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EC number: 806-543-7 | CAS number: 215917-77-4
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Endpoint summary
Administrative data
Key value for chemical safety assessment
Effects on fertility
Description of key information
There was no evidence of adverse effects on parental reproductive indices following repeated oral exposure of the test substance, with the NOAEL set as 1000 mg/kg/day in parental animals under the conditions of the test.
Link to relevant study records
- Endpoint:
- screening for reproductive / developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- 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:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
- Specific details on test material used for the study:
- Lot no.: 140220
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories Japan, Inc. (Hino Breeding Centre).
- Age at study initiation: (P) 9 wks
- Weight at study initiation: (P) Males: 320.9-367.7 g; Females: 214.9-240.8 g
- Housing: Males and females (except during the gestation and lactation periods); stainless steel cages. For females during the gestation and lactation periods; polymethylpentane cages.
- Diet (e.g. ad libitum): Ad libitum (except during the urine collection and during measurement of motor activity) autoclaved sterilized pellet diet (CRF-1, oriental yeast co. Ltd.). Animals were fasted on the day before scheduled necropsy.
- Water (e.g. ad libitum): Ad libitum (except during the measurement of motor activity) well water.
- Acclimation period: 6 Days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 to 24.3
- Humidity (%): 48.6 to 69.8
- Air changes (per hr): 10 to 20
- Photoperiod (hrs dark / hrs light): 12 hours light, 12 hours dark - Route of administration:
- oral: gavage
- Vehicle:
- other: 0.5% w/v% methyl cellulose aqueous solution
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
The dosing preparations were prepared once every 4-8 days (based on the results of previous stability and homogeniety assessments). The test substance was initially ground in an agate pestle and mortar, and a few drops of vehicle added. This suspension was then transferred into a measuring cylinder. The appropriate volumes of the vehicle was added to the measuring cyclinder and mixed to achieve the required concentrations which were then added into brown glass vials and stored refrigerated until use.
VEHICLE
- Concentration in vehicle: 0, 11, 33 and 100 mg/mL
- Amount of vehicle (if gavage): Dose volume of 10 mL/kg/day
- Lot/batch no. (if required): PDG1792 - Details on mating procedure:
- - M/F ratio per cage: 1:1
- Length of cohabitation: Until evidence of mating was apparent (upto 6 days).
- Proof of pregnancy: vaginal plug and/or sperm in vaginal smear referred to as day 0 of gestation.
- After successful mating each pregnant female was caged individually. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- At the initial test substance preparation, 15 mL of each of the analytical samples were tested for homogeneity and analytical determination. The measured concentrations were within acceptable ranges (actual values 98.4 to 100.3% of nominal).
- Duration of treatment / exposure:
- Males: From 14 days before mating (Days 1 to 15) until the day before the necropsy through the mating period (42 days in total).
Females: From 14 days before mating (Days 1 to 15) until Day 4 of lactation (day of delivery was Day 0 of lactation) through the mating and pregnancy periods and delivery. One female not which did not deliver was kept until day before the necropsy. - Frequency of treatment:
- Parental males and females daily by oral gavage.
- Details on study schedule:
- - Age at mating of the mated animals in the study: approximately 11 weeks
- Remarks:
- Doses / Concentrations:
0, 110, 330 and 1000 mg/kg/day.
Basis:
nominal conc. - No. of animals per sex per dose:
- - A total of 106 rats were used on study (48 males and 58 females).
- Each test group consisted of 12 males (including 5 males for the control and 1000 mg/kg groups in the recovery test) and 12 females (5 females
each were added for the control and 1000 mg/kg groups in the recovery test). - Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: A preceeding 14 Day repeated dose oral study with the test substance to rats, indicated that at a high dose of 1000 mg/kg/day would be expected to provide obvious toxicological changes.
- Parental animals: Observations and examinations:
- See Chapter 7.5.1, record Repeated dose toxicity: oral.001
- Oestrous cyclicity (parental animals):
- Vaginal smears were collected with swabs from all test females in the morning (same time every day) from the initial dosing day to the day of mating or end of the mating period to confirm the estrous cycle. The obtained smears were collected on a plate for each animal, and stained with Giemsa.The estrous cycle was classified into diestrus (D), proestrus (P), estrus (E), and metestrus (M). The mean estrous cycle (number of
days from the estrous period to the next estrous period) and the number of the estrous period during the test period were calculated. - Sperm parameters (parental animals):
- Not examined
- Litter observations:
- PARAMETERS EXAMINED
The following parameters were examined in [F1] offspring:
Number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities.
GROSS EXAMINATION OF DEAD PUPS:
Yes, for external abnormalities. - Postmortem examinations (parental animals):
- Necropsy and histopathology procedures are described in Chapter 7.5.1, record Repeated dose toxicity: oral.001
- Postmortem examinations (offspring):
- SACRIFICE
- The F1 offspring were sacrificed on Day 4 of lactation.
- These animals were subjected to postmortem macroscopic examination (external anomalies).
GROSS NECROPSY
- Gross necropsy consisted of a check for external anomalies, including that in the oral cavity. - Statistics:
- Histopathological findings were analysed using Fisher's exact probability test. Copulation index, fertility index, gestation index, delivery index and sex ratio were analysed using the Chi-squared test. Implantation index, stillborn rate, external anomaly index, external anomaly typing index, live birth index, and viability index were analysed using Wilcoxon's rank sum test.
Number of rearing, grip strength, motor activity, body weights, food consumption, urinalysis (reagent strip), hematology, blood chemistry, absolute and relative organ weight, estrous cycle, number of estrus, days until copulation, gestation length, number of corpora lutea, number of implantations, number of delivered offspring, number of live offspring, body weight of offspring (both sexes) were initially analysed using Bartlett's test. When the data was homogenous the Dunnet's multiple comparison test was applied, and when not homogenous, Steel's multiple comparison test was applied for the control group and each test group. For the urinalysis reagent strip, Steel's test was performed. - Reproductive indices:
- Compulation index (%), fertility index (%), gestation length, implantation index (%), gestation index (%) and delivery index (%) were the determined reproductive indices.
- Offspring viability indices:
- Live birth index (%), stillborn rate (%), Viability index on Day 4 (%), Sex ration (%), external anomaly index (%), and external anomaly typing index (%), were the determined offspring viability indices.
- Clinical signs:
- not examined
- Description (incidence and severity):
- Examined in section 7.5.1
- Body weight and weight changes:
- not examined
- Description (incidence and severity):
- Bodyweight examined in section 7.5.1
- Food consumption and compound intake (if feeding study):
- not examined
- Description (incidence and severity):
- Bodyweight examined in section 7.5.1
- Organ weight findings including organ / body weight ratios:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Description (incidence and severity):
- Examined in section 7.5.1
- Other effects:
- not examined
- Reproductive function: oestrous cycle:
- no effects observed
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- no effects observed
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Sex:
- male/female
- Basis for effect level:
- other: No adverse effects at highest dose tested
- Clinical signs:
- not examined
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- not examined
- Key result
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Sex:
- male/female
- Basis for effect level:
- other: No adverse effects at highest dose tested
- Key result
- Reproductive effects observed:
- not specified
- Conclusions:
- There was no evidence of adverse effects on parental reproductive indices and litter data following repeated oral exposure of the test substance, with the NOAEL set as 1000 mg/kg/day in parental animals and offspring under the conditions of the test.
Reference
There were no treatment-related differences in:
- Estrus cycling
- precoital time
- the number of pregnant females
- duration of gestation
- mean numbers of corpora lutae
- number of total, pre-implantation and post-implantation sites
Selected results by dose level (0, 110, 330 or 1000 mg/kg bw/day).
- females mated: 12/12, 12/12, 12/12, 12/12
- females pregnant: 12/12, 12/12, 12/12, 11/12
- females with live pups: 12/12, 12/12, 12/12, 11/12
- Copulation indices (%): 100, 100, 100, 100
- fertility Indices (%): 100, 100, 100, 91.7
No statistically significant difference was noted in number of live offspring at birth, number of stillborn at birth, sex ratio, stillborn rate, or viability indexon Day 4 between the control group and any treated group. In addition, a high value of the birth index was observed in the 1000 mg/kg group; however, this change was judged to be not related to the test substance treatment because the post-implantation losses were a few.
BODY WEIGHT (OFFSPRING)
No statistically significant difference was observed between the control group and any treated group in body weight on days 0 and 4 of postpartum.
GROSS PATHOLOGY (OFFSPRING)
No external anomalies were observed in any offspring.
Effect on fertility: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 1 000 mg/kg bw/day
- Study duration:
- subchronic
- Species:
- rat
Effect on fertility: via inhalation route
- Endpoint conclusion:
- no study available
Effect on fertility: via dermal route
- Endpoint conclusion:
- no study available
Effects on developmental toxicity
Description of key information
There was no evidence of adverse effects on litter data following repeated oral exposure of the test substance, with the NOAEL set as 1000 mg/kg/day in offspring under the conditions of the test.
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 1 000 mg/kg bw/day
Effect on developmental toxicity: via inhalation route
- Endpoint conclusion:
- no study available
Effect on developmental toxicity: via dermal route
- Endpoint conclusion:
- no study available
Justification for classification or non-classification
A reliable combined repeated dose and reproductive screening study was conducted which indicated that there was no evidence of adverse effects on parental reproductive indices and litter data following repeated oral exposure of the test substance, with the NOAEL set as 1000 mg/kg/day in parental animals and offspring under the conditions of the test. The test material was not classified for reproductive effects based on the available information under the CLP Regulation (EC) No 1272/2008, as amended for the twelfth time in Regulation (EC) No 2019/521.
Additional information
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.
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