Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

Reproductive toxicity study

Based on the data available from different studies, NOAEL for test chemical was considered to be 1000mg/kg /day for reproductive toxicity, when male and female rats were treated with test material orally. Thus, comparing this value with the criteria of CLP regulation test material is not likely to classify as reproductive toxicant.

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Remarks:
Experimental data from various test chemicals
Justification for type of information:
Weight of evidence approach based on the available information from various test chemicals.
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Qualifier:
equivalent or similar to
Guideline:
other: As mentioned below
Principles of method if other than guideline:
WoE report is based on reproductive toxicity studies on rats
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
other: 1.Crj: CD(SD) 2&3.Wistar BOR:Wisw (SPFcpb)
Sex:
male/female
Details on test animals and environmental conditions:
1.- Source: Charles River KK (Kanagawa)
- Age at study initiation: (P) x wks; (F1) x wks: 10 weeks
- Weight at study initiation: (P) Males: x-x g; Females: x-x g; (F1) Males: x-x g; Females: x-x g: 375 to 414 g for males and 239 to 266 g for females.
- Fasting period before study:
- Housing: One animal was housed and housed in an aluminum front and floor stainless steel mesh breeding cage in a breeding room. Maternal animals after gestation day 18 were kept on an aluminum front and floor stainless steel mesh breeding cage with nursery tray and nest material (manufactured by Care FRESHTM, Absorption corporation) until nursing 4th.
- Diet (e.g. ad libitum): NMF solid feed (radiation sterilized feed) and was taken free during the breeding period
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 ± 2 ° C
- Humidity (%): 55 ± 10%
- Air changes (per hr): 15 times / hour
- Photoperiod (hrs dark / hrs light): illuminance of 150 to 300 lux, illumination time of 12 hours (7 am lights, 7 pm off)
Route of administration:
oral: gavage
Type of inhalation exposure (if applicable):
not specified
Vehicle:
other: sesame oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: The test substance was suspended in sesame oil (manufactured by Nacalai Tesque, Inc.), and each group of administration liquids was prepared so as to have concentrations of 20, 60 and 200 mg / mL. After preparation, it was kept under light-shielded and refrigerated conditions until use. It was confirmed that the test substance in the administration solution was stable for at least 7 days under light shielded and refrigerated conditions at concentrations of 6 and 200 mg / mL.

DIET PREPARATION
- Rate of preparation of diet (frequency):
- Mixing appropriate amounts with (Type of food):
- Storage temperature of food:

VEHICLE
- Justification for use and choice of vehicle (if other than water): sesame oil
- Concentration in vehicle: 0 (vehicle), 100, 300, 1000 mg/kg/day
- Amount of vehicle (if gavage): 0.5 mL per 100 g body weight
- Lot/batch no. (if required):
- Purity:
Details on mating procedure:
- M/F ratio per cage: 1: 1.
- Length of cohabitation: Every night for a maximum of 14 days
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy Sperm in vaginal plaque, and that day was taken as the 0th day of pregnancy.
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility. Not specified
- Further matings after two unsuccessful attempts: [no / yes (explain)] Not specified
- After successful mating each pregnant female was caged (how): Not specified
- Any other deviations from standard protocol: Not specified
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
For the analysis of the concentration and homogeneity of the administration solution, samples were randomly extracted from batches of each group prepared at the start of preparation. As a result, the error with respect to the display density was in the range of -12.5 to -0.4% and within the reference range (within ± 15%). Therefore, it was confirmed that a prescribed amount of 2-amino-5-methylbenzenesulfonic acid was contained in the administration solution used.
Duration of treatment / exposure:
Study 2
For male- 48 days
For female – approx 68 days
Study 3
day 6 to 15 post coitum
Study 4
Males were dosed daily for a minimum of four weeks, including a minimum of two weeks prior to mating and continued throughout the mating period until the study was terminated. Females were dosed two weeks prior to mating, until conception, throughout pregnancy and at least four days after delivery
Frequency of treatment:
Daily
Details on study schedule:
Not specified
Remarks:
Study 2
0,100,300,1000mg/kgbw/day
Study 3
0,1000mg/kg bw/day
Study 4
0 (water), 62.5 (50), 250 and 1000 mg/kg-bw
No. of animals per sex per dose:
Study 1
Total: 96
0 mg/kg/day: 12 male, 12 female
100 mg/kg/day: 12 male, 12 female
300 mg/kg/day: 12 male, 12 female
1000 mg/kg/day: 12 male, 12 female
Study 2
Total:50
0 mg/kg bw (control group): 25 female rats
1000 mg/kg bw (test group): 25 female rats
Study 3
0 (water), 62.5 (50), 250 and 1000 mg/kg-bw
Study 4
Total: 96
0 mg/kg/day: 12 male, 12 female
62.5 mg/kg/day: 12 male, 12 female
250 mg/kg/day: 12 male, 12 female
1000 mg/kg/day: 12 male, 12 female

Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Doses were based on 28-day repeated dose toxicity study at a concentration of 0, 30, 100, 300 and 1000 mg / kg, increased the urine specific gravity, urine pH, Reduction or decrease in white blood cell count and total cholesterol was observed in females with an increase in GPT and a decrease in blood glucose, and autopsy revealed cecal expansion in both males and females. Based on these results, a preliminary test carried out at doses of 0, 100, 300 and 1000 mg / kg. Therefore, as in the preliminary test, high dose of 1000 mg / kg was also set, divided by the common ratio of about 3, and 300 and 100 mg / kg were set.
- Rationale for animal assignment (if not random): The animals were stratified based on the body weight at the start of administration, and 12 animals per group were sorted by a random sampling method.
- Other:
Parental animals: Observations and examinations:
Survival, general condition, body weights, food consumption were examined.
Oestrous cyclicity (parental animals):
Estrous cyclicity were examined.

Number of corpus luteum and the number of implantation were examined.
Sperm parameters (parental animals):
Not specified
Litter observations:
Number of births, clinical signs and body weight were examined.
Postmortem examinations (parental animals):
1.Organ weight, Gross pathology and histopathology were examined.
2.Animals were sacrificed on day 20 and necropsied.

GROSS NECROPSY: Yes

HISTOPATHOLOGY / ORGAN WEIGHTS: Yes
Postmortem examinations (offspring):
Gross pathology were examined.
Statistics:
Weight, food consumption, number of corpus luteums, number of implantation traces, number of births, number of stillbirths, sex ratio, average sex, pregnancy period, implantation rate, delivery rate, birth rate, abnormal incidence of abnormal outer table, newborn 4th Multiple comparison test 2-4) was performed on the survival rate, organ weight and relative weight of the subjects. For the birth rate, mating rate and conception rate, χ ^ 2 tests 5, 6) were used. The incidence of findings of pathological examination was tested using Fisher's direct probability test method 6). In addition, as for the results on newborns during the nursing period, the average per mother was taken as one sample. The level of significance was set at two levels of *: P <0.05 and **: P <0.01.
Reproductive indices:
Copulation index, fertility index, implantation index, gestation index, delivery index were examined.
Offspring viability indices:
viability index on day 0 and 4 were examined.
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
2.In male rats, 1 ocular secretion in the 100 mg / kg group of male, 1 hair loss in the 300 mg / kg group, 1 in the 1000 mg / kg group Crust and hair loss were observed in one case.
In females, hair removal was observed in the 100 mg / kg group through pregnancy and nursing periods.
3.There were no signs of toxicity in dams.
4.Rats at the 1000mg/kg /day dose showed oronasal bleeding during the first week and occasionally throughout the study.
Dermal irritation (if dermal study):
not specified
Mortality:
no mortality observed
Description (incidence):
2.No mortality were observed in treated male and femlae rats as compared to control.
4.No mortality were observed in treated male and femlae rats as compared to control.
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
2.In male, no effect on body weight were observed as compared to control. In female at 100 and 1000 mg / kg, statistically significant decrease in body weight were observed only on the 4th day of nursing compared to the control group. However, since there was no obvious difference on the other measurement day and it was a change only for 1 day, and since there was no obvious change in body weight gain during the nursing period, the influence of administration of the test substance It was not thought to be an accidental change.
4.No effects on body weight were observed in treated male and femlae rats as compared to control.
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
2.In male rats at 1000 mg/kg bw, statistically significant increase in daily food intake for the 8 to 15 days and the cumulative food consumption from 1 to 15 days were observed as compared to control.
In female rats, no effect on food consumption was observed as compared to control.
4.No effects on food consumption were observed in treated male and femlae rats as compared to control.
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, non-treatment-related
Description (incidence and severity):
2.At 300 and 1000 mg/kg bw, statistically significant decrase in absolute epididymis weight were observed but no relative weight change were observed as compared to control.
No effect on testicular weight were observed in treated male rats as compared to control.
4.No changes in organ weights of reproductive organs
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
No gross pathological changes were attributed to the administration of the test substance.

In males, black lesions of the lung were observed in the control group and 1 group in the 300 mg / kg group, red spots of the liver and 1 case of the same individual in the 300 mg / kg group, testis and epididymal atrophy was observed in one group of the same individual in the 300 mg / kg group, and one in each group in the 300 and 1000 mg / kg group of thinning of the coat.

Naturally delivered females were 9, 10, 12 and 12 in the control group, 100, 300 and 1000 mg / kg group, respectively. Observations of atrophy of the thymus were 1 and 2 cases respectively in the 300 and 1000 mg / kg group, 1 lung black spot, stomach ulcer and white spot of the adrenal gland in the 1000 mg / kg group, 1 each, ovarian cyst and coat Thinning was observed in each case in the 100 mg / kg group.

No abnormal findings were observed in one female in the 100 mg / kg group that did not mate.

No female with natural birth was observed in the control group and 1 group in the 100 mg / kg group, but no abnormal findings were observed in any of the animals.

Thymus atrophy and uterine nodule were observed in one case in two cases of dead animals in the control group, and no abnormal finding was found in the other one.
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
When treated with 1000 mg/kg bw, cell infiltration of the epididymis, case in skin erosion and squamous cell epithelial hyperplasia , 1 atrophy of the thymus, 1 lung inflammation, 1 stomach ulcer and 1 part of the adrenal cortex one hypertrophy were observed in male rats.
When treated with 300 mg/kg bw, seminiferous tubular atrophy of the testes, pulmonary inflammation, 1 case in the liver necrosis and 1 atrophy of the thymus were observed in male rats.

When treated with 100 mg/kg bw, 1 Young yolk sac cysts in females who spontaneously delivered, so it was considered that there was no effect on the ovaries of the test substances. 1 Skin inflammatory infiltration and squamous epithelial hyperplasia were observed.

In males and females who did not mate, seminiferous tubular atrophy of the testes was observed in males. No abnormal findings were observed in females.

No abnormal findings were observed in males who did not establish pregnancy and infertile females.

Atrophy of the thymus and purulent inflammation of the uterus were observed in one case in all the dead animals. No abnormal finding was observed in the other case.
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
No effect on copulation, implantation and sexual cycle of treated female rats were observed as compared to control.
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed
Description (incidence and severity):
1.No effect on gestation length, number of corpora lutea or implantations, implantation index, gestation index, delivery index, purturition or maternal behavior, numbers of offspring or live offspring, sex ratio and live birth index were observed in treated rats as compared to control.
2.No effect was observed on numbers of corpora lutea, implantation sites, and viable fetuses were found.
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/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
other: No effect
Remarks on result:
other: No effects on reproductive performance was observed
Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Clinical signs:
no effects observed
Description (incidence and severity):
1.No Clinical sign were observed in neonates as compared to control.
Dermal irritation (if dermal study):
not specified
Mortality / viability:
no mortality observed
Description (incidence and severity):
No effect on Viability of neonates were observed on day 0 and 4 as compared to control.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No effect on Body weight of neonates were observed on day 0 and 4 as compared to control.
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):
1.No abnormal findings were observed in females.
At autopsy on 4th day of nursing, in the male, thymus neck remnant was 1 in the control group, 1 in the renal pelvic enlargement in the 300 mg / kg group, in the female in the control group and in the 300 mg / kg group in the renal pelvic enlargement in the kidney It was recognized in 1 and 3 cases respectively. In both cases, expression was expressed in a few cases, which was not related to administration of the test substance.
2.Did not show any such malformations.
Histopathological findings:
no effects observed
Description (incidence and severity):
2.Skeletal variations were the same (nature and frequency) in test- and control group.
Other effects:
effects observed, treatment-related
Description (incidence and severity):
4.Noteworthy were the statistically insignificant, mild effects on litter mass of the high dose group and on pre-implantation loss of the 250mg/kg-bw/day and 1000mg/kg-bw/day dose group. Similarly there was a mild tendency of relatively low total numbers of pups born with increasing test item dosage and a low mean number of live pups per dam at day 4 post-partum.
Behaviour (functional findings):
not specified
Developmental immunotoxicity:
not specified
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
viability
clinical signs
mortality
body weight and weight gain
gross pathology
other: No effect observed
Remarks on result:
other: No effects on developmental toxicity
Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Reproductive effects observed:
not specified
Treatment related:
not specified
Conclusions:
NOAEL was considered to be 1000 mg/kg/day for P and F1 generation when male and female rats treated with test chemical orally by gavage for approx 68 days.
Executive summary:

Data available from different studies were reviewed to determine the reproductive toxicity of testchemical.The studies are as mentioned below:

Study 2

In a Preliminary Reproduction Toxicity Screening Test,Crj:CD(SD) male and female rat were treated with test chemical in the concentration of 0 (vehicle), 100, 300, 1000 mg/kg/day orally by gavage in sesame oil for male consecutive 48 days of 14 days before mating and 14 days of mating period and 20 days after the end of the mating period. The female administration period was 14 days before the mating and during the mating period (maximum 14 days) and through 3 days of postpartum feeding (41 to 46 days) throughout the gestation period of the female. The females who did not deliver after copulation establishment were for 41 and 43 days up to the day before dissection on 25th gestation. Females that failed to mate were consecutive 48 days of 20 days after the mating period. No mortality was observed in treated male and female rats as compared to control. In male rats, 1 ocular secretion in the 100 mg / kg group of male, 1 hair loss in the 300 mg / kg group, 1 in the 1000 mg / kg group Crust and hair loss were observed in one case and in females, hair removal was observed in the 100 mg / kg group through pregnancy and nursing periods. In male, no effect on body weight and in female at 100 and 1000 mg / kg, statistically significant decrease in body weight were observed only on the 4th day of nursing compared to the control group. However, since there was no obvious difference on the other measurement day and it was a change only for 1 day, and since there was no obvious change in body weight gain during the nursing period, the influence of administration of the test substance It was not thought to be an accidental change.In male rats at 1000 mg/kg bw, statistically significant increase in daily food intake for the 8 to 15 days and the cumulative food consumption from 1 to 15 days and in female rats, no effect on food consumption was observed as compared to control. Similarly,No reproductive effect on copulation, implantation and sexual cycle, gestation length, number of corpora lutea or implantations, implantation index, gestation index, delivery index, purturition or maternal behavior, numbers of offspring or live offspring, sex ratio and live birth index were observed in treated rats as compared to control. At 300 and 1000 mg/kg bw, statistically significant decrease in absolute epididymis weight were observed but no relative weight change and no effect on testicular weight were observed in treated male rats as compared to control. No gross pathological changes were attributed to the administration of the test substance. At 1000 mg/kg bw, cell infiltration of the epididymis, case in skin erosion and squamous cell epithelial hyperplasia , 1 atrophy of the thymus, 1 lung inflammation, 1 stomach ulcer and 1 part of the adrenal cortex one hypertrophy were observed in male rats. At 300 mg/kg bw, seminiferous tubular atrophy of the testes, pulmonary inflammation, 1 case in the liver necrosis and 1 atrophy of the thymus were observed in male rats. At 100 mg/kg bw, 1 Young yolk sac cysts in females who spontaneously delivered, so it was considered that there was no effect on the ovaries of the test substances. 1 Skin inflammatory infiltration and squamous epithelial hyperplasia were observed. In males and females who did not mate, seminiferous tubular atrophy of the testes was observed in males. No abnormal findings were observed in females. No abnormal findings were observed in males who did not establish pregnancy and infertile females. Atrophy of the thymus and purulent inflammation of the uterus were observed in one case in all the dead animals. No abnormal finding was observed in the other case. In addition,No effect on Viability and body weight of neonates were observed on day 0 and 4 andnoclinical sign were observed inneonates as compared to control.No abnormal findings were observed in females. At autopsy on 4th day of nursing, in the male, thymus neck remnant was 1 in the control group, 1 in the renal pelvic enlargement in the 300 mg / kg group, in the female in the control group and in the 300 mg / kg group in the renal pelvic enlargement in the kidney It was recognized in 1 and 3 cases respectively. In both cases, expression was expressed in a few cases, which was not related to administration of the test substance. Therefore, NOAEL was considered to be 1000 mg/kg/day for P and F1 generation when male and female rats treated with test chemical orally by gavage for approx68 days.

Study 3

The present study was conducted to determine the reproductive toxicity potential of test chemical.when administered orally to rats. Virgin female rats were used for the study. Two dose groups (25 animals each) were used, one test- (1000 mg/kg bw) and one control group (0 mg/kg bw). They were dosed from day 6-15 post coitum and kept off-dose from day 16-19. There were no signs of toxicity in dams. Animals were sacrificed on day 20 and necropsied. Reproductive parameters were examined [viz.no. of corpora lutea, no. of implantations and resorptions (complete, early and late)]. Foetuses were weighed, inspected macroscopically for external malformations and prepared for inspection for visceral and skeletal malformations (by transverse section and double staining respectively). They did not show any such malformations. Skeletal variations were the same (nature and frequency) in test- and control group. No effect was observed on numbers of corpora lutea, implantation sites, and viable fetuses were found.

Therefore, under the condition of this study, the no-observed-adverse-effect level (NOAEL) for dams and foetuses was considered to be 1000 mg/kg bw.

Study 4

In a Reproduction Toxicity Screening Test, wistar male and female rat were treated with test chemical in the dose concentration of0 (water), 62.5 (50), 250 and 1000 mg/kg-bw orally by gavage in water .12 males and 12 females were placed in each dose group. Males were dosed daily for a minimum of four weeks, including a minimum of two weeks prior to mating and continued throughout the mating period until the study was terminated. Females were dosed two weeks prior to mating, until conception, throughout pregnancy and at least four days after delivery. Females showing no evidence of copulation were re-grouped with proven sires for a second mating phase. All the animals were observed for Survival, general condition, body weights, food and water consumption. At the end of the in-life phase, gross necropsy was performed, with organ mass recorded, tissues and organs preserved and processed histologically. A histopathological examination was conducted on samples from the 1000mg/kg-bw/day dose groups and the vehicle groups.

No mortality was observed in treated male and female rats as compared to control. Rats at the1000mg/kg-bw/day dose showed oronasal bleeding during the first week and occasionally throughout the study. No effects were seen on body mass as well as food and water consumption was noted. at gross necropsy, No changes in organ weights of reproductive organs were noted. Noteworthy were the statistically insignificant, mild effects on litter mass of the high dose group and on pre-implantation loss of the 250mg/kg-bw/day and 1000 mg/kg-bw/day dose group. Similarly there was a mild tendency of relatively low total numbers of pups born with increasing test item dosage and a low mean number of live pups per dam at day 4 post-partum. Hence NOAEL was considered to be 1000 mg/kg/day for P generation and for F1 generation, when male and female wistar rats treated with test chemical orally by gavage .

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subchronic
Species:
rat
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 testchemical.The studies are as mentioned below:

Study 2 In a Preliminary Reproduction Toxicity Screening Test,Crj:CD(SD) male and female rat were treated with test chemical in the concentration of 0 (vehicle), 100, 300, 1000 mg/kg/day orally by gavage in sesame oil for male consecutive 48 days of 14 days before mating and 14 days of mating period and 20 days after the end of the mating period. The female administration period was 14 days before the mating and during the mating period (maximum 14 days) and through 3 days of postpartum feeding (41 to 46 days) throughout the gestation period of the female. The females who did not deliver after copulation establishment were for 41 and 43 days up to the day before dissection on 25th gestation. Females that failed to mate were consecutive 48 days of 20 days after the mating period. No mortality was observed in treated male and female rats as compared to control. In male rats, 1 ocular secretion in the 100 mg / kg group of male, 1 hair loss in the 300 mg / kg group, 1 in the 1000 mg / kg group Crust and hair loss were observed in one case and in females, hair removal was observed in the 100 mg / kg group through pregnancy and nursing periods. In male, no effect on body weight and in female at 100 and 1000 mg / kg, statistically significant decrease in body weight were observed only on the 4th day of nursing compared to the control group. However, since there was no obvious difference on the other measurement day and it was a change only for 1 day, and since there was no obvious change in body weight gain during the nursing period, the influence of administration of the test substance It was not thought to be an accidental change.In male rats at 1000 mg/kg bw, statistically significant increase in daily food intake for the 8 to 15 days and the cumulative food consumption from 1 to 15 days and in female rats, no effect on food consumption was observed as compared to control. Similarly,No reproductive effect on copulation, implantation and sexual cycle, gestation length, number of corpora lutea or implantations, implantation index, gestation index, delivery index, purturition or maternal behavior, numbers of offspring or live offspring, sex ratio and live birth index were observed in treated rats as compared to control. At 300 and 1000 mg/kg bw, statistically significant decrease in absolute epididymis weight were observed but no relative weight change and no effect on testicular weight were observed in treated male rats as compared to control. No gross pathological changes were attributed to the administration of the test substance. At 1000 mg/kg bw, cell infiltration of the epididymis, case in skin erosion and squamous cell epithelial hyperplasia , 1 atrophy of the thymus, 1 lung inflammation, 1 stomach ulcer and 1 part of the adrenal cortex one hypertrophy were observed in male rats. At 300 mg/kg bw, seminiferous tubular atrophy of the testes, pulmonary inflammation, 1 case in the liver necrosis and 1 atrophy of the thymus were observed in male rats. At 100 mg/kg bw, 1 Young yolk sac cysts in females who spontaneously delivered, so it was considered that there was no effect on the ovaries of the test substances. 1 Skin inflammatory infiltration and squamous epithelial hyperplasia were observed. In males and females who did not mate, seminiferous tubular atrophy of the testes was observed in males. No abnormal findings were observed in females. No abnormal findings were observed in males who did not establish pregnancy and infertile females. Atrophy of the thymus and purulent inflammation of the uterus were observed in one case in all the dead animals. No abnormal finding was observed in the other case. In addition,No effect on Viability and body weight of neonates were observed on day 0 and 4 andnoclinical sign were observed inneonates as compared to control.No abnormal findings were observed in females. At autopsy on 4th day of nursing, in the male, thymus neck remnant was 1 in the control group, 1 in the renal pelvic enlargement in the 300 mg / kg group, in the female in the control group and in the 300 mg / kg group in the renal pelvic enlargement in the kidney It was recognized in 1 and 3 cases respectively. In both cases, expression was expressed in a few cases, which was not related to administration of the test substance. Therefore, NOAEL was considered to be 1000 mg/kg/day for P and F1 generation when male and female rats treated with test chemical orally by gavage for approx68 days.

Study 3 The present study was conducted to determine the reproductive toxicity potential of test chemical.when administered orally to rats. Virgin female rats were used for the study. Two dose groups (25 animals each) were used, one test- (1000 mg/kg bw) and one control group (0 mg/kg bw). They were dosed from day 6-15 post coitum and kept off-dose from day 16-19. There were no signs of toxicity in dams. Animals were sacrificed on day 20 and necropsied. Reproductive parameters were examined [viz.no. of corpora lutea, no. of implantations and resorptions (complete, early and late)]. Foetuses were weighed, inspected macroscopically for external malformations and prepared for inspection for visceral and skeletal malformations (by transverse section and double staining respectively). They did not show any such malformations. Skeletal variations were the same (nature and frequency) in test- and control group. No effect was observed on numbers of corpora lutea, implantation sites, and viable fetuses were found. Therefore, under the condition of this study, the no-observed-adverse-effect level (NOAEL) for dams and foetuses was considered to be 1000 mg/kg bw.

Study 4 In a Reproduction Toxicity Screening Test, wistar male and female rat were treated with test chemical in the dose concentration of0 (water), 62.5 (50), 250 and 1000 mg/kg-bw orally by gavage in water .12 males and 12 females were placed in each dose group. Males were dosed daily for a minimum of four weeks, including a minimum of two weeks prior to mating and continued throughout the mating period until the study was terminated. Females were dosed two weeks prior to mating, until conception, throughout pregnancy and at least four days after delivery. Females showing no evidence of copulation were re-grouped with proven sires for a second mating phase. All the animals were observed for Survival, general condition, body weights, food and water consumption. At the end of the in-life phase, gross necropsy was performed, with organ mass recorded, tissues and organs preserved and processed histologically. A histopathological examination was conducted on samples from the 1000mg/kg-bw/day dose groups and the vehicle groups. No mortality was observed in treated male and female rats as compared to control. Rats at the1000mg/kg-bw/day dose showed oronasal bleeding during the first week and occasionally throughout the study. No effects were seen on body mass as well as food and water consumption was noted. at gross necropsy, No changes in organ weights of reproductive organs were noted. Noteworthy were the statistically insignificant, mild effects on litter mass of the high dose group and on pre-implantation loss of the 250mg/kg-bw/day and 1000 mg/kg-bw/day dose group. Similarly there was a mild tendency of relatively low total numbers of pups born with increasing test item dosage and a low mean number of live pups per dam at day 4 post-partum. Hence NOAEL was considered to be 1000 mg/kg/day for P generation and for F1 generation, when male and female wistar rats treated with test chemical orally by gavage .

Based on the data available from different studies, NOAEL for test chemical was considered to be 1000mg/kg /day for reproductive toxicity, when male and female rats were treated with test material orally. Thus, comparing this value with the criteria of CLP regulation test material is not likely to classify as reproductive toxicant.

Effects on developmental toxicity

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available

Justification for classification or non-classification

Thus, comparing this value with the criteria of CLP regulation test material is not likely to classify as reproductive toxicant.