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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was performed according to OECD guideline study with GLP compliance.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1997

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Details on test material:
solid

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
Eight-week-old Cr j: CD (SD) IGS rat (Nihon Challis • Riva Co., Ltd.) was purchased for 55 males and females and quarantined acclimatization for 13 days. During this period, observation of the general condition and measurement of body weight were carried out, and necropsy was performed for each of 3 males and females, after confirming that there was no abnormality, selecting animals that showed good growth and at 10 weeks of age It was used for the test. Body weight at the start of administration was 347.7~432 .2 g for male and 220.3~255.2 g for female.
Animals were exposed to a temperature of 24 °C +/- 2 °C (tolerance 21~27 °C), humidity 55 ± 10% (tolerance 35~75%), to 12 hours illumination (7:00 am at 7:00 am) and ventilation times 13~15 times / In the breeding room (No. 92) in the system C area, 23 stainless steel kegs (W 260 x H 200 x D 380 mm), 2~3 per sex during the quarantine conditioning period, 1 per sex during the administration period (One for each sex during the mating period), a polycarbonate keg with a bedding (Whiteflex, manufactured by Nihon Chara Riba Co., Ltd.) during the pregnancy and repatriation period (W 6 5 × H 1 85 × D 4 25 mm), one for each including fine-grown children during the question) housed and raised. Incidentally, the actual measured value of the temperature is a maximum of 26 ° C., the lowest 21 °C, the measured humidity was the maximum 57%, the lowest 50%. Well water (about 2 ppm) to which solid feed (MF, manufactured by Oriental Yeast Industry Co., Ltd.) was added as drinking water and sodium hypochlorite was added freely by an automatic water supply device or a water supply bottle, respectively. For feed and bedding, we analyzed at the Japan Food Analysis Center, Japan Foundation Analysis Center and drinking water was analyzed at Tsuruga Seinan Knu Research Center Co., Ltd., and confirmed that they conformed to acceptance criteria. Breeding equipment and feeds must be sterilized by high pressure steaming, the keg mounts and polycarbonate top cover are once every 4 weeks, the stainless steel key paper once a week, made of polycarbonate Jewel
The water bottle is exchanged at least once a week, the stainless steel keeper dish is exchanged three times a week (however, during the mating period every day), the breeding room is cleaned every day, the disinfectant is soaked in a mop I wiped it.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Details on exposure:
Routes of administration are specified in the OECD Test Method Guidelines and bioassociated with oral administration which is one of the anticipated route of exposure to human beings is 14 days before mating and after 35 days including the mating period. For a total of 49 days, females were administered for 14 days before mating, for a mating period (maximum 14 days), pregnancy period and up to 3 days of consultation, once daily, using gavage. The dose volume was 2.5 ml / kg, and the dosing volume for each animal was calculated based on the latest weights for male and females before mating and mating period, and for females after mating, the body weight at 0 day of pregnancy, respectively. A 0.5 W / V% CMC-Na solution was similarly administered to the control group.
Analytical verification of doses or concentrations:
no
Details on mating procedure:
Mating is done at around 4 pm on 15th day of administration, by a method of making them live together for one night in both sexes (1 2 weeks old). In the next morning, the mating was confirmed by the presence of sperm or plaster in land plants, and that day was designated as O pregnancy day. In addition, crossbreeding was conducted within the same group, and the mating period was a maximum of 2 weeks.
Duration of treatment / exposure:
male; 49 days: female; for 14 days before mating to day 3 of lactation
Frequency of treatment:
one administration/day
No. of animals per sex per dose:
12
Control animals:
yes, concurrent vehicle

Examinations

Maternal examinations:
General condition observation and body weight and food consumption measurement
For both males and females, observation of general condition and confirmation of viability and death for all cases were conducted before and after daily administration I went twice.
For body weight, in male, measurement was made twice a week throughout the administration period. In females, twice a week during the administration period and the mating period before mating, 0, 4, 7, 10, 14, 17 and 21 days during pregnancy during pregnancy, during the clearing period, it was measured at a clearance 0 (day of delivery) and on the 4th.
Regarding food intake, in males, measurements were made twice a week during the administration period excluding the mating period. In females, twice a week during the administration period before mating, 1, 4, 7, 10, 14, 17 and 21 days pregnancy during pregnancy, and on day 1 and day 4 of clearance during daily feeding .
Fetal examinations:
For childbirth, at the time of childbirth, the number of births, the number of newborn babies, the number of stillborn babies, the sex of newborn baby and the abnormal outer table were inspected. For newborn babies, weight is measured for each individual on the day of birth and on day 4 of fertility and the birth rate [(number of newborn infants / implantation number) × 100], the stillbirth rate [(the number of stillborn infants / the number of births) × 100] and the survival rate on 4th day of newborn baby [(number of births on 4th day of clearance / number of newborns) × 100] were calculated.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
In males, in the group of 20 mg / kg or less, there was no death and no change was observed in the general condition.
In females, two subjects in the 20 mg / kg group and 7 subjects in the 100 mg / kg group were autopsyed on the way because all the children died by 3 rd day nursing.
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, non-treatment-related
Description (incidence):
In males, one patient in the 100 mg / kg group had decreased spontaneous locomotor activity and slow respiration before administration on 18th administration, and died before administration on 21th administration.
In females, one patient in the 100 mg / kg group died before administration on the 22nd day of pregnancy. In addition, in another one of the 100 mg / kg group, subcutaneous carcinoma of the chest was observed from 9th pregnancy to the autopsy day (4th day of clearance). No deaths occurred in the group of 20 mg / kg or less, no change was observed in the general condition.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
In male, suppression of body weight increase or tendency was observed throughout the administration period in the group of 20 mg / kg or more, and the total body weight gain during the administration period showed a significant low value.
In females, increase inhibition was observed on days 4 and 8 during the administration period before the mating in the 100 mg / kg group. In addition, during pregnancy and rest period, suppression of body weight gain or tendency was observed in the group of 20 mg / kg or more.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
In males, there was a decrease in the early stage of administration in the group of 20 mg / kg or more and then recovered, but again decreased in the latter stage of administration after the end of the mating period.
In females, there was a decrease in the early stage of administration in the group of 20 mg / kg or more, and then recovered, but eyelid growth.
It decreased again on the day. Incidentally, in the 100 mg / kg group, an increase was observed at the administration day 8 15 days.
In addition, as an accidental change without dose correlation, increase in pregnancy 21 days was observed in the 4 mg / kg group.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
Red blood cell count and hematocrit decreased and MCH and MCHC increased in the 100 mg / kg group. In the 100 mg / kg group, the number of reticulocytes also increased. Increase in MCH was also observed in the 20 mg / kg group.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
Increases in albumin, A / G ratio, GOT, GPT, total cholesterol, phospholipids and total bilirubin and decreases in triglyceride, sodium and potassium were observed in the 100 mg / kg group. In addition, reduction of GPT, alkaline phosphatase and creatinine was observed in the 20 mg / kg group, but both were within the physiological variation range.
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
In males, the absolute and relative weight of the thymus decreased or decreased in the 100 mg / kg group, and the absolute and relative weights of the liver and accessory kidney increased or increased. In addition, in males, the absolute weight loss of the tiles was reduced in the 100 mg / kg group, and in the 20 mg / kg group, the relative weights of the lungs, kidneys, adrenal glands, testis and epididymis were increased, 100 mg / kg Increase in relative weight of brain, heart, lung, kidney, testis and epididymis in the group
In females, an increase in the relative weight of the brain was observed in the 100 mg / kg group.
In addition, as an incidental change without dose correlation, the absolute weight increase of the adrenal gland was observed in males in the 4 mg / kg group, and in the females in the 20 mg / kg group, the absolute and relative weights of the heart were observed .
Gross pathological findings:
not specified
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Hypertrophy of central leukocytes was observed in 5 males and 7 females in the 100 mg / kg group. In males, testicular atrophy was seen in epididymal spermatogranuloma and 2 cases in control group in 1 '1 and 3 cases in control group, 4 and 100 mg / kg group, respectively, and testicular atrophy was observed In one of the cases, reduction of sperm in the epididymal cavity and ce lld ebr i S was also observed. In females, one case of 100 mg / kg group showed proliferation of transitional epithelium of kidney and papilla, in which basophilic renal tubular epithelium basification and adenocarcinoma of mammary gland were each observed in each case It was done. In females, atrophy of the thymus was observed in 1, 3 and 1 cases of control group, 20 and 100 mg / kg group, respectively.
In the case of death, one males in the 100 mg / kg group treated with neutrophilic cell infiltration and granulation, neutrophilic cell infiltration and granulation, glandular erosion, edema of the lungs, atrophy of the tiles, Gland atrophy and out Blood, female erosion of the gland stomach, edema of the lung, atrophy of the tile and necrosis of the adrenal gland were observed.
Histopathological findings: neoplastic:
not specified

Maternal developmental toxicity

Number of abortions:
no effects observed
Description (incidence and severity):
Regarding the reproductive function of the parent animal, there was no effect of administration of the test substance on the sexual cycle, mating rate, attendant fetal rate, number of days required for mating, number of corpus luteum and number of implantation traces. In addition, the influence of test substance administration was not observed in gestation period, number of births and birth rate.
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
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
Changes in number of pregnant:
no effects observed

Effect levels (maternal animals)

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Key result
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
body weight and weight gain
food consumption and compound intake
Remarks on result:
other: males
Key result
Dose descriptor:
NOAEL
Effect level:
4 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
food consumption and compound intake
Remarks on result:
other: females

Results (fetuses)

Fetal body weight changes:
effects observed, treatment-related
Description (incidence and severity):
No abnormality was found in each group in the neonatal exterior examination as well.
In the examination of the soybean season, in 2 cases in the 20 mg / kg group and 7 cases in the 100 mg / kg group, poor behavior such as regrowth, lactation, warming and the like of children was observed, and in these mother animals All the children died, and in the group of 20 mg / kg or more, the survival rate of the newborn was decreased 4 days. Furthermore, in the 100 mg / kg group, both sexes showed a low value on the 4th day of the newborn's shooting.

Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): effects observed, treatment-related
Reduction in number of live offspring:
effects observed, non-treatment-related
Description (incidence and severity):
Furthermore, in the 100 mg / kg group, the increase in the mortality rate, the associated decrease in the fertility rate, and the decrease in female and male neonatal weight were observed. In addition, there was an increase in stillbirth rate in the 4 mg / kg group. However, similar changes were not observed in the 20 mg / kg group, so it was considered to be an accidental change.
Changes in sex ratio:
no effects observed
Description (incidence and severity):
There were no differences in the pregnancy period, the number of corpus luteums, the number of implantation traces, the number of births, the number of newborn babies, the birth rate and neonatal sex ratio in each group compared with the control group.
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
not examined

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
20 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
fetal/pup body weight changes

Fetal abnormalities

Key result
Abnormalities:
not specified

Overall developmental toxicity

Key result
Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The NOAEL of developmental toxicity was considered to be 20 mg/kg/day, based on decreases of birth index and body weight of pups.
Executive summary:

In the OECD combined repeat dose and reproductive/ developmental (one generation)toxicity screening test [OECD TG 422], this substance was given for 49 days from 14 days before mating in males and from 14 days before mating to day 3 of lactation in females. At the 100 mg/kg group, one female died in gestation and another female was not impregnated. Birth index was decreased with increase in stillborns at the 100 mg/kg. All pups of two dams at the 20 mg/kg and seven dams at 100 mg/kg died due to the lack of nursing activity, and the viability index on day 4 after birth was consequently decreased in these groups. The body weights of pups were also decreased at birth and day 4 of lactation in the 100 mg/kg group. The decrease of litter size observed at the 100 mg/kg seems to be the chemical-induced effect although it is not statistically significant. No malformations or variations were observed in the pups.