Divinylbenzene

Developmental toxicity / teratogenicity

Administrative data

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

Data source

Reference

Reference 1

Reference Type:

review article or handbook

Title:

Repeated oral administration toxicity / reproductive developmental toxicity combined study of test material

Author:

J- check

Year:

2003

Bibliographic source:

Ministry of Health and Welfare, Japan, 2003

Reference 2

Reference Type:

secondary source

Title:

The reproductive toxicity study of test material

Author:

HSDB

Year:

2018

Bibliographic source:

Hazardous Substances Data Bank,2018

Materials and methods

Test guideline

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

Test material

Test material information

Constituent 1

Reference substance name:

Divinylbenzene

EC Number:

215-325-5

EC Name:

Divinylbenzene

Cas Number:

1321-74-0

Molecular formula:

C10H10

IUPAC Name:

1,2-di(ethenyl)benzene

Details on test material:

- Name of test material: Divinylbenzene- IUPAC name: 1,2-di(ethenyl)benzene - Molecular formula: C10H10- Molecular weight: 131.1969 g/mol- Substance type: Organic- Physical state: No data - Purity: No data- Impurities (identity and concentrations): No data

Test animals

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)

Administration / exposure

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

Doses / concentrations

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

Examinations

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

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

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

Maternal developmental toxicity

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

Effect levels (maternal animals)

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

Maternal abnormalities

Abnormalities:

not specified

Localisation:

not specified

Results (fetuses)

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

Effect levels (fetuses)

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

Fetal abnormalities

Abnormalities:

not specified

Localisation:

other: not specified

Overall developmental toxicity

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

Any other information on results incl. tables

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 dam^a)   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 dam^c)	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 dam^d)	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 dam^e)	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 dam^f)	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 dam^g)	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 dam^h)	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)

Applicant's summary and conclusion

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 4^thday 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 23^rdpregnancy. 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 4^thday 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.