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EC number: 215-325-5 | CAS number: 1321-74-0
- Life Cycle description
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- Endpoint summary
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- 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
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- Toxicological Summary
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- Acute Toxicity
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- Toxicity to reproduction
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- Additional toxicological data
Endpoint summary
Administrative data
Key value for chemical safety assessment
Effects on fertility
Description of key information
Reproductive toxicity study
The data available for 1,2-di(ethenyl)benzene was reviewed to determine the reproductive toxicity. No Observed Adverse Effect Level (NOAEL) for reproductive toxicity in male was considered to be 1000mg/kg/day and for female was considered to be 300mg/kg. No Observed Adverse Effect Level (NOAEL) for developmental toxicity was considered to be 30 mg/kg as body weight was found to be lower by administration of 100 mg / kg ,When male and female Sprague-Dawley rats were treated with 1,2-di(ethenyl)benzene orally.Thus, comparing this value with the criteria of CLP regulation1,2-di(ethenyl)benzene not likely to classify as reproductive toxicant.
Link to relevant study records
- Endpoint:
- screening for reproductive / developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- data from handbook or collection of data
- Justification for type of information:
- Data from J- check
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Principles of method if other than guideline:
- Repeated oral administration toxicity / reproductive developmental toxicity combined study of test material was performed on rats
- GLP compliance:
- not specified
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS- Source: Charles River Japan- Age at study initiation: 8-week-old- Weight at study initiation: Males :315 to 352 g Females :211 to 239 g - Fasting period before study:- Housing: stainless steel cages were used to keep up to 5 groups per cage. In addition, the mother animals were individually transferred to a plastic cage containing autoclaved bedding (Sunflake, Japan Charles River ) on the 18th day of pregnancy,- Use of restrainers for preventing ingestion (if dermal): yes/no- Diet (e.g. ad libitum): solid feed (CRF- 1, Oriental Yeast Co., Ltd. ), ad libitum- Water (e.g. ad libitum): drinking water was freely ingested in tap water. ad libitum- Acclimation period: 7 daysENVIRONMENTAL CONDITIONS- Temperature (°C):20 to 24 ° C.- Humidity (%):40 to 70%,- Air changes (per hr):12 times / hour- Photoperiod (hrs dark / hrs light):light and darkeach for 12 hours (lighting: 6 am to 6 pm)
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- Details on exposurePREPARATION OF DOSING SOLUTIONS:The test substance was prepared by diluting it with corn oil.DIET PREPARATION- Rate of preparation of diet (frequency):No data available- Mixing appropriate amounts with (Type of food )- Storage temperature of food: No data availableVEHICLE- Justification for use and choice of vehicle (if other than water): test material soluble corn oil- Concentration in vehicle: 0, 30, 100, 300 and1000 mg / kg- Amount of vehicle (if gavage): 5 ml/kg- Lot/batch no. (if required): No data available- Purity: No data available
- Details on mating procedure:
- - M/F ratio per cage:1:1- Length of cohabitation:14 days - Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy:a female who confirmed sperm or vaginal plug in vaginal plaque was a mating animal and the day was counted as the 0th day of pregnancy- After successful mating each pregnant female was caged (how):an individual cage
- Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- 50 days
- Frequency of treatment:
- daily
- Remarks:
- 0, 30, 100, 300, 1000 mg/kg bw/day
- No. of animals per sex per dose:
- Total:1200 mg/kg bw/day: 12 male and 12 females 30mg/kg bw/day:12 male and 12 females100mg/kg bw/day:12 male and 12 females300 mg/kg bw/day:12 male and 12 females1000 mg/kg bw/day:12 male and 12 females
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: The dose was determined according to the results of a preliminary test (administration stage: 0, 125, 250, 500 and 1000 mg / kg, 5 groups in each group) by oral administration for 2 weeks using the male rat previously performed.
- Positive control:
- No data available
- Parental animals: Observations and examinations:
- Parental animals observation and examinationsCAGE SIDE OBSERVATIONS: yes DETAILED CLINICAL OBSERVATIONS: Yes Time schedule: They were observed daily for mortality and clinical signs of toxicityBODY WEIGHT: YesTime schedule for examinations: male: Body weight was measured twice a week. Female: Body weights were measured 14 days before the mating and twice weekly during the mating period, on 0, 7, 14 and 21 gestation during gestation, on 0 and 4 nursing during the feeding period, respectivelyFOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes Feeding amount was measured twice weekly 14 days before the start of the mating and after the end of the mating period. Also, during pregnancy, gestation was measured on 2, 9, 16 and 21 gestation, and during nursing during 4 days of nursing.Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: YCompound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data: No data availableWATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data Time schedule for examinations:
- Oestrous cyclicity (parental animals):
- No data available
- Sperm parameters (parental animals):
- No data available
- Litter observations:
- number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight were observed 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.]ASSESSMENT OF DEVELOPMENTAL NEUROTOXICITY:ASSESSMENT OF DEVELOPMENTAL IMMUNOTOXICITY:
- Postmortem examinations (parental animals):
- Postmortem examinations (Parent Animal)SACRIFICE: A Cesarean section was performed on each female on gestation day 20 immediately following sacrifice by carbon dioxide inhalation.GROSS NECROPSY: The thoracic and abdominal cavities and organs of the dams were examined for grossly evident morphological changes and the carcasses discardedHISTOPATHOLOGY / ORGAN WEIGHTSThe tissues indicated in Table [#] were prepared for microscopic examination and weighed, respectively.: macroscopic examination was performed
- Postmortem examinations (offspring):
- SACRIFICE - The F1 offspring not selected as parental animals and all F2 offspring were sacrificed at [#?] days of age. - These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination) as follows: GROSS NECROPSY: yes - Gross necropsy consisted of [external and internal examinations including the cervical, thoracic, and abdominal viscera.]
- Statistics:
- For the significant difference test, a homogeneous distribution test by the Bartlett method, and if it is equipartised, a variance analysis is performed by the one-way method, and if it is significant, it is done by the Dunnett method. On the other hand, in the case where it was not recognized as equal variance, we performed analysis by one-way method using rank order (Kruskal-Wallis test), and if significant, use Dunnett type test method using ranking.
- Reproductive indices:
- No data available
- Offspring viability indices:
- No data available
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- No abnormalities were observed in any animals throughout the observation period in the control group. Salivation was observed after administration in groups above 30 mg / kg. In the 1000mg / kg group, skin temperature warming and depilation were observed in one case and contamination of the coat in 1 to 8 cases. Salivation was observed in each group up to about 30 minutes after administration, and no change was observed in salivation duration even when administration was continued. Damage to the incisors was observed in the 100 mg / kg group, but only one case was found and it was judged as a contingent case
- Dermal irritation (if dermal study):
- not specified
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- for male: Death and moribund cases were not observed in either group.For female animals, one case of death and one case of moribund were observed in the 1000 mg / kg group
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- The body weights of the 30 and 100 mg / kg group were almost the same as those of the control group. In the 300 mg / kg group, the body weight was significantly lower on the 8th day of administration than in the control group. In the 1000 mg / kg group, there was a significant lower value of body weight on 4 to 50 days of administration than in the control group.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- The food consumption of the 30 mg / kg group was almost the same as that of the control group.In the 100 mg / kg group, a significant increase in food intake was observed on Days 34 and 38 compared to the control group. In the 300 mg / kg group, a significant increase in food intake was observed on the 34 th to 48 th day of administration compared with the control group. In the 1000 mg / kg group, a significant low value of food intake was found on the 3rd day of administration compared to the control group, and a significant high value of food intake was observed on the 13th to 48th days of administration.
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- not specified
- Clinical biochemistry findings:
- not specified
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Necrotic necrosis of the liver, seminiferous tube atrophy of the testes, and sperm granulomas of the epididymis were observed, but they were judged as accidental changes because they were seen at the same degree in the control group or in a small number.
- Histopathological findings: neoplastic:
- not specified
- Other effects:
- not specified
- Reproductive function: oestrous cycle:
- no effects observed
- Description (incidence and severity):
- There was no significant difference in the number of estrous cycles in the administration period (14 days) before mating with the control group in each administration group.
- Reproductive function: sperm measures:
- not specified
- Reproductive performance:
- no effects observed
- Description (incidence and severity):
- Matings were confirmed in all cases except for one control group. There was no significant difference in the number of days required for copulation between the control group and each administration group. In addition, no significant difference was found in the copulation ratio between each administration group and the control group.One unfertilized female was found in the 1000 mg / kg administration group, but there was no significant difference in the conception rate between each administration group and the control group. Conceptional females who did not obtain newborn babies were only one in the 30 mg / kg group, except for deaths in the 1000 mg / kg group and moribund cases.There was no significant difference between the gestation period and the control group in each administration group. In addition, no abnormality was found in the delivery status in any of the animals.In the 30, 100 and 300 mg / kg groups, there were no significant differences in the corpus luteum count, implantation trace number and implantation rate compared to the control group. In the 1000 mg / kg group, the number of corpus luteum and the number of implantation traces were significantly lower than in the control group.In the control group, 100, 300 and 1000 mg / kg group, the birth rate was 100%. In the 30 mg / kg group, the baby rate was 91.7% because no newborn was obtained in one case, but it was judged that it was not based on administration. In the control group, 30, 100 and 300 mg / kg group, no abnormalities were observed in the nursing condition. In the 1000 mg / kg group, 3 maternal animals showed mammary gland development defects and poor nesting defects from day 0 of nursing or day 1 of nursing, and 7 cases of newborn mothers who died in all cases were observed.
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- clinical signs
- mortality
- body weight and weight gain
- food consumption and compound intake
- organ weights and organ / body weight ratios
- gross pathology
- histopathology: non-neoplastic
- reproductive performance
- Remarks on result:
- other: No toxic effects on reproductive function
- Dose descriptor:
- NOAEL
- Effect level:
- 300 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- clinical signs
- mortality
- body weight and weight gain
- food consumption and compound intake
- organ weights and organ / body weight ratios
- gross pathology
- histopathology: non-neoplastic
- reproductive function (oestrous cycle)
- reproductive performance
- Remarks on result:
- other: No effects on reproductive performance
- Critical effects observed:
- not specified
- System:
- other: not specified
- Organ:
- not specified
- Treatment related:
- not specified
- Dose response relationship:
- not specified
- Relevant for humans:
- not specified
- Clinical signs:
- not specified
- Dermal irritation (if dermal study):
- not specified
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- In the 30 mg / kg group, the body weight was significantly higher in males and females on day 0 of nursing than in the control group, but not in a dose dependent manner. In the 100, 300 and 1000 mg / kg group, the body weight was significantly lower in males and females on day 0 of nursing compared to the control group. In the 1000 mg / kg group, there was no significant difference compared with the control group, but the body weight tended to be low in males and females on 4th day of nursing.
- Food consumption and compound intake (if feeding study):
- not specified
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- not specified
- Clinical biochemistry findings:
- not specified
- Urinalysis findings:
- not specified
- Sexual maturation:
- not specified
- Organ weight findings including organ / body weight ratios:
- not specified
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- In the 30 mg / kg group, tail defects and tail were observed, and in the 100 mg / kg group tail necrosis was observed, but both were findings observed in external table observation or general condition observation, and it was judged as a contingent case . Besides, no abnormality was found in any group.
- Histopathological findings:
- not specified
- Other effects:
- not specified
- Behaviour (functional findings):
- not specified
- Developmental immunotoxicity:
- not specified
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 30 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- not specified
- Basis for effect level:
- viability
- body weight and weight gain
- gross pathology
- Remarks on result:
- other: No developmental toxic effects was observed
- Critical effects observed:
- not specified
- System:
- other: not specified
- Organ:
- not specified
- Treatment related:
- not specified
- Dose response relationship:
- not specified
- Relevant for humans:
- not specified
- Reproductive effects observed:
- not specified
- Treatment related:
- not specified
- Relation to other toxic effects:
- not specified
- Dose response relationship:
- not specified
- Relevant for humans:
- not specified
- Conclusions:
- No Observed Adverse Effect Level (NOAEL) for reproductive toxicity in male was considered to be 1000mg/kg/day and for female was considered to be 300mg/kg. No Observed Adverse Effect Level (NOAEL) for developmental toxicity was considered to be 30 mg/kg as body weight was found to be lower by administration of 100 mg / kg ,When male and female Sprague-Dawley rats were treated with 1,2-di(ethenyl)benzene orally.
- Executive summary:
Thecombined repeat dose and reproductive/ developmental toxicity screening test was performed on male and femaleSprague-Dawley rats [Crj: CD (SD) IGS, (SPF)]. The test materialsolublein corn oil in dose concentration 0, 30,100,300,1000mg/kg and administered orally by gavage.The dose was determined according to the results of a preliminary test (administration stage: 0, 125, 250, 500 and 1000 mg / kg, 5 groups in each group) by oral administration for 2 weeks using the male rat previously performed. Male and female rats administered for 14 days were mated together in a 1: 1 combination within the same group. The mating period was limited to 14 days and consecutive living crosses were made until mating was confirmed. Mating was confirmed approximately every morning at a fixed time and a female who confirmed sperm or vaginal plug in vaginal plaque was a mating animal and the day was counted as the 0th day of pregnancy. The general condition and the presence or absence of death was observed twice a day before and after administration. Body weight was measured twice a week. Feeding amount was measured twice weekly 14 days before the start of the mating and after the end of the mating period. The sex cycle was observed once a day from the administration start date to the mating confirmation date. In addition, when the estrus period was observed over 2 consecutive days, it was counted as 1 time. Females who did not deliver until 25th day of pregnancy were sacrificed by exsanguination from the abdominal aorta under ether anesthesia and autopsied, and the success or failure of the pregnancy was confirmed by the presence or absence of implantation. The mother animal was observed daily until the 4th day of nursing and the autopsy was done after leaving the abdominal aorta from the abdominal aorta under ether anesthesia on the day when all newborns died or on the 4thday of nursing. At birth the number of total births and sex, the number of stillborn babies, the number of neonates and the presence or absence of outer table abnormalities were observed. Body weight was measured on day 0 of nursing (birthday) and 4th day.
Death and moribund cases were not observed in either group in male while in female Deaths and moribund cases were not observed in the control group, 30, 100 and 300 mg / kg group.
In the 1000 mg / kg group, one patient died on the 17th day of pregnancy and one died during labor on the 23rdpregnancy. In death cases, salivation, depilation, epidermal decline, loss of locomotor activity, bleeding from the vaginal opening was observed. In the moribund case, salivation, warming of the epidermis, and decline of locomotor activity were observed. In the general condition observation of surviving cases, no abnormalities were observed in any animals throughout the observation period in the control group and 30 mg / kg group. Salivation was observed after administration in the group of 100 mg / kg or more. In the 1000 mg / kg group, hair loss was seen in one case, and the stain on the hair was observed in 1 or 2 cases. Body weights of the 30, 100 and 300 mg / kg group were almost the same as those of the control group, and no significant difference was observed on any measurement day. In the 1000 mg / kg group, there was a significant lower value of body weight. Before the mating, food intake in the 30, 100 and 300 mg / kg group was almost similar to that of the control group, and no significant difference was observed on any measurement day. In the 1000 mg / kg group, a significant lowering of food intake was observed on the 3rd day of administration, on the 21st day of pregnancy, on the 4thday of nursing compared with the control group. At necropsy of the moribund case in the 1000 mg / kg group, atrophy of thymus and dark red spots of glandular gastric mucosa were observed. In the 1000 mg / kg group, significant lower values of the absolute weights of the brain, pituitary and heart as compared with the control group, and significant higher values of the relative weights of the brain and ovary were observed, but these changes were absolute Since a certain tendency was not observed in weight and relative weight, it was judged that it was not based on administration. There was no significant difference in the number of estrous cycles in the administration period (14 days) before mating with the control group in each administration group. There was no significant difference between the gestation period and the control group in each administration group. In addition, no abnormality was found in the delivery status in any of the animals.
In the 30, 100 and 300 mg / kg groups, there were no significant differences in the corpus luteum count, implantation trace number and implantation rate compared to the control group. In the 1000 mg / kg group, the number of corpus luteum and the number of implantation traces were significantly lower than in the control group. In the control group, 100, 300 and 1000 mg / kg group, the birth rate was 100%. In the 30 mg / kg group, the baby rate was 91.7% because no newborn was obtained in one case, but it was judged that it was not based on administration. In the control group, 30, 100 and 300 mg / kg group, no abnormalities were observed in the nursing condition. In the 1000 mg / kg group, 3 maternal animals showed mammary gland development defects and poor nesting defects from day 0 of nursing or day 1 of nursing, and 7 cases of newborn mothers who died in all cases were observed. In the 30, 100 and 300 mg / kg groups, there was no significant difference in the number of neonates, birth rate and sex ratio on day 0 of nursing compared to the control group. In the 30 and 100 mg / kg group, there was no significant difference in the output of children compared with the control group. In the 300 mg / kg group, the child's output rate was significantly higher than that of the control group, but not the dose-dependent change. In the 1000 mg / kg group, there was a significant lower number of neonates and fertility rates on day 0 of nursing compared to the control group, and a low value trend of the output rate of children with no significant difference. In the 30, 100 and 300 mg / kg groups, there was no significant difference in the number of surviving children on 4th day of nursing, the survival rate on 4th day of feeding and the sex ratio compared to the control group. In the 1000 mg / kg group, the number of surviving children on 4th day of nursing and the survival rate on 4th day of nursing were significantly lower than in the control group. In the general condition of the newborn, tail trauma, tail loss, and epidermal decline were seen in each case in the 30 mg / kg group, but both cases were judged to be contingent cases. In the 1000 mg / kg group, a case of trauma of the tail was found in 4 cases in the 4th abdomen (3 mice were mother animals in which mammary gland development failure and nesting defect were observed). In the 30 mg / kg group, the body weight was significantly higher in males and females on day 0 of nursing than in the control group, but not in a dose dependent manner. In the 100, 300 and 1000 mg / kg group, the body weight was significantly lower in males and females on day 0 of nursing compared to the control group. In the 1000 mg / kg group, there was no significant difference compared with the control group, but the body weight tended to be low in males and females on 4th day of nursing. In the 30 mg / kg group, tail defects and tail were observed, and in the 100 mg / kg group tail necrosis was observed, but both were findings observed in external table observation or general condition observation, and it was judged as a contingent case. Besides, no abnormality was found in any group. HenceNo Observed Adverse Effect Level (NOAEL) for reproductive toxicity in male was considered to be 1000mg/kg/day and for female was considered to be 300mg/kg. No Observed Adverse Effect Level (NOAEL) for developmental toxicity was considered to be 30 mg/kg as body weight was found to be lower by administration of 100 mg / kg,When male and femaleSprague-Dawleyrats were treated withtest materialorally.
Reference
Table : Number of estrous cases and reproductive performance of male and female rats in combined repeat dose and reproductive/ developmental toxicity screening test of test material by oral administration
Dose (mg/kg) | 0 | 30 | 100 | 300 | 1000 |
Number of females Number of estrous cases before mating Mean ± S.D. | 12
3.3 ± 0.7 | 12
3.3 ± 0.9 | 12
3.4 ± 0.5 | 12
3.7 ± 0.5 | 12
2.8 ± 1.1 |
Number of pairs
Number of pairs with successful copulation
Copulation index (%)a)
Number of conceiving days Mean ± S.D.
Number of pregnant females
Fertility index (%)b)
Number of pregnant females with live pups | 12
11
91.7
3.1± 1.0
11
100.0
11 | 12
12
100.0
2.3 ± 1.1
12
100.0
11 | 12
12
100.0
2.7 ± 3.4
12
100.0
12 | 12
12
100.0
2.5 ± 1.0
12
100.0
12 | 12
12
100.0
3.5 ± 2.0
11
91.7
9 |
a) : (Number of pairs with successful copulation/number of pairs) X 100
b) : (Number of pregnant females/number of pairs with successful copulation) X 100
Table : Observation of pups in combined repeat dose and reproductive/developmental toxicity screening test of test material by oral administration.
Dose (mg/kg) | 0 | 30 | 100 | 300 | 1000 |
No. Of Dams | 11 | 12 | 12 | 12 | 9 |
Length of gestation( days) Mean ± S.D. per dam |
22.09 ± 0.30 |
22.42 ± 0.67 |
22.08 ± 0.29 |
22.08 ± 0.29 |
22.22 ± 0.44 |
Number of corpora lutea
Mean ± S.D. per dam |
17.5 ± 1.3 |
17.5 ± 1.9 |
17.5 ± 1.5
|
16.1 ± 2.5 |
15.0 ± 2.1* |
Number of implantation scars
Mean ± S.D. per dam |
16.3 ± 1.2 |
16.5 ± 1.3 |
16.1 ± 1.3 |
14.7 ± 2.5 |
13.7 ± 0.2** |
Implantation index
Mean ± S.D. per dama)
Gestation index( %)b) |
92.7 ± 4.6
100.0 |
94.7 ± 6.9
91.7 |
91.9 ± 5.6
100.0 |
91.2 ± 10.1
100.0 |
91.3 ± 8.7
100.0 |
Number of live pups born
Mean ± S.D. per dam |
14.8 ± 1.0 |
13.6 ± 4.4 |
14.7 ± 1.5 |
14.4 ± 2.6 |
9.1 ± 3.0** |
Sex ratio at birth
Mean ± S.D. per damc) |
1.06 ± 0.64 |
1.19 ± 0.66 (11) |
1.25 ± 0.48 |
0.89 ± 0.45 |
1.20 ± 0.78 |
Birth index
Mean ± S.D. per damd) |
91.2 ± 5.6 |
83.9 ± 27.2 |
91.4 ± 9.1 |
98.3 ± 4.4** |
69.3 ± 27.3 |
Number of pups born
Mean ± S.D. per dam |
15.1 ± 0.8 |
15.3 ± 1.6 |
15.0 ± 1.8 |
14.4 ± 2.6 |
11.7 ± 3.1** |
Delivery index
Mean ± S.D. per dame) |
92.8 ± 5.0 |
92.9 ± 6.3 |
93.4 ± 9.3 |
98.3 ± 4.4 |
86.2 ± 21.7 |
Live birth index
Mean ± S.D. per damf) |
98.1 ± 3.3 |
90.1 ± 28.6 |
98.0 ± 3.8 |
100.0 ± 0.0 |
80.7 ± 23.6* |
Number of live pups on day 4 of lactation
Mean ± S.D. per dam |
14.5 ± 0.7 |
14.2 ± 2.0 (11) |
14.6 ± 1.4 |
14.3 ± 2.5 |
2.2 ± 4.4** |
Viability index
Mean ± S.D. per damg) |
97.6 ± 4.2 |
95.5 ± 9.2 (11) |
99.5 ± 1.7 |
98.9 ±2.5 |
20.2 ± 40.4** |
Number of external anomalies
Mean ± S.D. per damh) |
0.0 ± 0.0 |
0.6 ± 2.1 (11) |
0.5 ± 1.7 |
0.0 ± 0.0 |
0.0 ± 0.0 |
Anury
Mean ± S.D. per dam |
0.0 ± 0.0 |
0.6 ± 2.1 (11) |
0.0 ± 0.0 |
0.0 ± 0.0 |
0.0 ± 0.0 |
Necrosis of tail
Mean ± S.D. per dam |
0.0 ± 0.0 |
0.0 ± 0.0 (11) |
0.5 ± 1.7 |
0.0 ± 0.0 |
0.0 ± 0.0 |
Body weight of pups( g)
Mean ± S.D. per dam |
|
|
|
|
|
Male
Day 0
Day 4 |
6.46 ± 0.56
10.17 ± 0.89
|
6.66 ± 0.44**(11)
10.43 ± 1.00 (11) |
6.31 ± 0.46**
9.76 ± 1.26 |
6.28 ± 0.53**
9.86 ± 1.03
|
4.89 ± 0.75**
7.90 (2) |
Female
Day 0
Day 4 |
6.18 ± 0.47
9.66 ± 0.74 |
6.30 ± 0.42**(11)
9.94 ± 1.12 (11) |
5.96 ± 0.47**
9.43 ± 1.25 |
5.84 ± 0.52**
9.18 ± 1.15 |
4.50 ± 0.76**
7.05 (2) |
a) : (Number of implantation mars/number of corpora lutea) X100
b) : (Number of dams with live pups/number of pregnant dams) x100
c) :Number of male pups/number of female pups.
d) : (Number of live pups born/number of implantation scars) X 100
e) : (Number of pups born/number of implantation scars) X 100.
f) : (Number of live pups born/number of pups born) x100
g) : (Number of live pups on day 4/number of live pups born) X 100
h) : (Number of pups with external anomalies/number of live pup s) X 100
Figures in parentheses indicate number of dams.
Significantly different from control( *: p<0.05, **: p<0.01)
Effect on fertility: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 300 mg/kg bw/day
- Study duration:
- subchronic
- Species:
- rat
- Quality of whole database:
- Data is Klimicsh 2 and from authoritative database
Effect on fertility: via inhalation route
- Endpoint conclusion:
- no study available
Effect on fertility: via dermal route
- Endpoint conclusion:
- no study available
Additional information
Reproductive toxicity study
Data available from different studies were reviewed to determine the reproductive toxicity of 1,2-di(ethenyl)benzene.The studies are as mentioned below:
The combined repeat dose and reproductive/ developmental toxicity screening test was performed on male and femaleSprague-Dawley rats [Crj: CD (SD) IGS, (SPF)]. The test materialsolublein corn oil in dose concentration 0, 30,100,300,1000mg/kg and administered orally by gavage.The dose was determined according to the results of a preliminary test (administration stage: 0, 125, 250, 500 and 1000 mg / kg, 5 groups in each group) by oral administration for 2 weeks using the male rat previously performed. Male and female rats administered for 14 days were mated together in a 1: 1 combination within the same group. The mating period was limited to 14 days and consecutive living crosses were made until mating was confirmed. Mating was confirmed approximately every morning at a fixed time and a female who confirmed sperm or vaginal plug in vaginal plaque was a mating animal and the day was counted as the 0th day of pregnancy. The general condition and the presence or absence of death was observed twice a day before and after administration. Body weight was measured twice a week. Feeding amount was measured twice weekly 14 days before the start of the mating and after the end of the mating period. The sex cycle was observed once a day from the administration start date to the mating confirmation date. In addition, when the estrus period was observed over 2 consecutive days, it was counted as 1 time. Females who did not deliver until 25th day of pregnancy were sacrificed by exsanguination from the abdominal aorta under ether anesthesia and autopsied, and the success or failure of the pregnancy was confirmed by the presence or absence of implantation. The mother animal was observed daily until the 4th day of nursing and the autopsy was done after leaving the abdominal aorta from the abdominal aorta under ether anesthesia on the day when all newborns died or on the 4thday of nursing. At birth the number of total births and sex, the number of stillborn babies, the number of neonates and the presence or absence of outer table abnormalities were observed. Body weight was measured on day 0 of nursing (birthday) and 4th day.
Death and moribund cases were not observed in either group in male while in female Deaths and moribund cases were not observed in the control group, 30, 100 and 300 mg / kg group.In the 1000 mg / kg group, one patient died on the 17th day of pregnancy and one died during labor on the 23rdpregnancy. In death cases, salivation, depilation, epidermal decline, loss of locomotor activity, bleeding from the vaginal opening was observed. In the moribund case, salivation, warming of the epidermis, and decline of locomotor activity were observed. In the general condition observation of surviving cases, no abnormalities were observed in any animals throughout the observation period in the control group and 30 mg / kg group. Salivation was observed after administration in the group of 100 mg / kg or more. In the 1000 mg / kg group, hair loss was seen in one case, and the stain on the hair was observed in 1 or 2 cases. Body weights of the 30, 100 and 300 mg / kg group were almost the same as those of the control group, and no significant difference was observed on any measurement day. In the 1000 mg / kg group, there was a significant lower value of body weight. Before the mating, food intake in the 30, 100 and 300 mg / kg group was almost similar to that of the control group, and no significant difference was observed on any measurement day. In the 1000 mg / kg group, a significant lowering of food intake was observed on the 3rd day of administration, on the 21st day of pregnancy, on the 4thday of nursing compared with the control group. At necropsy of the moribund case in the 1000 mg / kg group, atrophy of thymus and dark red spots of glandular gastric mucosa were observed. In the 1000 mg / kg group, significant lower values of the absolute weights of the brain, pituitary and heart as compared with the control group, and significant higher values of the relative weights of the brain and ovary were observed, but these changes were absolute Since a certain tendency was not observed in weight and relative weight, it was judged that it was not based on administration. There was no significant difference in the number of estrous cycles in the administration period (14 days) before mating with the control group in each administration group. There was no significant difference between the gestation period and the control group in each administration group. In addition, no abnormality was found in the delivery status in any of the animals.
In the 30, 100 and 300 mg / kg groups, there were no significant differences in the corpus luteum count, implantation trace number and implantation rate compared to the control group. In the 1000 mg / kg group, the number of corpus luteum and the number of implantation traces were significantly lower than in the control group. In the control group, 100, 300 and 1000 mg / kg group, the birth rate was 100%. In the 30 mg / kg group, the baby rate was 91.7% because no newborn was obtained in one case, but it was judged that it was not based on administration. In the control group, 30, 100 and 300 mg / kg group, no abnormalities were observed in the nursing condition. In the 1000 mg / kg group, 3 maternal animals showed mammary gland development defects and poor nesting defects from day 0 of nursing or day 1 of nursing, and 7 cases of newborn mothers who died in all cases were observed. In the 30, 100 and 300 mg / kg groups, there was no significant difference in the number of neonates, birth rate and sex ratio on day 0 of nursing compared to the control group. In the 30 and 100 mg / kg group, there was no significant difference in the output of children compared with the control group. In the 300 mg / kg group, the child's output rate was significantly higher than that of the control group, but not the dose-dependent change. In the 1000 mg / kg group, there was a significant lower number of neonates and fertility rates on day 0 of nursing compared to the control group, and a low value trend of the output rate of children with no significant difference. In the 30, 100 and 300 mg / kg groups, there was no significant difference in the number of surviving children on 4th day of nursing, the survival rate on 4th day of feeding and the sex ratio compared to the control group. In the 1000 mg / kg group, the number of surviving children on 4th day of nursing and the survival rate on 4th day of nursing were significantly lower than in the control group. In the general condition of the newborn, tail trauma, tail loss, and epidermal decline were seen in each case in the 30 mg / kg group, but both cases were judged to be contingent cases. In the 1000 mg / kg group, a case of trauma of the tail was found in 4 cases in the 4th abdomen (3 mice were mother animals in which mammary gland development failure and nesting defect were observed). In the 30 mg / kg group, the body weight was significantly higher in males and females on day 0 of nursing than in the control group, but not in a dose dependent manner. In the 100, 300 and 1000 mg / kg group, the body weight was significantly lower in males and females on day 0 of nursing compared to the control group. In the 1000 mg / kg group, there was no significant difference compared with the control group, but the body weight tended to be low in males and females on 4th day of nursing. In the 30 mg / kg group, tail defects and tail were observed, and in the 100 mg / kg group tail necrosis was observed, but both were findings observed in external table observation or general condition observation, and it was judged as a contingent case. Besides, no abnormality was found in any group. HenceNo Observed Adverse Effect Level (NOAEL) for reproductive toxicity in male was considered to be 1000mg/kg/day and for female was considered to be 300mg/kg. No Observed Adverse Effect Level (NOAEL) for developmental toxicity was considered to be 30 mg/kg as body weight was found to be lower by administration of 100 mg / kg,When male and femaleSprague-Dawley rats were treated withtest material orally.
Based on the data available from different studies,1,2-di(ethenyl)benzenedid not showed reproductive toxicity at dose concentration 300mg/kg bw/day.Hence the test chemical is not likely to classify as a reproductive toxicant as per the criteria mentioned in CLP regulation.
Effects on developmental toxicity
Description of key information
Developmental toxicity study
The data available for 1,2-di(ethenyl)benzene was reviewed to determine the developmental toxicity .No Observed Adverse Effect Level (NOAEL) for reproductive toxicity in male was considered to be 1000mg/kg/day and for female was considered to be 300mg/kg. No Observed Adverse Effect Level (NOAEL) for developmental toxicity was considered to be 30 mg/kg as body weight was found to be lower by administration of 100 mg / kg ,When male and female Sprague-Dawley rats were treated with test material orally.Thus, comparing this value with the criteria of CLP regulation 1,2-di(ethenyl)benzene not likely to classify as reproductive and developmental toxicant.
Link to relevant study records
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- data from handbook or collection of data
- Justification for type of information:
- Data from J-check
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- other: As mentioned below
- Principles of method if other than guideline:
- Repeated oral administration toxicity / reproductive developmental toxicity combined study of test material was performed on rats
- GLP compliance:
- not specified
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Remarks:
- [Crj: CD (SD) IGS, (SPF)]
- Details on test animals or test system and environmental conditions:
- Details on test animals and env. conditionsTEST ANIMALS- Source: Charles River Japan- Age at study initiation: 8-week-old- Weight at study initiation: Males :315 to 352 g Females :211 to 239 g - Fasting period before study:- Housing: stainless steel cages were used to keep up to 5 groups per cage. In addition, the mother animals were individually transferred to a plastic cage containing autoclaved bedding (Sunflake, Japan Charles River ) on the 18th day of pregnancy,- Use of restrainers for preventing ingestion (if dermal): yes/no- Diet (e.g. ad libitum): solid feed (CRF- 1, Oriental Yeast Co., Ltd. ), ad libitum- Water (e.g. ad libitum): drinking water was freely ingested in tap water. ad libitum- Acclimation period: 7 daysENVIRONMENTAL CONDITIONS- Temperature (°C):20 to 24 ° C.- Humidity (%):40 to 70%,- Air changes (per hr):12 times / hour- Photoperiod (hrs dark / hrs light):light and darkeach for 12 hours (lighting: 6 am to 6 pm)
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- Details on exposurePREPARATION OF DOSING SOLUTIONS:The test substance was prepared by diluting it with corn oil.DIET PREPARATION- Rate of preparation of diet (frequency):No data available- Mixing appropriate amounts with (Type of food )- Storage temperature of food: No data availableVEHICLE- Justification for use and choice of vehicle (if other than water): test material soluble corn oil- Concentration in vehicle: 0, 30, 100, 300 and1000 mg / kg- Amount of vehicle (if gavage): 5 ml/kg- Lot/batch no. (if required): No data available- Purity: No data available
- Analytical verification of doses or concentrations:
- not specified
- Details on mating procedure:
- - Impregnation procedure: [artificial insemination / purchased timed pregnant / cohoused] - If cohoused: - M/F ratio per cage: 1:1 - Length of cohabitation: 14 days - After ... days of unsuccessful pairing replacement of first male by another male with proven fertility. - Further matings after two unsuccessful attempts: [no / yes (explain)] - Verification of same strain and source of both sexes: [yes / no (explain)] - Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy:a female who confirmed sperm or vaginal plug in vaginal plaque was a mating animal and the day was counted as the 0th day of pregnancy - Any other deviations from standard protocol:
- Duration of treatment / exposure:
- 50 days
- Frequency of treatment:
- Daily
- Duration of test:
- 50 days
- Remarks:
- 0, 30, 100, 300, 1000 mg/kg bw/day
- No. of animals per sex per dose:
- Total:1200 mg/kg bw/day: 12 male and 12 females 30mg/kg bw/day:12 male and 12 females100mg/kg bw/day:12 male and 12 females300 mg/kg bw/day:12 male and 12 females1000 mg/kg bw/day:12 male and 12 females
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- No data available
- Maternal examinations:
- Parental animals observation and examinationsCAGE SIDE OBSERVATIONS: yes DETAILED CLINICAL OBSERVATIONS: Yes Time schedule: They were observed daily for mortality and clinical signs of toxicityBODY WEIGHT: YesTime schedule for examinations: male: Body weight was measured twice a week. Female: Body weights were measured 14 days before the mating and twice weekly during the mating period, on 0, 7, 14 and 21 gestation during gestation, on 0 and 4 nursing during the feeding period, respectivelyFOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes Feeding amount was measured twice weekly 14 days before the start of the mating and after the end of the mating period. Also, during pregnancy, gestation was measured on 2, 9, 16 and 21 gestation, and during nursing during 4 days of nursing.Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: YCompound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data: No data available
- Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes Examinations included: - Gravid uterus weight: Yes - Number of corpora lutea: Yes - Number of implantations: Yes - Number of early resorptions: Yes - Number of late resorptions: Yes - Other:
- Fetal examinations:
- - External examinations: Yes: all per litter - Soft tissue examinations:No data - Skeletal examinations: No data - Head examinations: No data
- Statistics:
- For the significant difference test, a homogeneous distribution test by the Bartlett method, and if it is equipartised, a variance analysis is performed by the one-way method, and if it is significant, it is done by the Dunnett method. On the other hand, in the case where it was not recognized as equal variance, we performed analysis by one-way method using rank order (Kruskal-Wallis test), and if significant, use Dunnett type test method using ranking.
- Indices:
- No data available
- Historical control data:
- No data available
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- No abnormalities were observed in any animals throughout the observation period in the control group. Salivation was observed after administration in groups above 30 mg / kg. In the 1000mg / kg group, skin temperature warming and depilation were observed in one case and contamination of the coat in 1 to 8 cases. Salivation was observed in each group up to about 30 minutes after administration, and no change was observed in salivation duration even when administration was continued. Damage to the incisors was observed in the 100 mg / kg group, but only one case was found and it was judged as a contingent case.
- Dermal irritation (if dermal study):
- not specified
- Mortality:
- no mortality observed
- Description (incidence):
- For male: Death and moribund cases were not observed in either group.For female animals, one case of death and one case of moribund were observed in the 1000 mg / kg group
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- The body weights of the 30 and 100 mg / kg group were almost the same as those of the control group, and no significant difference was observed on any measurement day. In the 300 mg / kg group, the body weight was significantly lower on the 8th day of administration than in the control group. In the 1000 mg / kg group, there was a significant lower value of body weight on 4 to 50 days of administration than in the control group.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- The food consumption of the 30 mg / kg group was almost the same as that of the control group, and no significant difference was observed on any measurement day. In the 100 mg / kg group, a significant increase in food intake was observed on Days 34 and 38 compared to the control group. In the 300 mg / kg group, a significant increase in food intake was observed on the 34 th to 48 th day of administration compared with the control group. In the 1000 mg / kg group, a significant low value of food intake was found on the 3rd day of administration compared to the control group, and a significant high value of food intake was observed on the 13th to 48th days of administration.
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- not specified
- Clinical biochemistry findings:
- not specified
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- not specified
- Description (incidence and severity):
- In the 30 mg / kg group, there was no significant difference in absolute weight and relative weight of any organ compared to the control group. In the 100 mg / kg group, a significant elevation of the relative weight of the liver was observed compared to the control group. In the 300 mg / kg group, a significant high value of the absolute weight of the kidney as well as a significant high value of the relative weight of the liver and kidney was observed compared to the control group. In the 1000 mg / kg group, the relative weights of the liver and kidney were significantly higher than the control group, and there was no significant difference, but the absolute weight tendency of the kidney was high. Besides, in the 1000 mg / kg group, significant lower values of the absolute weights of the heart, spleen and epididymis as compared with the control group, and significant higher values of relative weights of the brain and testis were observed The change in absolute weight and relative weight was not found to have a certain tendency, so it was judged that it was not based on administration.
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- There was no abnormality in any of the control group, 30, 100 and 300 mg / kg group. In the 1000 mg / kg group, dark red spots of glandular gastric mucosa were found in one case but judged as a contingent case.At necropsy of surviving cases, no abnormality was observed in the control group and 300 mg / kg group. At 30 mg / kg group, thymus atrophy was found in one case. In the 100 mg / kg group, ulcers of the forestomachial mucosa were found in one case. In the 1000 mg / kg group, whitening of the adrenal glands on both sides occurred in 1 case and atrophy of the thymus was seen in 7 cases. Thymus atrophy was observed at necropsy of deaths in the 1000 mg / kg group. At necropsy of the moribund case in the 1000 mg / kg group, atrophy of thymus and dark red spots of glandular gastric mucosa were observed.
- Neuropathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- Necrotic necrosis of the liver, seminiferous tube atrophy of the testes, and sperm granulomas of the epididymis were observed, but they were judged as accidental changes because they were seen at the same degree in the control group or in a small number
- Histopathological findings: neoplastic:
- not specified
- Other effects:
- not specified
- Number of abortions:
- not specified
- Pre- and post-implantation loss:
- effects observed, treatment-related
- Description (incidence and severity):
- In the 1000 mg / kg group, the number of corpus luteum and the number of implantation traces were significantly lower than in the control group
- Total litter losses by resorption:
- not specified
- Early or late resorptions:
- not specified
- Dead fetuses:
- no effects observed
- Changes in pregnancy duration:
- no effects observed
- Description (incidence and severity):
- Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.DescriptionIncidenceAndSeverityEffectsOnPregnancyDuration): There was no significant difference between the gestation period and the control group in each administration group - Changes in number of pregnant:
- no effects observed
- Other effects:
- not specified
- Dose descriptor:
- NOAEL
- Effect level:
- 300 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- clinical signs
- dead fetuses
- early or late resorptions
- effects on pregnancy duration
- food consumption and compound intake
- gross pathology
- histopathology: non-neoplastic
- mortality
- number of abortions
- pre and post implantation loss
- Remarks on result:
- other: no effects on reproductive performance
- Abnormalities:
- not specified
- Localisation:
- not specified
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- In the 30 mg / kg group, the body weight was significantly higher in males and females on day 0 of nursing than in the control group, but not in a dose dependent manner. In the 100, 300 and 1000 mg / kg group, the body weight was significantly lower in males and females on day 0 of nursing compared to the control group. In the 1000 mg / kg group, there was no significant difference compared with the control group, but the body weight tended to be low in males and females on 4th day of nursing.
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not specified - Reduction in number of live offspring:
- no effects observed
- Changes in sex ratio:
- not specified
- Changes in litter size and weights:
- not specified
- Changes in postnatal survival:
- not specified
- Description (incidence and severity):
- In the 30 mg / kg group, tail defects and tail were observed, and in the 100 mg / kg group tail necrosis was observed, but both were findings observed in external table observation or general condition observation, and it was judged as a contingent case . Besides, no abnormality was found in any group.
- External malformations:
- effects observed, treatment-related
- Skeletal malformations:
- not specified
- Visceral malformations:
- not specified
- Other effects:
- not specified
- Dose descriptor:
- NOAEL
- Effect level:
- 30 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- not specified
- Basis for effect level:
- fetal/pup body weight changes
- changes in litter size and weights
- external malformations
- Remarks on result:
- other: No developmental toxic effects observed
- Abnormalities:
- not specified
- Localisation:
- other: not specified
- Developmental effects observed:
- not specified
- Treatment related:
- not specified
- Relation to maternal toxicity:
- not specified
- Dose response relationship:
- not specified
- Relevant for humans:
- not specified
- Conclusions:
- No Observed Adverse Effect Level (NOAEL) for developmental toxicity was considered to be 30mg/kg/day. When male and female Sprague-Dawley rats were treated with test material orally.
- Executive summary:
Thecombined repeat dose and reproductive/ developmental toxicity screening test was performed on male and femaleSprague-Dawley rats [Crj: CD (SD) IGS, (SPF)]. The test materialsolublein corn oil in dose concentration 0, 30,100,300,1000mg/kg and administered orally by gavage.The dose was determined according to the results of a preliminary test (administration stage: 0, 125, 250, 500 and 1000 mg / kg, 5 groups in each group) by oral administration for 2 weeks using the male rat previously performed. Male and female rats administered for 14 days were mated together in a 1: 1 combination within the same group. The mating period was limited to 14 days and consecutive living crosses were made until mating was confirmed. Mating was confirmed approximately every morning at a fixed time and a female who confirmed sperm or vaginal plug in vaginal plaque was a mating animal and the day was counted as the 0th day of pregnancy. The general condition and the presence or absence of death was observed twice a day before and after administration. Body weight was measured twice a week. Feeding amount was measured twice weekly 14 days before the start of the mating and after the end of the mating period. The sex cycle was observed once a day from the administration start date to the mating confirmation date. In addition, when the estrus period was observed over 2 consecutive days, it was counted as 1 time. Females who did not deliver until 25th day of pregnancy were sacrificed by exsanguination from the abdominal aorta under ether anesthesia and autopsied, and the success or failure of the pregnancy was confirmed by the presence or absence of implantation. The mother animal was observed daily until the 4th day of nursing and the autopsy was done after leaving the abdominal aorta from the abdominal aorta under ether anesthesia on the day when all newborns died or on the 4thday of nursing. At birth the number of total births and sex, the number of stillborn babies, the number of neonates and the presence or absence of outer table abnormalities were observed. Body weight was measured on day 0 of nursing (birthday) and 4th day.
Death and moribund cases were not observed in either group in male while in female Deaths and moribund cases were not observed in the control group, 30, 100 and 300 mg / kg group.
In the 1000 mg / kg group, one patient died on the 17th day of pregnancy and one died during labor on the 23rdpregnancy. In death cases, salivation, depilation, epidermal decline, loss of locomotor activity, bleeding from the vaginal opening was observed. In the moribund case, salivation, warming of the epidermis, and decline of locomotor activity were observed. In the general condition observation of surviving cases, no abnormalities were observed in any animals throughout the observation period in the control group and 30 mg / kg group. Salivation was observed after administration in the group of 100 mg / kg or more. In the 1000 mg / kg group, hair loss was seen in one case, and the stain on the hair was observed in 1 or 2 cases. Body weights of the 30, 100 and 300 mg / kg group were almost the same as those of the control group, and no significant difference was observed on any measurement day. In the 1000 mg / kg group, there was a significant lower value of body weight. Before the mating, food intake in the 30, 100 and 300 mg / kg group was almost similar to that of the control group, and no significant difference was observed on any measurement day. In the 1000 mg / kg group, a significant lowering of food intake was observed on the 3rd day of administration, on the 21st day of pregnancy, on the 4thday of nursing compared with the control group. At necropsy of the moribund case in the 1000 mg / kg group, atrophy of thymus and dark red spots of glandular gastric mucosa were observed. In the 1000 mg / kg group, significant lower values of the absolute weights of the brain, pituitary and heart as compared with the control group, and significant higher values of the relative weights of the brain and ovary were observed, but these changes were absolute Since a certain tendency was not observed in weight and relative weight, it was judged that it was not based on administration. There was no significant difference in the number of estrous cycles in the administration period (14 days) before mating with the control group in each administration group. There was no significant difference between the gestation period and the control group in each administration group. In addition, no abnormality was found in the delivery status in any of the animals.
In the 30, 100 and 300 mg / kg groups, there were no significant differences in the corpus luteum count, implantation trace number and implantation rate compared to the control group. In the 1000 mg / kg group, the number of corpus luteum and the number of implantation traces were significantly lower than in the control group. In the control group, 100, 300 and 1000 mg / kg group, the birth rate was 100%. In the 30 mg / kg group, the baby rate was 91.7% because no newborn was obtained in one case, but it was judged that it was not based on administration. In the control group, 30, 100 and 300 mg / kg group, no abnormalities were observed in the nursing condition. In the 1000 mg / kg group, 3 maternal animals showed mammary gland development defects and poor nesting defects from day 0 of nursing or day 1 of nursing, and 7 cases of newborn mothers who died in all cases were observed. In the 30, 100 and 300 mg / kg groups, there was no significant difference in the number of neonates, birth rate and sex ratio on day 0 of nursing compared to the control group. In the 30 and 100 mg / kg group, there was no significant difference in the output of children compared with the control group. In the 300 mg / kg group, the child's output rate was significantly higher than that of the control group, but not the dose-dependent change. In the 1000 mg / kg group, there was a significant lower number of neonates and fertility rates on day 0 of nursing compared to the control group, and a low value trend of the output rate of children with no significant difference. In the 30, 100 and 300 mg / kg groups, there was no significant difference in the number of surviving children on 4th day of nursing, the survival rate on 4th day of feeding and the sex ratio compared to the control group. In the 1000 mg / kg group, the number of surviving children on 4th day of nursing and the survival rate on 4th day of nursing were significantly lower than in the control group. In the general condition of the newborn, tail trauma, tail loss, and epidermal decline were seen in each case in the 30 mg / kg group, but both cases were judged to be contingent cases. In the 1000 mg / kg group, a case of trauma of the tail was found in 4 cases in the 4th abdomen (3 mice were mother animals in which mammary gland development failure and nesting defect were observed). In the 30 mg / kg group, the body weight was significantly higher in males and females on day 0 of nursing than in the control group, but not in a dose dependent manner. In the 100, 300 and 1000 mg / kg group, the body weight was significantly lower in males and females on day 0 of nursing compared to the control group. In the 1000 mg / kg group, there was no significant difference compared with the control group, but the body weight tended to be low in males and females on 4th day of nursing. In the 30 mg / kg group, tail defects and tail were observed, and in the 100 mg / kg group tail necrosis was observed, but both were findings observed in external table observation or general condition observation, and it was judged as a contingent case. Besides, no abnormality was found in any group. Hence No Observed Adverse Effect Level (NOAEL) for developmental toxicity was considered to be 30 mg/kg as body weight was found to be lower by administration of 100 mg / kg,When male and femaleSprague-Dawleyrats were treated withtest materialorally.
Reference
Table : Number of estrous cases and reproductive performance of male and female rats in combined repeat dose and reproductive/ developmental toxicity screening test of test material by oral administration
Dose (mg/kg) | 0 | 30 | 100 | 300 | 1000 |
Number of females Number of estrous cases before mating Mean ± S.D. | 12
3.3 ± 0.7 | 12
3.3 ± 0.9 | 12
3.4 ± 0.5 | 12
3.7 ± 0.5 | 12
2.8 ± 1.1 |
Number of pairs
Number of pairs with successful copulation
Copulation index (%)a)
Number of conceiving days Mean ± S.D.
Number of pregnant females
Fertility index (%)b)
Number of pregnant females with live pups | 12
11
91.7
3.1± 1.0
11
100.0
11 | 12
12
100.0
2.3 ± 1.1
12
100.0
11 | 12
12
100.0
2.7 ± 3.4
12
100.0
12 | 12
12
100.0
2.5 ± 1.0
12
100.0
12 | 12
12
100.0
3.5 ± 2.0
11
91.7
9 |
a) : (Number of pairs with successful copulation/number of pairs) X 100
b) : (Number of pregnant females/number of pairs with successful copulation) X 100
Table : Observation of pups in combined repeat dose and reproductive/developmental toxicity screening test of test material by oral administration.
Dose (mg/kg) | 0 | 30 | 100 | 300 | 1000 |
No. Of Dams | 11 | 12 | 12 | 12 | 9 |
Length of gestation( days) Mean ± S.D. per dam |
22.09 ± 0.30 |
22.42 ± 0.67 |
22.08 ± 0.29 |
22.08 ± 0.29 |
22.22 ± 0.44 |
Number of corpora lutea
Mean ± S.D. per dam |
17.5 ± 1.3 |
17.5 ± 1.9 |
17.5 ± 1.5
|
16.1 ± 2.5 |
15.0 ± 2.1* |
Number of implantation scars
Mean ± S.D. per dam |
16.3 ± 1.2 |
16.5 ± 1.3 |
16.1 ± 1.3 |
14.7 ± 2.5 |
13.7 ± 0.2** |
Implantation index
Mean ± S.D. per dama)
Gestation index( %)b) |
92.7 ± 4.6
100.0 |
94.7 ± 6.9
91.7 |
91.9 ± 5.6
100.0 |
91.2 ± 10.1
100.0 |
91.3 ± 8.7
100.0 |
Number of live pups born
Mean ± S.D. per dam |
14.8 ± 1.0 |
13.6 ± 4.4 |
14.7 ± 1.5 |
14.4 ± 2.6 |
9.1 ± 3.0** |
Sex ratio at birth
Mean ± S.D. per damc) |
1.06 ± 0.64 |
1.19 ± 0.66 (11) |
1.25 ± 0.48 |
0.89 ± 0.45 |
1.20 ± 0.78 |
Birth index
Mean ± S.D. per damd) |
91.2 ± 5.6 |
83.9 ± 27.2 |
91.4 ± 9.1 |
98.3 ± 4.4** |
69.3 ± 27.3 |
Number of pups born
Mean ± S.D. per dam |
15.1 ± 0.8 |
15.3 ± 1.6 |
15.0 ± 1.8 |
14.4 ± 2.6 |
11.7 ± 3.1** |
Delivery index
Mean ± S.D. per dame) |
92.8 ± 5.0 |
92.9 ± 6.3 |
93.4 ± 9.3 |
98.3 ± 4.4 |
86.2 ± 21.7 |
Live birth index
Mean ± S.D. per damf) |
98.1 ± 3.3 |
90.1 ± 28.6 |
98.0 ± 3.8 |
100.0 ± 0.0 |
80.7 ± 23.6* |
Number of live pups on day 4 of lactation
Mean ± S.D. per dam |
14.5 ± 0.7 |
14.2 ± 2.0 (11) |
14.6 ± 1.4 |
14.3 ± 2.5 |
2.2 ± 4.4** |
Viability index
Mean ± S.D. per damg) |
97.6 ± 4.2 |
95.5 ± 9.2 (11) |
99.5 ± 1.7 |
98.9 ±2.5 |
20.2 ± 40.4** |
Number of external anomalies
Mean ± S.D. per damh) |
0.0 ± 0.0 |
0.6 ± 2.1 (11) |
0.5 ± 1.7 |
0.0 ± 0.0 |
0.0 ± 0.0 |
Anury
Mean ± S.D. per dam |
0.0 ± 0.0 |
0.6 ± 2.1 (11) |
0.0 ± 0.0 |
0.0 ± 0.0 |
0.0 ± 0.0 |
Necrosis of tail
Mean ± S.D. per dam |
0.0 ± 0.0 |
0.0 ± 0.0 (11) |
0.5 ± 1.7 |
0.0 ± 0.0 |
0.0 ± 0.0 |
Body weight of pups( g)
Mean ± S.D. per dam |
|
|
|
|
|
Male
Day 0
Day 4 |
6.46 ± 0.56
10.17 ± 0.89
|
6.66 ± 0.44**(11)
10.43 ± 1.00 (11) |
6.31 ± 0.46**
9.76 ± 1.26 |
6.28 ± 0.53**
9.86 ± 1.03
|
4.89 ± 0.75**
7.90 (2) |
Female
Day 0
Day 4 |
6.18 ± 0.47
9.66 ± 0.74 |
6.30 ± 0.42**(11)
9.94 ± 1.12 (11) |
5.96 ± 0.47**
9.43 ± 1.25 |
5.84 ± 0.52**
9.18 ± 1.15 |
4.50 ± 0.76**
7.05 (2) |
a) : (Number of implantation mars/number of corpora lutea) X100
b) : (Number of dams with live pups/number of pregnant dams) x100
c) :Number of male pups/number of female pups.
d) : (Number of live pups born/number of implantation scars) X 100
e) : (Number of pups born/number of implantation scars) X 100.
f) : (Number of live pups born/number of pups born) x100
g) : (Number of live pups on day 4/number of live pups born) X 100
h) : (Number of pups with external anomalies/number of live pup s) X 100
Figures in parentheses indicate number of dams.
Significantly different from control( *: p<0.05, **: p<0.01)
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 30 mg/kg bw/day
- Study duration:
- subchronic
- Species:
- rat
- Quality of whole database:
- Data is Klimicsh 2 and from authoritative database
Effect on developmental toxicity: via inhalation route
- Endpoint conclusion:
- no study available
Effect on developmental toxicity: via dermal route
- Endpoint conclusion:
- no study available
Additional information
Developmental toxicity study
Data available from different studies were reviewed to determine the developmental toxicity of 1,2-di(ethenyl)benzene.The studies are as mentioned below:
The combined repeat dose and reproductive/ developmental toxicity screening test was performed on male and female Sprague-Dawley rats [Crj: CD (SD) IGS, (SPF)]. The test material soluble in corn oil in dose concentration 0, 30,100,300,1000mg/kg and administered orally by gavage.The dose was determined according to the results of a preliminary test (administration stage: 0, 125, 250, 500 and 1000 mg / kg, 5 groups in each group) by oral administration for 2 weeks using the male rat previously performed. Male and female rats administered for 14 days were mated together in a 1: 1 combination within the same group. The mating period was limited to 14 days and consecutive living crosses were made until mating was confirmed. Mating was confirmed approximately every morning at a fixed time and a female who confirmed sperm or vaginal plug in vaginal plaque was a mating animal and the day was counted as the 0th day of pregnancy. The general condition and the presence or absence of death was observed twice a day before and after administration. Body weight was measured twice a week. Feeding amount was measured twice weekly 14 days before the start of the mating and after the end of the mating period. The sex cycle was observed once a day from the administration start date to the mating confirmation date. In addition, when the estrus period was observed over 2 consecutive days, it was counted as 1 time. Females who did not deliver until 25th day of pregnancy were sacrificed by exsanguination from the abdominal aorta under ether anesthesia and autopsied, and the success or failure of the pregnancy was confirmed by the presence or absence of implantation. The mother animal was observed daily until the 4th day of nursing and the autopsy was done after leaving the abdominal aorta from the abdominal aorta under ether anesthesia on the day when all newborns died or on the 4thday of nursing. At birth the number of total births and sex, the number of stillborn babies, the number of neonates and the presence or absence of outer table abnormalities were observed. Body weight was measured on day 0 of nursing (birthday) and 4th day.
Death and moribund cases were not observed in either group in male while in female Deaths and moribund cases were not observed in the control group, 30, 100 and 300 mg / kg group.
In the 1000 mg / kg group, one patient died on the 17th day of pregnancy and one died during labor on the 23rdpregnancy. In death cases, salivation, depilation, epidermal decline, loss of locomotor activity, bleeding from the vaginal opening was observed. In the moribund case, salivation, warming of the epidermis, and decline of locomotor activity were observed. In the general condition observation of surviving cases, no abnormalities were observed in any animals throughout the observation period in the control group and 30 mg / kg group. Salivation was observed after administration in the group of 100 mg / kg or more. In the 1000 mg / kg group, hair loss was seen in one case, and the stain on the hair was observed in 1 or 2 cases. Body weights of the 30, 100 and 300 mg / kg group were almost the same as those of the control group, and no significant difference was observed on any measurement day. In the 1000 mg / kg group, there was a significant lower value of body weight. Before the mating, food intake in the 30, 100 and 300 mg / kg group was almost similar to that of the control group, and no significant difference was observed on any measurement day. In the 1000 mg / kg group, a significant lowering of food intake was observed on the 3rd day of administration, on the 21st day of pregnancy, on the 4thday of nursing compared with the control group. At necropsy of the moribund case in the 1000 mg / kg group, atrophy of thymus and dark red spots of glandular gastric mucosa were observed. In the 1000 mg / kg group, significant lower values of the absolute weights of the brain, pituitary and heart as compared with the control group, and significant higher values of the relative weights of the brain and ovary were observed, but these changes were absolute Since a certain tendency was not observed in weight and relative weight, it was judged that it was not based on administration. There was no significant difference in the number of estrous cycles in the administration period (14 days) before mating with the control group in each administration group. There was no significant difference between the gestation period and the control group in each administration group. In addition, no abnormality was found in the delivery status in any of the animals.
In the 30, 100 and 300 mg / kg groups, there were no significant differences in the corpus luteum count, implantation trace number and implantation rate compared to the control group. In the 1000 mg / kg group, the number of corpus luteum and the number of implantation traces were significantly lower than in the control group. In the control group, 100, 300 and 1000 mg / kg group, the birth rate was 100%. In the 30 mg / kg group, the baby rate was 91.7% because no newborn was obtained in one case, but it was judged that it was not based on administration. In the control group, 30, 100 and 300 mg / kg group, no abnormalities were observed in the nursing condition. In the 1000 mg / kg group, 3 maternal animals showed mammary gland development defects and poor nesting defects from day 0 of nursing or day 1 of nursing, and 7 cases of newborn mothers who died in all cases were observed. In the 30, 100 and 300 mg / kg groups, there was no significant difference in the number of neonates, birth rate and sex ratio on day 0 of nursing compared to the control group. In the 30 and 100 mg / kg group, there was no significant difference in the output of children compared with the control group. In the 300 mg / kg group, the child's output rate was significantly higher than that of the control group, but not the dose-dependent change. In the 1000 mg / kg group, there was a significant lower number of neonates and fertility rates on day 0 of nursing compared to the control group, and a low value trend of the output rate of children with no significant difference. In the 30, 100 and 300 mg / kg groups, there was no significant difference in the number of surviving children on 4th day of nursing, the survival rate on 4th day of feeding and the sex ratio compared to the control group. In the 1000 mg / kg group, the number of surviving children on 4th day of nursing and the survival rate on 4th day of nursing were significantly lower than in the control group. In the general condition of the newborn, tail trauma, tail loss, and epidermal decline were seen in each case in the 30 mg / kg group, but both cases were judged to be contingent cases. In the 1000 mg / kg group, a case of trauma of the tail was found in 4 cases in the 4th abdomen (3 mice were mother animals in which mammary gland development failure and nesting defect were observed). In the 30 mg / kg group, the body weight was significantly higher in males and females on day 0 of nursing than in the control group, but not in a dose dependent manner. In the 100, 300 and 1000 mg / kg group, the body weight was significantly lower in males and females on day 0 of nursing compared to the control group. In the 1000 mg / kg group, there was no significant difference compared with the control group, but the body weight tended to be low in males and females on 4th day of nursing. In the 30 mg / kg group, tail defects and tail were observed, and in the 100 mg / kg group tail necrosis was observed, but both were findings observed in external table observation or general condition observation, and it was judged as a contingent case. Besides, no abnormality was found in any group. HenceNo Observed Adverse Effect Level (NOAEL) for reproductive toxicity in male was considered to be 1000mg/kg/day and for female was considered to be 300mg/kg. No Observed Adverse Effect Level (NOAEL) for developmental toxicity was considered to be 30 mg/kg as body weight was found to be lower by administration of 100 mg / kg,When male and femaleSprague-Dawleyrats were treated withtest materialorally.
Based on the data available from different studies,1,2-di(ethenyl)benzene did not showeddevelopmental toxicityat dose concentrationabove 30 mg/kg bw/day.Hence the test chemical is not likely to classify as a reproductive and developmental toxicant as per the criteria mentioned in CLP regulation.
Justification for classification or non-classification
Thus, comparing this value with the criteria of CLP regulation 1,2-di(ethenyl)benzene not likely to classify as reproductive and developmental toxicant.
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