d in F2 litters. Although pup feed consumption was slightly decreased, the higher concentration of test material in the maternal diet they consumed would have resulted in a dose on a mg/kg/day basis greater than that targeted for the adults.
- Sexual maturation:
- no effects observed
- Description (incidence and severity):
- No significant effects were observed on the sex ratios of pups in the F2 litters at any dose level.
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- No treatment-related gross pathologic observations were observed at any dose level in the F2 weanlings.
- Other effects:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No treatment-related effects were observed on pup survival indices, pup sex ratios at any dose level for the F2 matings/litters.
Effect levels (F2)
- Key result
- Dose descriptor:
- NOEL
- Generation:
- F2
- Effect level:
- 20 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- food consumption and compound intake
- Remarks on result:
- other: The effect observed on pup body weight is transient
Overall reproductive toxicity
- Key result
- Reproductive effects observed:
- no
Applicant's summary and conclusion
- Conclusions:
- NOEL (Male) (Parental) (Systemic): 20 mg/kg bw/d
NOEL (Female) (Parental) (Systemic): 100 mg/kg bw/d (Highest dose tested)
NOEL (Male/Female) (Parental) (Reproductive): 100 mg/kg bw/d (Highest dose tested)
NOEL (Male/Female) (Neonatal): 20 mg/kg bw/d - Executive summary:
The study was conducted according to OECD guideline 416 and EPA 83-4 to evaluate the effects of test substance on the reproductive capability and neonatal growth and survival of rats. Groups of 30 male and 30 female Sprague-Dawley rats, approximately 6 weeks of age, were fed diets that provided 0, 5, 20 or 100 mg/kg/day, 7 days/week, for two generations.
Dietary exposure of adult male and female rats to 100 mg/kg/day test substance resulted in parental and developmental effects. Parental effects consisted of centrilobular hepatocellular enlargement in high dose P1 and P2 male rats only. This effect was noted previously in a 13-week study with Fischer 344 rats. Slight decreases in female feed consumption were noted only during the final week of the P1 and P2 lactation periods, but were not associated with body weight effects in maternal animals. No significant effects were observed for P1 or P2 females given 100 mg/kg/day or male or female rats given 5 or 20 mg/kg/day in either parental generation. Additionally, no treatment-related effects were observed on any reproductive parameters or gross/histopathology of the reproductive organs for P1 or P2 adult animals at any dose level tested.
Minimal neonatal effects were also observed at 100 mg/kg/day test substance in the F1a, F1b, and F2 litters. Decreases, both statistically identified and otherwise, were noted on Day 21 of lactation in the mean body weights of male and female pups in this dose group. These transient decreases were attributed, in part, to the decreased feed consumption noted during the final week of the P1 and P2 lactation periods. Although pup feed consumption was slightly decreased, the higher concentration of test material in the maternal diet they consumed would have resulted in a dose on a mg/kg/day basis greater than that targeted for the adults. No adverse effects were observed on pup body weights at doses of 5 or 20 mg/kg/day in either generation. Neonatal survival was not adversely affected at any dose level in either generation.
Under the conditions of this study, the parental no-observed-effect level (NOEL) for systemic effects was 20 mg/kg/day for males and 100 mg/kg/day for females. The NOEL for reproductive effects was 100 mg/kg/day, the highest dose level tested. Based upon the transient effects observed on pup body weights, the NOEL for neonatal effects was conservatively determined to be 20 mg/kg/day.
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