Registration Dossier

Toxicological information

Endpoint summary

Currently viewing:

Administrative data

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Effects on fertility

Description of key information

Reproductive Toxicity Study:

In a one-generation study, the effect of the test chemical on reproduction and development was investigated in male and female Sprague-Dawley rats. The rats were exposed daily to 0, 10, 100 or 500 mg/kg/day of the test chemical by oral administration. At dose 100 mg/kg/day changes in testosterone level in serum were observed, the weights of sex organs such as vagina, testes and ventral prostate were decreased while the weights of liver, adrenal gland and thyroid gland increased by 100 mg/kg/day of the test chemical. Organ weights of liver, adrenal gland and thyroid gland of F0 rats were increased by 500 mg/kg/day of the test chemical, body weight of F1 offspring was significantly decreased with change in relative weight of liver and brain also. Therefore, LOAEL was considered to be 100 mg/kg/day when male and female Sprague-Dawley rats were exposed to the test chemical at different concentrations.

Effect on fertility: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
100 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
The data is from a Klimisch 2 level and is refered from relaible source of journal.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Summary of the test chemical for toxicity to reproduction:

Reproductive Toxicity Study 1:

In a toxicological study, the effect of the test chemical was investigated in pregnant gilts and their foetuses. The pregnant gilts were exposed daily to 0, 50, 200 or 400 mg/kg body weight/day of the test chemical in diet. A significant lower weight gain (P < 0.001) was seen in the highest dosage group and no effects were observed when food consumption was compared between the dosage groups. A dose related increase in the absolute and relative organ weights was found for the liver and the thyroid gland. The autopsy of the dams only revealed sporadic and common pathological lesions. No changes were found in the reproductive organs. Examination of the foetuses did not reveal any consistent sign of a teratological effect attributed to the test chemical. Therefore, based on the observations for reproduction and teratology only, NOAEL was considered to be 400 mg/kg body weight/day. However, observations of increased absolute and relative weights of liver and thyroid gland was also seen at ≥50 mg/kg body weight/day, rendering in a NOEL at ≥50 mg/kg body weight/day when pregnant gilts were daily exposed to the test chemical.

Reproductive Toxicity Study 2:

In a teratogenic study, ICI SPF mice were exposed to 0 or 500 mg/kg/day of test chemical by oral gavage. The results showed that the number of aborted mice fetuses was unexpectedly high, however, the aborted embryos showed no abnormality upon examination. Therefore, LOEL was considered to be 500 mg/kg/day of the test chemical in female ICI SPF mice and its offspring.

Reproductive Toxicity Study 3:

In a reproductive study, female albino CD-1 mice were exposed to the test chemicals by oral administration at concentrations of 0, 2, 10, 48 or 225 mg/kg/day on Day 6 through 15 of gestation. Treatment with 225 mg/kg/day of the test chemicals did not cause mortality and the number of corpora lutea were similar to control, as well as fetal body weight. No significant change in the number of implantation sites in dams were observed and the number of complete resorptions were only present in controls. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the control groups. Therefore, NOAEL was considered to be 225 mg/kg/day when pregnant female albino CD-1 mice were exposed to the test chemical on a daily basis by oral gavage.

Reproductive Toxicity Study 4:

In a reproductive toxicity study, the effects the test chemical were evaluated in a one generation study with Sprague-Dawley rats. The test chemical was administered to female rat by diet at a level of 0 %(0 mg/kg/bw/day),0.125 %(approximately 110 mg/kg bw/day prior to breeding,100 mg/kg bw/day during gestation and 220 mg/kg bw/day during lactation), 0.25 % (approximately 220 mg/kg bw/day prior to breeding,210 mg/kg bw/day during gestation and 440 mg/kg bw/day during lactation) or 0.5 % (approximately 420 mg/kg bw/day prior to breeding,410 mg/kg bw/day during gestation and 800 mg/kg bw/day during lactation). Toxic effect was observed as mortality in offspring and delayed startle response when treated with 0.5% and 0.25 %. There were no evidence of adverse effects on the body weight and reproductive parameters of the parental generation. In addition, there was no significant adverse effect on behavior of parental generation. Therefore, NOAEL considered to be 0.125% (equivalent to a dose of at least 100 mg/kg body weight /day)in both the F0 and F1 generations when female Sprague-Dawley rats were exposed to the test chemical in diet for 90 days.

Reproductive Toxicity Study 5:

In a reproductivetoxicity study, maleCrj:CD (SD)rat were exposed to the test chemicalbyoral gavagein the concentrations of 0, 50, 100, 250 or 500 mg/kg/day. Toxic changes were observed as decreasedbody weight gain when male rats were treated with of TP and TP with the test chemical 250 mg/kg/day. No change in food consumption were observed in treated rats. Relative liver weight, right and left adrenal gland weight were significantly increased when treated with 500 mg/kg/day of the test chemical. Treatment with TP or TP with the test chemical 250 mg/kg/day in male rat resulted in significantly decreased right and left adrenal gland weights, while the relative and absolute weights of androgen-dependent accessory sex organs were not affected by the treatment of the test chemical alone. The relative TP-stimulated ventral prostate weight was significantly increased by the test chemical 250 mg/kg, but the absolute and formalin-fixed weight was not significantly changed. The absolute and relative weights of LABC, seminal vesicle with coagulating glands, glans penis, Cowper’s gland were not changed. Therefore, NOAEL is considered to be 50 mg/kg/body weight/day in a male F1 generation when the male rats were exposed to the test chemicalby gavage for 10 days.

Reproductive Toxicity Study 6:

In a reproductive toxicity study, female Crj:CD (SD) rat were exposed to the test chemical by subcutaneous injection into dorsal surface, caudal to the nape of neck in the concentrations of 0, 50, 100, 250 or 500 mg/kg/day. Toxic changes were observed as decreased body weight gain when female rats were treated with of 250 or 500 mg/kg/day. Changes were also observed in uterine weight in female rat treated with 50 mg/kg/day. In addition, a significant increase were observed in relative liver and uterus weightsand in absolute and relative vagina weight when treated with 17β-estradiol + the test chemical 500 mg/kg/body weight/ day as compare to 17β-estradiol alone. Therefore, LOAEL is considered to be 50 mg/kg/body weight/day in a female F1 generation when these were exposed to the test chemical by subcutaneous injection for 3 days.

Based on the studies summarized in the above table it can be observed that NOAEL value varies from 10 - 400 mg/kg bw /d and LOAEL and LOEL values is found to be in the range of 50-500 mg/Kg bw/d based on the data from publication for target substance. The effect observed on the above doses are

 

·        Changes in body and organ weights and in hormonal levels

·        No effect on the reproduction or teratology.

·        Increased absolute and relative weights of liver and thyroid gland.

·        No adverse effect observed but the number of corpora lutea and the number of fetuses, as well as animal weight, are low compared to control animals.

·        No adverse effects on Body weight, maternal and fetal survival

·        Effect on survival, body weight and reproductive performance

·        Effect on body weight gain, feed and water consumption, and hormone measurement and organ weight.

·        Effect on body weight gain and organ weight

 

Thus based on above discussion it can be concluded that the test chemical is expected to show toxicological effect based on Low effective dose value (LOAEL) which is 50 mg/Kg bw/d. It was found that it has the effects on the female triggering the endocrine disruptive (ED) effects. Thus based on this value it can be concluded that the test chemical is considered to be weakly toxic to reproduction at the above mentioned dose. Also there are evidences of adverse endocrine disruptive effect of the test chemical. Thus can be considered to be classified as reproductive toxicity category 2 as per the CLP regulation for the observed ED effects from various old as well as new studies.

Justification for selection of Effect on fertility via oral route:

The low observed adversed effect level (LOAEL)  of the test chemical was found at a dose level of 100 mg/kg bw/day and NOEL value was observed at  dose level of 10 mg/kg bw/day in Sprague-Dawley  Rats .

Effects on developmental toxicity

Description of key information

Developmental Toxicity Study:

The teratogenicity study on the test chemical was carried out in SPF New Zealand White rabbits. Different parameters like gross malformations, incidence of variation in skeletal ossification, minor skeletal anomalies and major skeletal malformations were examined, the data do not show any difference among controls and the test chemical dosed animals. Thus from above findings we can conclude that administration by gavage of the test chemical to pregnant rabbits did not induce any teratological effect when given daily from day 7 to 18 of the gestation period in doses of 50, 200 and 400 mg/kg body wt./day

Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
100 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
The data is from a Klimisch 2 level and is refered from relaible source of journal.
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

Summary of the test chemical for developmental toxicity:

Developmental Toxicity Study 1:

The study was conducted to test reproductive and development effects of the test chemical on male and female SD rats. The test chemical was administered orally to Sprague-Dawley rats at doses of 10, 100 and 500 mg/kg/day ,in this study different parameters like Hormonal analysis,sperm analysis, reproductive functions of F0 & F1 Rats were analysed. The Body weight of F1 pups on PND 0 was not different between control and treatment groups but decreased, in both male and female pups on PND 21 by the test chemical 500 mg/kg and the growth retardation of male pups was not recovered until 13 weeks old . The absolute and relative weight of liver of F1 female pups was decreased,the absolute weight of spleen at the test chemical 10, 100 and 500 mg/kg groups and the absolute and relative weights of vagina at the test chemical 100 and 500 mg/kg group were decreased. Thus from above findings we can conclude that the low observed adversed effect level (LOAEL) of the test chemical was found at a dose level of 100 mg/kg bw/day in Sprague-Dawley Rats.

Developmental Toxicity Study 2:

In a teratologic evaluation, female albino CD-1 mice were exposed to the test chemical by oral administration at concentrations of 0, 2, 10, 48 or 225 mg/kg/day on Day 6 through 15 of gestation. Treatment with 225 mg/kg/day of the test chemical did not cause mortality and the number of corpora lutea were similar to control, as well as fetal body weight. No significant change in the number of implantation sites in dams were observed and the number of complete resorptions were only present in controls. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the control groups. Therefore, NOAEL was considered to be 225 mg/kg/day when pregnant female albino CD-1 mice were exposed to the test chemical on a daily basis by oral gavage.

Developmental Toxicity Study 3:

Thus based on above discussion it can be concluded that the test chemical is expected to show no toxicological effect based on low observed adverse effective dose value (LOAEL) which is higher than 100 mg/Kg bw/d vial oral whereas NOAEL values found to be 120 - 750 mg/kg bw/d. Thus it can be concluded that the test chemical is considered to be not toxic to maternal toxicity as well as developmental effects via oral route for above mentioned doses. Also there are no known evidence of adverse effect on reproduction to Human of the test chemical as well as estrogen receptor binding affinity does not indicates any mechanistic trigger based on absence of noncyclic structure that would raise concern of the test chemical developmental toxicity.

Developmental Toxicity Study 4:

In a teratologic evaluation, female golden hamsters were exposed to the test chemical by oral administration at concentrations of 0, 1, 5, 24 or 120 mg/kg/day on Day 6 through 10 of gestation. One female in each of the group control, 5 and 120 mg/kg/day died during pregnancy, however, this might be due to internal damages corresponding to incorrect handling during gavage administration. The number of corpora lutea varied slightly between the different treatment groups without any consistency, and no significant change in the number of implantation sites and complete resorptions were observed. The test chemical treatment increased the number of live fetuses (litter size) and average fetus body weight was also increased. No skeletal abnormalities in the test groups was observed compared to control. Therefore, NOAEL was considered to be ≤120 mg/kg/day when pregnant female golden hamsters were exposed to the test chemical on a daily basis by oral gavage.

Developmental Toxicity Study 5:

In a teratogenic study, ICI SPF mice were exposed to 0 or 500 mg/kg/day of the test chemical by oral gavage. The results showed that the number of aborted mice fetuses was unexpectedly high, however, the aborted embryos showed no abnormality upon examination. Therefore, NOEAL was considered to be 500 mg/kg/day of the test chemical in ICI SPF mice.

Justification for selection of Effect on developmental toxicity: via oral route:

The low observed adversed effect level (LOAEL)  ofthe test chemical was found at a dose level of 100 mg/kg bw/day  in Sprague-Dawley  Rats.

Justification for classification or non-classification

The above studies suggest that the test chemical will be classified in reproductive toxicity 'category 2' as per the C & L criteria set by EU based on the adverse endocrine disruptive effects.