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EC number: 457-320-2 | CAS number: -
- 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
![](https://echa.europa.eu/o/diss-blank-theme/images/factsheets/A-REACH/factsheet/print_toxicological-information.png)
Toxicity to reproduction
Administrative data
- Endpoint:
- screening for reproductive / developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 18 Sept 2009 - 15 April 2010
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Reference
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 18 Sept 2009 - 15 April 2010
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- according to guideline
- Guideline:
- other: OECD Guideline 421
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: U.S. EPA OPPTS Guideline 870.3550
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
- Species:
- rat
- Strain:
- Crj: CD(SD)
- Details on test animals or test system and environmental conditions:
- Each rat was uniquely identified by a Monel® metal ear tag displaying the animal number.
TEST ANIMALS
- Source: Charles River Laboratories, Inc., Raleigh, NC
- Age at study initiation: approximately 12 weeks
- Weight at study initiation: males (day 0) 351 g to 443 g, females (day 0) 220 g to 281 g.
- Housing: Following receipt and until pairing, all F0 animals were housed individually in clean, stainless steel wire mesh cages suspended above cage board. The cage-board was changed at least 3 times per week. The rats were paired for mating in the home cage of the male. Following positive evidence of mating, the males were housed in suspended wire mesh cages until the scheduled necropsy, and the females were transferred to plastic maternity cages with nesting material, ground corncob bedding (Bed O'Cobs®; The Andersons, Cob Products Division, Maumee, OH). The nesting material is periodically analyzed by the manufacturer for contaminants. No contaminants were present in the bedding at concentrations sufficient to interfere with the outcome of the study. The results of these analyses are maintained at WIL Research Laboratories, LLC. The dams and their litters were housed in these cages until euthanasia on lactation day 4. Females with no evidence of mating or that failed to deliver were housed in plastic maternity cages until post-cohabitation or post-mating day 25. Animals were maintained in accordance with the Guide for the Care and Use of Laboratory Animals (National Research Council, 1996). The animal facilities at WIL Research Laboratories, LLC are accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC International).
- Diet: Provided ad libitum. PMI Nutrition International, LLC Certified Rodent LabDiet® 5002. Feeders were changed and sanitized once per week.
- Water: Provided ad libitum. Reverse osmosis-purified (on site) drinking water, delivered by an automatic watering system.
- Acclimation period: 21 days
ENVIRONMENTAL CONDITIONS
- Temperature: 22°C +/- 3°C (target); 21.1°C to 21.4°C (actual temps)
- Humidity: 50% +/- 20% (target); 37.7% to 57.1% (actual temps)
- Air changes: 10/hr minimum
- Photoperiod: 12-hour light (0600 hours to 1800 hours)/12-hour dark
IN-LIFE DATES: From: 22 September 2009 To: 6 January 2010 - Route of administration:
- oral: gavage
- Vehicle:
- other: Mineral Oil USP
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: The test substance (45% [w/w] in 55% [w/w] mineral oil) can become non-homogeneous upon stationary storage; therefore, the bulk test substance was warmed to approximately 60ºC and inverted approximately 20 times prior to preparing the formulations. The test substance formulations were prepared daily during 13-18 October 2009 and approximately weekly thereafter as single formulations for each dosage level, divided into aliquots for daily dispensation, and stored at room temperature. The test substance formulations were stirred continuously throughout the dose administration procedures. The vehicle and test substance formulations were administered orally by gavage, via an appropriately sized flexible, Teflon®-shafted, stainless steel ball-tipped dosing cannula (Natume, Japan) once daily.
VEHICLE
- Lot/batch no. (if required): (lot nos. XX1110 and YG1036, exp dates: 15 July 2010 and 18 September 2011.
- Supplier: Spectrum Chemical Manufacturing Corporation, New Brunswick, NJ and Gardena, CA. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The analyzed dosing formulations were within the WIL Research Laboratories, LLC’s standard operating procedure range for suspensions (85% to 115%), were homogeneous, and were stable for 10 days at room temperature. Based on these results, the protocol-specified dosages of test substance were administered to the animals. The test substance was not detected in the vehicle formulation that was administered to the control group (Group 1).
Prior to the initiation of dose administration, quadruplicate samples for homogeneity and concentration determination were collected from the top, middle, and bottom strata of the 20 and 200 mg/mL non-dosing formulations. For the assessment of 5- and 10-day stability and aliquot resuspension homogeneity, aliquots approximately equivalent in volume to a daily dispensation aliquot, were transferred from the pre-initiation batch into the same type of storage container that was used for the daily aliquots for dosing. After storage at room temperature for 5 and 10 days, each aliquot was resuspended for a minimum of 30 minutes by warming the test substance formulations to 60ºC (while stirring), and quadruplicate samples were withdrawn from the top and bottom strata of each aliquot for assessment of 5- and 10-day stability and aliquot resuspension homogeneity. Samples for homogeneity and concentration analyses were collected from the middle stratum of the control formulation and the top, middle, and bottom strata of each batch of test substance dosing formulations. Samples from the first and last dosing batch were analyzed for homogeneity and concentration. All analyses were conducted by the Analytical Chemistry Department, WIL Research Laboratories, LLC using a validated high performance liquid chromatography method using ultraviolet absorbance detection. - Details on mating procedure:
- The animals were paired on a 1:1 basis within each treatment group following 14 days of treatment for the males and females. Each female was housed in the home cage of the male. Positive evidence of mating was confirmed by the presence of a vaginal copulatory plug or the presence of sperm following a vaginal lavage and verified by a second biologist. Each mating pair was examined daily. The day when evidence of mating was identified was termed gestation day 0. If evidence of copulation was not detected after 14 days of pairing, any females that had not shown evidence of mating were placed in plastic maternity cages.
For the purpose of calculating pre-coital intervals, rats paired over a 12-hour dark cycle were considered to have been paired for 1 day. - Duration of treatment / exposure:
- Males: Dosed during study days 0–27 (14 days prior to pairing through 1 day prior to scheduled euthanasia) for a total of 28 doses.
Females: Dosed from study day 0 through the day prior to euthanasia (14 days prior to pairing through lactation day 3) for a total of 39-45 doses. Females with no evidence of mating or that failed to deliver were dosed through the day prior to euthanasia (post cohabitation day 25 or post-mating day 25) for a total of 39-42 doses. - Frequency of treatment:
- Once daily at approximately the same time each day
- Duration of test:
- Premating through PND 4
- No. of animals per sex per dose:
- 12/sex/group
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: Based on results of a previous study.
- Rationale for animal assignment (if not random): body weight stratification in a block design using a computer randomization procedure - Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily for mortality and moribundity
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Detailed physical examinations were recorded weekly (prior to test substance administration during the treatment period) and on the day of necropsy. Each male and female was also observed for signs of toxicity approximately 1-2 and 3 hours following dose administration. The absence or presence of findings was recorded for individual animals. In addition, findings at the time of dose administration were recorded for individual animals. Females expected to deliver were observed twice daily during the period of expected parturition and at parturition for dystocia (prolonged labor, delayed labor) or other difficulties.
BODY WEIGHT: Yes
- Time schedule for examinations: Males: recorded weekly throughout the study and prior to the scheduled euthanasia. Females: recorded weekly until evidence of copulation was observed. Once evidence of mating was observed, female body weights were recorded on gestation days 0, 4, 7, 11, 14, 17, and 20 and on lactation days 0 (when possible), 1, and 4.
FOOD CONSUMPTION: Yes
- Individual food consumption was recorded on the corresponding weekly body weight days until pairing. Food intake was not recorded during the mating period. Once evidence of mating was observed, female food consumption was recorded on gestation days 0, 4, 7, 11, 14, 17, and 20 and on lactation days 1 and 4.
POST-MORTEM EXAMINATIONS: Yes
- F0 males were sacrificed following completion of the mating period; F0 females were sacrificed on post-mating day or post-cohabitation day #25, or on lactation day 4.
GROSS PATHOLOGY: Yes, all animals were euthanized using carbon dioxide inhalation.
- Organs examined (F0): Necropsy included examination of the external surface, all orifices, the external surface of the brain, and the cranial, thoracic, abdominal, and pelvic cavities, including viscera.
- Organs weighed (F0): brain, epididymides, kidneys, liver, ovaries with oviducts, pituitary, testes
HISTOPATHOLOGY: Yes (control and high-dose groups)
Tissues examined (F0): Coagulating glands, mammary gland (female only), ovaries and oviducts, pituitary gland, prostate gland, seminal vesicles, testes with epididymides and vas deferens (fixed in Bouin's solution), uterus with cervix and vagina, all gross lesions. After fixation, protocol-specified tissues were trimmed according to WIL SOP's and the protocol. Trimmed tissues were processed into paraffin blocks, sectioned at 4 to 8 microns, mounted on glass microscope slides, and stained with hematoxylin and eosin. - Ovaries and uterine content:
- Organ weights: Ovaries with oviducts
- Fetal examinations:
- Evaluations of offspring were conducted postnatally. See other information below.
- Statistics:
- Analyses were conducted using two-tailed tests (except as noted otherwise) for minimum significance levels of 1% and 5%, comparing each test substance-treated group to the control group by sex. Each mean was presented with the standard deviation (S.D.), standard error (S.E.), and the number of animals (N) used to calculate the mean. Data obtained from nongravid females were excluded from statistical analyses following the mating period. Where applicable, the litter was used as the experimental unit.
Parental mating, fertility, conception, and copulation indices were analyzed using the Chi square test with Yates’ correction factor (Hollander and Wolfe, 1999). Histopathological findings were analyzed by the Fisher’s Exact Test (Steel, 1980). Mean parental body weights (weekly, gestation, and lactation), body weight changes, and food consumption, offspring body weights and body weight changes, gestation length, numbers of corpora lutea and former implantation sites, number of pups born, live litter size on PND 0, unaccounted-for sites, absolute and relative organ weights, and pre coital interval values were subjected to a parametric one way analysis of variance (ANOVA) (Snedecor and Cochran, 1980) to determine intergroup differences between the control and test substance-treated groups. If the ANOVA revealed significant (p<0.05) intergroup variance, Dunnett's test (Dunnett, 1964) was used to compare the test substance-treated groups to the control group. Mean litter proportions (percent per litter) of males at birth and postnatal survival were subjected to the Kruskal-Wallis nonparametric ANOVA (Kruskal and Wallis, 1952) to determine intergroup differences between the control and test substance-treated groups. If the ANOVA revealed significant (p<0.05) intergroup variance, Dunn’s test (Dunn, 1964) was used to compare the test substance-treated groups to the control group. - Indices:
- Mean Live Litter Size, Postnatal Survival Between Birth and PND 0 or PND 4 (% Per Litter), and Postnatal Survival Between PND 0-1 and PND 1-4 (% Per Litter) were calculated.
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Test substance-related, adverse behaviour/CNS-related findings of intermittent tremors, repetitive movement of mouth and jaws, excessive pawing and/or licking of the cage floor and/or walls (females only, beginning on study day 13), and/or head twitch were noted in the 1000 mg/kg/day group males and females at 1-2 and/or 3 hours following dose administration beginning on study day 12 and continuing sporadically throughout the remainder of treatment. Test substance-related, non-adverse, salivation or evidence thereof (clear material around the mouth) was noted in the 1000 mg/kg/day group males and females generally throughout the treatment period prior to dosing and 1 2 and/or 3 hours following dose administration. In addition, clinical findings of orange, orangish-red, and/or red material on various body surfaces were noted for males and females in all test substance-treated groups at all observation time points generally throughout the treatment period and were considered to be associated with the dark red color of the dosing formulations and were not considered adverse.
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- effects observed, non-treatment-related
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- Females in the top dose group (1000 mg/kg/day) had a higher mean liver weight when compared with the control group
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- One female from this group had yellow areas on the liver at the time of necropsy, which correlated histologically to areas of liquefactive necrosis. The affected rat also had the highest liver weight. The relationship between administration of the test substance and the hepatic necrosis is uncertain, as the liver was examined microscopically only for the animal with gross necropsy findings in the liver. There were no other test substance-related histologic changes.
- Other effects:
- no effects observed
- Description (incidence and severity):
- The following indices were calculated: Male Mating Index (%), Female Mating Index (%), Male Fertility Index (%), Female Fertility Index (%), Male Copulation Index (%), Female Conception Index (%), Pre-Coital Interval (days). No test substance-related effects on reproductive performance were observed at any dosage level. No statistically significant differences were noted between the control and test substance treated groups. The mean numbers of days between pairing and coitus in the test substance-treated groups were similar to the control group value.
- Details on maternal toxic effects:
- Maternal toxic effects:yes
Details on maternal toxic effects:
Test substance-related, adverse behavior/CNS-related findings of intermittent tremors, repetitive movement of mouth and jaws, excessive pawing and/or licking of the cage floor and/or walls (females only, beginning on study day 13), and/or head twitch were noted in the 1000 mg/kg/day group males and females at 1-2 and/or 3 hours following dose administration beginning on study day 12 and continuing sporadically throughout the remainder of treatment. Female rats in the top dose group (1000 mg/kg/day) had a higher mean liver weight when compared with the control group. - Key result
- Dose descriptor:
- NOAEL
- Remarks:
- systemic
- Effect level:
- 300 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- other: maternal toxicity
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- developmental toxicity
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Key result
- Abnormalities:
- no effects observed
- Changes in litter size and weights:
- no effects observed
- Description (incidence and severity):
- The mean number of pups born, live litter size, and the percentage of males at birth in the 100, 300, and 1000 mg/kg/day groups were similar to the control group values. Postnatal survival between birth and PND 0 (relative to number born), PND 0-1 and 1-4, and from birth to PND 4 in the 100, 300, and 1000 mg/kg/day groups was unaffected by parental test substance administration. No statistically significant differences from the control group were noted.
Mean male and female pup body weights and body weight changes in the 100, 300, and 1000 mg/kg/day groups were unaffected by test substance administration during PND 1-4. No statistically significant differences from the control group were noted. - Changes in postnatal survival:
- no effects observed
- Description (incidence and severity):
- The mean number of pups born, live litter size, and the percentage of males at birth in the 100, 300, and 1000 mg/kg/day groups were similar to the control group values. Postnatal survival between birth and PND 0 (relative to number born), PND 0-1 and 1-4, and from birth to PND 4 in the 100, 300, and 1000 mg/kg/day groups was unaffected by parental test substance administration. No statistically significant differences from the control group were noted.
Pups (litters) that were found dead numbered 1(1), 2(2), 2(1), and 6(4) in the control, 100, 300, and 1000 mg/kg/day groups, respectively. The numbers of pups (litters) found dead during PND 0-4 numbered 1(1), 2(2), 2(1), and
6(4) in the control, 100, 300, and 1000 mg/kg/day groups, respectively. Aside from the presence or absence of milk in the stomach, no other internal findings were noted. - Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:no effects
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Abnormalities:
- not specified
- Key result
- Developmental effects observed:
- no
- Conclusions:
- The NOAEL for developmental/neonatal effects is 1000 mg/kg bw/day, the highest dose tested.
- Executive summary:
EC# 457-320-2 has been tested in a guideline (OECD 421) reproductive/developmental toxicity GLP screening study. The test substance in the mineral oil vehicle was administered orally by gavage once daily to 3 groups of Crl:CD(SD) rats, each group consisting of 12 males and 12 females. Dosage levels were 100, 300, and 1000 mg/kg/day administered at a dosage volume of 5 mL/kg. A concurrent control group of 12 rats/sex received the vehicle (mineral oil, USP) on a comparable regimen. Males and females were approximately 12 weeks of age at the beginning of test substance administration. Males received 14 daily doses prior to mating. Males were dosed throughout the mating period through 1 day prior to euthanasia for a total of 28 doses. Females received 14 daily doses prior to pairing and were dosed through lactation day 3 for a total of 39–45 doses; females with no evidence of mating or those that failed to deliver were dosed through the day prior to euthanasia (post-cohabitation day 25 or post-mating day 25) for a total of 39–42 doses. All animals were observed twice daily for mortality and moribundity. Clinical observations, body weights, and food consumption were recorded at appropriate intervals. All F0 females were allowed to deliver and rear their pups until lactation day 4. F1 clinical observations and body weights were recorded on postnatal days (PND) 1 and 4. Necropsies were performed on pups that died. All other F1 pups were euthanized on PND 4 and discarded without further examination. F0 males were euthanized following completion of the mating period and F0 females were euthanized on post-mating day 25 (females with evidence of mating), post-cohabitation day 25 (females with no evidence of mating), or on lactation day 4. Complete necropsies were conducted on all F0 animals, and selected organs were weighed. Selected tissues of the reproductive system were examined microscopically from all F0 animals in the control and high-dose groups.
All male and female rats survived to the scheduled necropsy. Test substance-related, adverse behavior/CNS-related findings of intermittent tremors, repetitive movement of mouth and jaws, excessive pawing and/or licking of the cage floor and/or walls (females only, beginning on study day 13), and/or head twitch were noted in the 1000 mg/kg/day group males and females at 1-2 and/or 3 hours following dose administration beginning on study day 12 and continuing sporadically throughout the remainder of treatment. There were no test substance-related effects on mean body weights, body weight gains, or food consumption for males throughout the treatment period or for females during the pre-mating, gestation, or lactation treatment periods at any dosage level.
There were no test substance-related effects on male and female reproductive performance (mating, fertility, copulation, and conception indices and pre-coital intervals), mean gestation lengths, or the process of parturition at any dosage level.
Female rats in the top dose group (1000 mg/kg/day) also had an increased mean liver weight when compared with the control group. In reproductive tissues, no test substance-related changes in organ weights, gross necropsy observations, or histologic changes were detected. In addition, the mean numbers of unaccounted-for sites, former implantation sites, and corpora lutea were similar between the control and test substance-treated groups.
There were no effects on the numbers of pups born, live litter size, percentage of males at birth, pup survival, or on mean male and female pup body weights and body weight gains during PND 1–4. No test substance-related clinical findings were noted for pups at any dosage level; no test substance-related macroscopic findings were observed in pups that were found dead.
In the absence of test substance-related effects on reproductive performance, gestation lengths, parturition, live litter size, numbers of pups born, and reproductive organs, a dosage level of 1000 mg/kg/day (the highest dosage level tested) was considered to be the no-observed-adverse-effect level (NOAEL) for reproductive toxicity of the test substance when administered orally by gavage to Crl:CD(SD) rats. Based on behavior/CNS-related findings and increased mean liver weights at 1000 mg/kg/day, the NOAEL for male and female systemic toxicity was considered to be 300 mg/kg/day. Based on the absence of effects on postnatal survival or pup body weights, the NOAEL for neonatal toxicity was determined to be 1000 mg/kg/day.
PND 0 LITTER DATA AND POSTNATAL SURVIVAL
The mean number of pups born, live litter size, and the percentage of males at birth in the 100, 300, and 1000 mg/kg/day groups were similar to the control group values. Postnatal survival between birth and PND 0 (relative to number born), PND 0-1 and 1-4, and from birth to PND 4 in the 100, 300, and 1000 mg/kg/day groups was unaffected by parental test substance administration. No statistically significant differences from the control group were noted.
GENERAL PHYSICAL CONDITION
The general physical condition of all F1 pups in this study were unaffected by test substance administration.
OFFSPRING BODY WEIGHTS
Mean male and female pup body weights and body weight changes in the 100, 300, and 1000 mg/kg/day groups were unaffected by test substance administration during PND 1 4. No statistically significant differences from the control group were noted. NECROPSIES OF PUPS FOUND DEAD
The numbers of pups (litters) found dead during PND 0-4 numbered 1(1), 2(2), 2(1), and 6(4) in the control, 100, 300, and 1000 mg/kg/day groups, respectively. Aside from the presence or absence of milk in the stomach, no other internal findings were noted.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 010
- Report date:
- 2010
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: U.S. EPA OPPTS Guideline 870.3550
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Test material form:
- liquid
- Details on test material:
- Dark opaque red liquid
Batch: 30848-47
Expiry: 15-Sept-2012
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Crj: CD(SD)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- Each rat was uniquely identified by a Monel® metal ear tag displaying the animal number.
TEST ANIMALS
- Source: Charles River Laboratories, Inc., Raleigh, NC
- Age at study initiation: approximately 12 weeks
- Weight at study initiation: males (day 0) 351 g to 443 g. females (day 0) 220 g to 281 g.
- Housing: Following receipt and until pairing, all F0 animals were housed individually in clean, stainless steel wire mesh cages suspended above cage board. The cage-board was changed at least 3 times per week. The rats were paired for mating in the home cage of the male. Following positive evidence of mating, the males were housed in suspended wire mesh cages until the scheduled necropsy, and the females were transferred to plastic maternity cages with nesting material, ground corncob bedding (Bed O'Cobs®; The Andersons, Cob Products Division, Maumee, OH). The nesting material is periodically analyzed by the manufacturer for contaminants. No contaminants were present in the bedding at concentrations sufficient to interfere with the outcome of the study. The results of these analyses are maintained at WIL Research Laboratories, LLC. The dams and their litters were housed in these cages until euthanasia on lactation day 4. Females with no evidence of mating or that failed to deliver were housed in plastic maternity cages until post-cohabitation or post-mating day 25. Animals were maintained in accordance with the Guide for the Care and Use of Laboratory Animals (National Research Council, 1996). The animal facilities at WIL Research Laboratories, LLC are accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC International).
- Diet: Provided ad libitum. PMI Nutrition International, LLC Certified Rodent LabDiet® 5002. Feeders were changed and sanitized once per week.
- Water: Provided ad libitum. Reverse osmosis-purified (on site) drinking water, delivered by an automatic watering system.
- Acclimation period: 21 days
ENVIRONMENTAL CONDITIONS
- Temperature: 22°C +/- 3°C (target); 21.1°C to 21.4°C (actual temps)
- Humidity: 50% +/- 20% (target); 37.7% to 57.1% (actual temps)
- Air changes: 10/hr minimum
- Photoperiod: 12-hour light (0600 hours to 1800 hours)/12-hour dark
IN-LIFE DATES: From: 22 September 2009 To: 6 January 2010
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: Mineral oil USP
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: The test substance (45% [w/w] in 55% [w/w] mineral oil) can become non-homogeneous upon stationary storage; therefore, the bulk test substance was warmed to approximately 60ºC and inverted approximately 20 times prior to preparing the formulations. The test substance formulations were prepared daily during 13-18 October 2009 and approximately weekly thereafter as single formulations for each dosage level, divided into aliquots for daily dispensation, and stored at room temperature. The test substance formulations were stirred continuously throughout the dose administration procedures. The vehicle and test substance formulations were administered orally by gavage, via an appropriately sized flexible, Teflon®-shafted, stainless steel ball-tipped dosing cannula (Natume, Japan) once daily.
VEHICLE
- Lot/batch no. (if required): (lot nos. XX1110 and YG1036, exp dates: 15 July 2010 and 18 September 2011.
- Supplier: Spectrum Chemical Manufacturing Corporation, New Brunswick, NJ and Gardena, CA, - Details on mating procedure:
- The animals were paired on a 1:1 basis within each treatment group following 14 days of treatment for the males and females. Each female was housed in the home cage of the male. Positive evidence of mating was confirmed by the presence of a vaginal copulatory plug or the presence of sperm following a vaginal lavage and verified by a second biologist. Each mating pair was examined daily. The day when evidence of mating was identified was termed gestation day 0. If evidence of copulation was not detected after 14 days of pairing, any females that had not shown evidence of mating were placed in plastic maternity cages.
For the purpose of calculating pre-coital intervals, rats paired over a 12-hour dark cycle were considered to have been paired for 1 day. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The analyzed dosing formulations were within the WIL Research Laboratories, LLC’s standard operating procedure range for suspensions (85% to 115%), were homogeneous, and were stable for 10 days at room temperature. Based on these results, the protocol-specified dosages of test substance were administered to the animals. The test substance was not detected in the vehicle formulation that was administered to the control group (Group 1).
Prior to the initiation of dose administration, quadruplicate samples for homogeneity and concentration determination were collected from the top, middle, and bottom strata of the 20 and 200 mg/mL non-dosing formulations. For the assessment of 5- and 10-day stability and aliquot resuspension homogeneity, aliquots approximately equivalent in volume to a daily dispensation aliquot, were transferred from the pre-initiation batch into the same type of storage container that was used for the daily aliquots for dosing. After storage at room temperature for 5- and 10-days, each aliquot was resuspended for a minimum of 30 minutes by warming the test substance formulations to 60ºC (while stirring), and quadruplicate samples were withdrawn from the top and bottom strata of each aliquot for assessment of 5- and 10-day stability and aliquot resuspension homogeneity. Samples for homogeneity and concentration analyses were collected from the middle stratum of the control formulation and the top, middle, and bottom strata of each batch of test substance dosing formulations. Samples from the first and last dosing batch were analyzed for homogeneity and concentration. All analyses were conducted by the Analytical Chemistry Department, WIL Research Laboratories, LLC using a validated high performance liquid chromatography method using ultraviolet absorbance detection. - Duration of treatment / exposure:
- Males: Dosed during study days 0-27 (14 days prior to pairing through 1 day prior to scheduled euthanasia) for a total of 28 doses.
Females: Dosed from study day 0 through the day prior to euthanasia (14 days prior to pairing through lactation day 3) for a total of 39-45 doses. Females with no evidence of mating or that failed to deliver were dosed through the day prior to euthanasia (post cohabitation day 25 or post-mating day 25) for a total of 39-42 doses. - Frequency of treatment:
- Once daily at approximately the same time each day
- Details on study schedule:
- The animals were approximately 14 weeks old when paired on study day 13.
Doses / concentrationsopen allclose all
- Remarks:
- Doses / Concentrations:
100, 300, or 1000 mg/kg/day administered at a dosage volume of 5 mL/kg.
Basis:
other: actual (gavage)
- Dose / conc.:
- 100 mg/kg bw/day (nominal)
- Dose / conc.:
- 300 mg/kg bw/day (nominal)
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 12/sex/group
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: Based on results of a previous study.
- Rationale for animal assignment (if not random): body weight stratification in a block design using a computer randomization procedure
- Positive control:
- None
Examinations
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily for mortality and moribundity
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Detailed physical examinations were recorded weekly (prior to test substance administration during the treatment period) and on the day of necropsy. Each male and female was also observed for signs of toxicity approximately 1-2 and 3 hours following dose administration. The absence or presence of findings was recorded for individual animals. In addition, findings at the time of dose administration were recorded for individual animals. Females expected to deliver were observed twice daily during the period of expected parturition and at parturition for dystocia (prolonged labor, delayed labor) or other difficulties.
BODY WEIGHT: Yes
- Time schedule for examinations: Males: recorded weekly throughout the study and prior to the scheduled euthanasia. Females: recorded weekly until evidence of copulation was observed. Once evidence of mating was observed, female body weights were recorded on gestation days 0, 4, 7, 11, 14, 17, and 20 and on lactation days 0 (when possible), 1, and 4.
FOOD CONSUMPTION: Yes
- Individual food consumption was recorded on the corresponding weekly body weight days until pairing. Food intake was not recorded during the mating period. Once evidence of mating was observed, female food consumption was recorded on gestation days 0, 4, 7, 11, 14, 17, and 20 and on lactation days 1 and 4. - Oestrous cyclicity (parental animals):
- Not evaluated
- Sperm parameters (parental animals):
- Not evaluated
- Litter observations:
- PARTURITION
All females were allowed to deliver naturally and rear their young to PND 4. During the period of expected parturition, the females were observed twice daily for initiation and completion of parturition and for signs of dystocia. On the day parturition was initiated (PND 0), pups were sexed and examined for gross malformations, and the numbers of stillborn and live pups were recorded. Individual gestation length was calculated using the date delivery started.
LITTER VIABILITY AND DEATHS
Each litter was examined daily for survival, and all deaths were recorded. All pups were individually identified by application of tattoo markings on the digits following completion of parturition. A daily record of litter size was maintained. Intact offspring found dead were necropsied using a fresh dissection technique, which included examination of the heart and major vessels. The carcass of each pup was then discarded.
CLINICAL OBSERVATIONS
Litters were examined daily for survival and any adverse changes in appearance or behavior. Each pup received a detailed physical examination on PND 1 and 4. Any abnormalities in nursing behavior were recorded.
BODY WEIGHTS
Pups were individually weighed on PND 1 and 4. Mean pup weights were presented by sex for each litter and by dose group. When body weights could not be determined for a pup during a given interval (due to an unscheduled death, weighing error, etc.), group mean values were calculated for that interval using the available data. The time periods a given pup was not weighed were designated as “NA” (Not Applicable) on the individual report tables.
SEX DETERMINATION
Pups were individually sexed on PND 0 and 4. - Postmortem examinations (parental animals):
- POST-MORTEM EXAMINATIONS: Yes
- F0 males were sacrificed following completion of the mating period; F0 females were sacrificed on post-mating day or post-cohabitation day #25, or on lactation day 4.
GROSS PATHOLOGY: Yes, all animals were euthanized using carbon dioxide inhalation.
- Organs examined (F0): Necropsy included examination of the external surface, all orifices, the external surface of the brain, and the cranial, thoracic, abdominal, and pelvic cavities, including viscera.
- Organs weighed (F0): brain, epididymides, kidneys, liver, ovaries with oviducts, pituitary, testes
HISTOPATHOLOGY: Yes (control and high-dose groups)
Tissues examined (F0): Coagulating glands, mammary gland (female only), ovaries and oviducts, pituitary gland, prostate gland, seminal vesicles, testes with epididymides and vas deferens (fixed in Bouin's solution), uterus with cervix and vagina, all gross lesions. After fixation, protocol-specified tissues were trimmed according to WIL SOP's and the protocol. Trimmed tissues were processed into paraffin blocks, sectioned at 4 to 8 microns, mounted on glass microscope slides, and stained with hematoxylin and eosin. - Postmortem examinations (offspring):
- On PND 4, surviving F1 pups were euthanized via an intraperitoneal injection of sodium pentobarbital and discarded without examination.
- Statistics:
- Analyses were conducted using two-tailed tests (except as noted otherwise) for minimum significance levels of 1% and 5%, comparing each test substance-treated group to the control group by sex. Each mean was presented with the standard deviation (S.D.), standard error (S.E.), and the number of animals (N) used to calculate the mean. Data obtained from nongravid females were excluded from statistical analyses following the mating period. Where applicable, the litter was used as the experimental unit.
Parental mating, fertility, conception, and copulation indices were analyzed using the Chi square test with Yates’ correction factor (Hollander and Wolfe, 1999). Histopathological findings were analyzed by the Fisher’s Exact Test (Steel, 1980). Mean parental body weights (weekly, gestation, and lactation), body weight changes, and food consumption, offspring body weights and body weight changes, gestation length, numbers of corpora lutea and former implantation sites, number of pups born, live litter size on PND 0, unaccounted-for sites, absolute and relative organ weights, and pre coital interval values were subjected to a parametric one way analysis of variance (ANOVA) (Snedecor and Cochran, 1980) to determine intergroup differences between the control and test substance-treated groups. If the ANOVA revealed significant (p<0.05) intergroup variance, Dunnett's test (Dunnett, 1964) was used to compare the test substance-treated groups to the control group. Mean litter proportions (percent per litter) of males at birth and postnatal survival were subjected to the Kruskal-Wallis nonparametric ANOVA (Kruskal and Wallis, 1952) to determine intergroup differences between the control and test substance-treated groups. If the ANOVA revealed significant (p<0.05) intergroup variance, Dunn’s test (Dunn, 1964) was used to compare the test substance-treated groups to the control group. - Reproductive indices:
- Mating, fertility, and copulation/conception indices were calculated.
- Offspring viability indices:
- Mean Live Litter Size, Postnatal Survival Between Birth and PND 0 or PND 4 (% Per Litter), and Postnatal Survival Between PND 0-1 and PND 1-4 (% Per Litter) were calculated.
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Test substance-related, adverse behaviour/CNS-related findings of intermittent tremors, repetitive movement of mouth and jaws, excessive pawing and/or licking of the cage floor and/or walls (females only, beginning on study day 13), and/or head twitch were noted in the 1000 mg/kg/day group males and females at 1-2 and/or 3 hours following dose administration beginning on study day 12 and continuing sporadically throughout the remainder of treatment. Test substance-related, non-adverse, salivation or evidence thereof (clear material around the mouth) was noted in the 1000 mg/kg/day group males and females generally throughout the treatment period prior to dosing and 1 2 and/or 3 hours following dose administration. In addition, clinical findings of orange, orangish-red, and/or red material on various body surfaces were noted for males and females in all test substance-treated groups at all observation time points generally throughout the treatment period and were considered to be associated with the dark red color of the dosing formulations and were not considered adverse.
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- There were no test substance-related effects on mean body weights or body weight gains.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- There were no test substance-related effects on food consumption for males throughout the treatment period or for females during the pre-mating, gestation, or lactation treatment periods at any dosage level.
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not examined
- Haematological findings:
- not specified
- Clinical biochemistry findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- no effects observed
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- not specified
- Reproductive function: sperm measures:
- not specified
- Reproductive performance:
- no effects observed
- Description (incidence and severity):
- The following indices were calculated: Male Mating Index (%), Female Mating Index (%), Male Fertility Index (%), Female Fertility Index (%), Male Copulation Index (%), Female Conception Index (%), Pre-Coital Interval (days). No test substance-related effects on reproductive performance were observed at any dosage level. No statistically significant differences were noted between the control and test substance treated groups. The mean numbers of days between pairing and coitus in the test substance-treated groups were similar to the control group value.
Details on results (P0)
Test substance-related, adverse behavior/CNS-related findings of intermittent tremors, repetitive movement of mouth and jaws, excessive pawing and/or licking of the cage floor and/or walls (females only, beginning on study day 13), and/or head twitch were noted in the 1000 mg/kg/day group males and females at 1-2 and/or 3 hours following dose administration beginning on study day 12 and continuing sporadically throughout the remainder of treatment. Test substance-related, non-adverse, salivation or evidence thereof (clear material around the mouth) was noted in the 1000 mg/kg/day group males and females generally throughout the treatment period prior to dosing and 1 2 and/or 3 hours following dose administration. In addition, clinical findings of orange, orangish-red, and/or red material on various body surfaces were noted for males and females in all test substance-treated groups at all observation time points generally throughout the treatment period and were considered to be associated with the dark red color of the dosing formulations and were not considered adverse.
BODY WEIGHT AND WEIGHT GAIN
There were no test substance-related effects on mean body weights or body weight gains.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
There were no test substance-related effects on food consumption for males throughout the treatment period or for females during the pre-mating, gestation, or lactation treatment periods at any dosage level.
ORGAN WEIGHTS
Females in the top dose group (1000 mg/kg/day) had a higher mean liver weight when compared with the control group.
GROSS AND MICROSCOPIC PATHOLOGY
One female from this group had yellow areas on the liver at the time of necropsy, which correlated histologically to areas of liquefactive necrosis. The affected rat also had the highest liver weight. The relationship between administration of the test substance and the hepatic necrosis is uncertain, as the liver was examined microscopically only for the animal with gross necropsy findings in the liver. There were no other test substance-related histologic changes.
In reproductive tissues, no test substance-related changes in organ weights, gross necropsy observations, or histologic changes were detected.
REPRODUCTIVE PERFORMANCE
The following indices were calculated: Male Mating Index (%), Female Mating Index (%), Male Fertility Index (%), Female Fertility Index (%), Male Copulation Index (%), Female Conception Index (%), Pre-Coital Interval (days). No test substance-related effects on reproductive performance were observed at any dosage level. No statistically significant differences were noted between the control and test substance treated groups. The mean numbers of days between pairing and coitus in the test substance-treated groups were similar to the control group value.
GESTATION LENGTH
Mean gestation lengths in the 100, 300, and 1000 mg/kg/day groups were similar to those in the control group. No statistically significant differences were noted. No signs of dystocia were noted in these groups.
Effect levels (P0)
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- systemic effects
- Effect level:
- 300 mg/kg bw/day (actual dose received)
- Sex:
- male/female
- Basis for effect level:
- other: Based on behavior/CNS-related findings and increased mean liver weights at 1000 mg/kg/day.
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- reproductive effects
- Effect level:
- >= 1 000 mg/kg bw/day (actual dose received)
- Sex:
- male/female
- Basis for effect level:
- other: No effects seen at the highest dose level.
Target system / organ toxicity (P0)
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 1 000 mg/kg bw/day (actual dose received)
- System:
- central nervous system
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- not specified
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- no effects observed
- Mortality / viability:
- mortality observed, non-treatment-related
- Description (incidence and severity):
- The mean number of pups born, live litter size, and the percentage of males at birth in the 100, 300, and 1000 mg/kg/day groups were similar to the control group values. Postnatal survival between birth and PND 0 (relative to number born), PND 0-1 and 1-4, and from birth to PND 4 in the 100, 300, and 1000 mg/kg/day groups was unaffected by parental test substance administration. No statistically significant differences from the control group were noted.
The numbers of pups (litters) found dead during PND 0-4 numbered 1(1), 2(2), 2(1), and 6(4) in the control, 100, 300, and 1000 mg/kg/day groups, respectively. Aside from the presence or absence of milk in the stomach, no other internal findings were noted. - Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- Mean male and female pup body weights and body weight changes in the 100, 300, and 1000 mg/kg/day groups were unaffected by test substance administration during PND 1-4. No statistically significant differences from the control group were noted.
- Anogenital distance (AGD):
- not examined
- Nipple retention in male pups:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- not examined
Details on results (F1)
The mean number of pups born, live litter size, and the percentage of males at birth in the 100, 300, and 1000 mg/kg/day groups were similar to the control group values. Postnatal survival between birth and PND 0 (relative to number born), PND 0-1 and 1-4, and from birth to PND 4 in the 100, 300, and 1000 mg/kg/day groups was unaffected by parental test substance administration. No statistically significant differences from the control group were noted.
GENERAL PHYSICAL CONDITION
The general physical condition of all F1 pups in this study were unaffected by test substance administration.
OFFSPRING BODY WEIGHTS
Mean male and female pup body weights and body weight changes in the 100, 300, and 1000 mg/kg/day groups were unaffected by test substance administration during PND 1-4. No statistically significant differences from the control group were noted.
NECROPSIES OF PUPS FOUND DEAD
The numbers of pups (litters) found dead during PND 0-4 numbered 1(1), 2(2), 2(1), and 6(4) in the control, 100, 300, and 1000 mg/kg/day groups, respectively. Aside from the presence or absence of milk in the stomach, no other internal findings were noted.
Effect levels (F1)
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- neonatal toxicity
- Generation:
- F1
- Effect level:
- >= 1 000 other: mg/kg/bw (maternal)
- Sex:
- male/female
- Basis for effect level:
- other: No effects seen on litter data, postnatal survival or pup body weights through PND 4.
Target system / organ toxicity (F1)
- Key result
- Critical effects observed:
- no
Overall reproductive toxicity
- Key result
- Reproductive effects observed:
- no
Applicant's summary and conclusion
- Conclusions:
- Based on behavior/CNS-related findings and increased mean liver weights at 1000 mg/kg/day, the NOAEL for male and female systemic toxicity was considered to be 300 mg/kg/day. Based on the absence of effects on postnatal survival or pup body weights, the NOAEL for neonatal toxicity was determined to be 1000 mg/kg/day.
- Executive summary:
EC# 457-320-2 has been tested in a guideline (OECD 421) reproductive/developmental toxicity GLP screening study. The test substance in mineral oil vehicle was administered orally by gavage once daily to 3 groups of Crl:CD(SD) rats, each group consisting of 12 males and 12 females. Dosage levels were 100, 300, and 1000 mg/kg/day administered at a dosage volume of 5 mL/kg. A concurrent control group of 12 rats/sex received the vehicle (mineral oil, USP) on a comparable regimen. Males and females were approximately 12 weeks of age at the beginning of test substance administration. Males received 14 daily doses prior to mating. Males were dosed throughout the mating period through 1 day prior to euthanasia for a total of 28 doses. Females received 14 daily doses prior to pairing and were dosed through lactation day 3 for a total of 39–45 doses; females with no evidence of mating or those that failed to deliver were dosed through the day prior to euthanasia (post-cohabitation day 25 or post-mating day 25) for a total of 39–42 doses. All animals were observed twice daily for mortality and moribundity. Clinical observations, body weights, and food consumption were recorded at appropriate intervals. All F0 females were allowed to deliver and rear their pups until lactation day 4. F1 clinical observations and body weights were recorded on postnatal days (PND) 1 and 4. Necropsies were performed on pups that died. All other F1 pups were euthanized on PND 4 and discarded without further examination. F0 males were euthanized following completion of the mating period and F0 females were euthanized on post-mating day 25 (females with evidence of mating), post-cohabitation day 25 (females with no evidence of mating), or on lactation day 4. Complete necropsies were conducted on all F0 animals, and selected organs were weighed. Selected tissues of the reproductive system were examined microscopically from all F0 animals in the control and high-dose groups.
All male and female rats survived to the scheduled necropsy. Test substance-related, adverse behaviour/CNS-related findings of intermittent tremors, repetitive movement of mouth and jaws, excessive pawing and/or licking of the cage floor and/or walls (females only, beginning on study day 13), and/or head twitch were noted in the 1000 mg/kg/day group males and females at 1–2 and/or 3 hours following dose administration beginning on study day 12 and continuing sporadically throughout the remainder of treatment. There were no test substance-related effects on mean body weights, body weight gains, or food consumption for males throughout the treatment period or for females during the pre-mating, gestation, or lactation treatment periods at any dosage level.
There were no test substance-related effects on male and female reproductive performance (mating, fertility, copulation, and conception indices and pre-coital intervals), mean gestation lengths, or the process of parturition at any dosage level.
Females in the top dose group (1000 mg/kg/day) had a higher mean liver weight when compared with the control group. In reproductive tissues, no test substance-related changes in organ weights, gross necropsy observations, or histologic changes were detected. In addition, the mean numbers of unaccounted-for sites, former implantation sites, and corpora lutea were similar between the control and test substance-treated groups.
There were no effects on the numbers of pups born, live litter size, percentage of males at birth, pup survival, or on mean male and female pup body weights and body weight gains during PND 1–4. No test substance-related clinical findings were noted for pups at any dosage level; no test substance-related macroscopic findings were observed in pups that were found dead.
In the absence of test substance-related effects on reproductive performance, gestation lengths, parturition, live litter size, numbers of pups born, and reproductive organs, a dosage level of 1000 mg/kg/day (the highest dosage level tested) was considered to be the no-observed-adverse-effect level (NOAEL) for reproductive toxicity of the test substance when administered orally by gavage to Crl:CD(SD) rats. Based on behaviour/CNS-related findings and increased mean liver weights at 1000 mg/kg/day, the NOAEL for male and female systemic toxicity was considered to be 300 mg/kg/day. Based on the absence of effects on postnatal survival or pup body weights, the NOAEL for neonatal toxicity was determined to be 1000 mg/kg/day.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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