N,N,N-trimethylanilinium chloride

Endpoint summary

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 material was considered to be 50mg /kg bw/day.When male and female rats were treated with test material orally,Thus, comparing this value with the criteria of CLP regulation test material is 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 for cross-reference:

read-across: supporting information

Reason / purpose for cross-reference:

read-across: supporting information

Reason / purpose for cross-reference:

read-across: supporting information

Qualifier:

equivalent or similar to guideline

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

Justification for study design:

No data available

Species:

rat

Strain:

other: 1&2.Sprague-Dawley 3.Wistar derived albino

Details on species / strain selection:

No data available

Sex:

male/female

Details on test animals or test system and environmental conditions:

No data available

Route of administration:

other: 1.oral: feed 2.oral: gavage

Vehicle:

not specified

Details on exposure:

1.Details on exposure
PREPARATION OF DOSING SOLUTIONS: test material mixed with feed

DIET PREPARATION
- Rate of preparation of diet (frequency):No data available
- Mixing appropriate amounts with (Type of food)
- Storage temperature of food: No data available
VEHICLE
- Justification for use and choice of vehicle (if other than water):
- Concentration in vehicle:
- Amount of vehicle (if gavage): No data available

- Lot/batch no. (if required): No data available
- Purity: No data available
2.Details on exposure
PREPARATION OF DOSING SOLUTIONS: test material dissolved in Milli-Q water

DIET PREPARATION
- Rate of preparation of diet (frequency):No data available
- Mixing appropriate amounts with (Type of food)
- Storage temperature of food: No data available
VEHICLE
- Justification for use and choice of vehicle (if other than water):
- Concentration in vehicle:10, 30 and 100 mg/kg/day
- Amount of vehicle (if gavage): 5 ml/kg/day.

- Lot/batch no. (if required): No data available
- Purity: No data available

Details on mating procedure:

1.- M/F ratio per cage:1:1
- Length of cohabitation: three weeks
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: [no / yes (explain)]
- After successful mating each pregnant female was caged (how):
- Any other deviations from standard protocol:
2.timed-pregnant female rats were used

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

1.F0: 19 weeks (from 1st prebreed dose to last F0
sacrifice)
F1: 24 weeks (from 1st F1 wean to last F1 sacrifice)
F2: to weaning
Premating exposure period for males: F0: 10 weeks; F1: 10 to 14 weeks (beginning with
1st weaning)
Premating exposure period for females: F0: 10 weeks; F1: 10 to 14 weeks (beginning with
1st weaning)
2.10 days (Days 6 through 15 of gestation)

Frequency of treatment:

1.
7 days/week
2.Once daily during exposure period

Details on study schedule:

1.After a 10-week pre-breed period rats were mated (one male to one female) for three weeks to produce the F1 generation. At weaning, 28 F1 weanlings/sex/group were selected to produce the F2 generation,After their pre-breed exposure, F1 animals were paired as described above. All procedures during mating, gestation, and lactation of the F1 parents and selected F2 weanlings were performed as described above.

Remarks:

Study 1.
0,300, 1000 and 2000 ppm ( Mean consumption for the males and females throughout the study was 22.5, 72.6 and 145.5 mg/kg/day for the 300, 1000 and 2000 ppm groups, respectively.
Study 2.
0,10, 30 and 100 mg/kg/day
Study 3.
0,5, 15 and 50 mg/kg/day

No. of animals per sex per dose:

Study 1.
Total:224
0 mg/kg/day:28 male and 28 female
23 mg/kg/day:28 male and 28 female
73 mg/kg/day:28 male and 28 female
145 mg/kg/day:28 male and 28 female
Study 2.
Total:100
0 mg/kg/day:25 female
10 mg/kg/day:25 female
30 mg/kg/day:25 female
100mg/kg/day:25 female
3.Total:88-148
0 mg/kg/day:22-37 pregnant rats
5 mg/kg/day:22-37 pregnant rats
15 mg/kg/day:22-37 pregnant rats
50mg/kg/day:22-37 pregnant rats

Control animals:

yes, concurrent no treatment

Details on study design:

2.- Dose selection rationale: A range-finding study was conducted to determine dose levels for the definitive developmental toxicity study. Five groups of five timedpregnant
female rats each were dosed with test material at concentrations of 25, 50, 100, 200 or 400 mg/kg/day by oral gavage on gestation days (GD) 6 through 15.

Positive control:

3.Yes, concurrent positive (aspirin, 250 mg/kg/day)

Parental animals: Observations and examinations:

1.Parental animals observation and examinations
CAGE SIDE OBSERVATIONS: yes

DETAILED CLINICAL OBSERVATIONS: Yes

Time schedule: daily


BODY WEIGHT: Yes
Time schedule for examinations: daily
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes Food consumption was determined weekly.

Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data: No data available


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
Time schedule for examinations:

2.Parental animals observation and examinations
CAGE SIDE OBSERVATIONS: yes

DETAILED CLINICAL OBSERVATIONS: Yes

Time schedule: female rats were observed for mortality twice daily, clinical
signs of toxicity daily (twice daily during dosing)


BODY WEIGHT: Yes
Time schedule for examinations: maternal body weights and food consumption were
measured at varying intervals.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes Food consumption was determined weekly.

Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data: No data available


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
Time schedule for examinations:

OTHER:

Oestrous cyclicity (parental animals):

No data available

Sperm parameters (parental animals):

No data available

Litter observations:

number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies were observed

Postmortem examinations (parental animals):

1.SACRIFICE
- Male animals: All surviving animals [describe when, e.g. as soon as possible after the last litters in each generation were produced.]
- Maternal animals: All surviving animals [describe when, e.g. after the last litter of each generation was weaned.]

GROSS NECROPSY: yes
- Gross necropsy consisted of [external and internal examinations including the cervical, thoracic, and abdominal viscera.]

HISTOPATHOLOGY / ORGAN WEIGHTS: yes
The tissues indicated in Table [#] were prepared for microscopic examination and weighed, respectively.
2.At scheduled sacrifice on GD 21, a gross necropsy was performed on all dams. In addition, the dams were evaluated for body weight, liver and gravid uterine weight, number of corpora lutea, and number and status of implantation sites

Postmortem examinations (offspring):

1.SACRIFICE
- The F1 offspring not selected as parental animals and all F2 offspring were sacrificed at [#?] days of age.
- These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination) as follows:

GROSS NECROPSY: yes
- Gross necropsy consisted of [external and internal examinations including the cervical, thoracic, and abdominal viscera.]

HISTOPATHOLOGY / ORGAN WEIGTHS: yes
The tissues indicated in Table [#] were prepared for microscopic examination and weighed, respectively.
2.All live fetuses were dissected from the uterus weighed and examined for external malformation and variations and gender determinations. Approximately one-half of the live fetuses in each litter were examined for thoracic and abdominal visceral abnormalities. These fetuses were decapitated and their heads were fixed in Bouin’s solution for examination of craniofacial structures by serial sectioning. Intact fetuses (approximately one-half) were processed for skeletal staining with alizarin red S and examined for skeletal malformations and variations.

Statistics:

1.The results of the quantitative continuous variables (e.g., body weights, food consumption, etc.) were compared for the three treatment groups and one control group by use of Levene’s test for equal variances, analysis of variance and (pooled or separate variance) t-test. Non-parametric data were statistically evaluated using the Kruskall-Wallis test followed by the Mann-Whitney U test for pairwise comparisons when appropriate. Frequency data were compared using the Fisher’s exact test.
2.Quantitative continuous variables were compared for the three treatment groups and the control group by use of Levene’s test for equality of variances, analysis of variance (ANOVA), and t-tests. Nonparametric data were evaluated using the Kruskal-Wallis test, followed by the Mann- Whitney U test when appropriate. Incidence data were compared using the Fisher’s Exact Test.
3.Confidence Belts for proportions with a confidence coefficient of 0.95 was used to compare the experimental and control groups. If the significance was not clearly definable, the probability of the occurrence was determined by the computation of exact probabilities.

Reproductive indices:

No data available

Offspring viability indices:

No data available

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

2.Treatment-related clinical signs included perioral wetness in 67% of dams in the 100 mg/kg group. Audible respiration during and subsequent to the treatment period also was observed in three dams in the 100 mg/kg group. One dam in this group exhibited dehydration, unkempt appearance, loose feces, urine stains and perioral wetness. Audible respiration was observed in two dams in the 30 mg/kg group. One of these dams also exhibited urine stains, gasping, perinasal encrustation, loose feces and perioral wetness. No treatment-related clinical signs were observed in animals in the 10 mg/kg group during or subsequent to treatment.
3.There were no clinical signs reported

Dermal irritation (if dermal study):

not specified

Mortality:

mortality observed, treatment-related

Description (incidence):

3.There were 3 deaths of dames in the 50 mg/kg/day test group.Increased mortality was observed at 50 mg/kg/day; however, this finding was not statistically significant

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

1.Males exhibited no reduction in body weight. Females at 2000 ppm had reductions in body weight for weeks 5, 6, 9 and 10 of treatment. Body weight gain was reduced at 2000 ppm for one week during the prebreed treatment. Food consumption in F0 females at 2000 ppm was reduced for the first four exposure weeks.
Females in the 2000 ppm group showed significant reductions in body weights on day 0 of gestation, but no body weight gain reductions. Body weight gains throughout lactation and body weights on lactation day 21 were increased in the females in the 2000 ppm group.
2.There were no effects of treatment on gestational body weight and weight gain, corrected body weight .
3.There were no effects of treatment on gestational body weight.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

1.During gestation and lactation was unaffected by test substance treatment.
2.Food consumption was reduced for days 6 - 9 of gestation in the 30 and 100 mg/kg groups.

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:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

No treatment-related lesions were observed in the necropsy of F0 males and females. No treatment-related lesions were observed in the
histopathologic examination of selected organs from F0 males and females at 2000 ppm.

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

no effects observed

Description (incidence and severity):

1.Reproductive parameters were unaffected by treatment.
2.Pregnancy rate was equivalent among groups and ranged from 84 to 100%. Twenty-one to 25 live litters were available for evaluation from each group.
There were no statistically significant differences between treated and control animals in gestational parameters (including total number of implantations, number of viable and nonviable implants per litter).
3.Effects on gestation were not noted in any treatment group.

Dose descriptor:

NOAEL

Effect level:

> 50 - <= 145 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

food consumption and compound intake

histopathology: non-neoplastic

reproductive performance

Remarks on result:

other: No effects on reproductive parameters were observed

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality:

no mortality observed

Description (incidence):

1.There were no apparent treatment-related deaths of adult animals on study.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

1.F1 males at 2000 ppm exhibited no reduction in body weights but did have reduced weight gain in the second treatment week.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

1.Food consumption was reduced for F1 males at 2000 ppm for two of the 10 treatment weeks. There were no significant effects on F1 females.

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

Gross pathological findings:

not specified

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

1.No treatment-related lesions were observed in the necropsy of F1 males and females.
There were no treatment-related lesions observed in the histopathologic examination of selected organs from the 2000 ppm group.

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

no effects observed

Description (incidence and severity):

1.Reproductive parameters were unaffected by treatment. Maternal body weights at 2000 ppm were unaffected during the gestational and lactational periods. Gestational food consumption was reduced for days 7 - 11 and 14 - 17 at 2000 ppm.

Dose descriptor:

NOAEL

Effect level:

145 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

mortality

body weight and weight gain

food consumption and compound intake

histopathology: non-neoplastic

reproductive performance

Remarks on result:

other: Reproductive parameters were unaffected by treatment.

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality / viability:

no mortality observed

Description (incidence and severity):

No effects of treatment on postnatal deaths (postnatal days 0 - 28) were observed.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

1.Pups exhibited reduced body weights per litter on days 21 (weaning) and 28 (postweaning) at 2000 ppm. F1 pup body weight gains were reduced for lactation days 14 - 21 and 21 - 28 (postweaning).
2.There were no statistically significant differences between treated and control fetal body weights per litter
3.There were no treatment-related effects related to bodyweight.

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.There were no statistically significant differences between treated and control fetal in the incidences of external, visceral or skeletal malformations or variations.
3.There were no malformations or gross finding at necropsy. There were no treatment-related variations or malformations with respect to skeletal or visceral findings.

Histopathological findings:

no effects observed

Description (incidence and severity):

No treatment-related lesions were observed in the necropsy of F1 pups that died during lactation or of randomly selected F1 pups (10/sex/dose)

Other effects:

not specified

Behaviour (functional findings):

not specified

Developmental immunotoxicity:

not specified

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

73 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

not specified

Basis for effect level:

viability

mortality

body weight and weight gain

histopathology: non-neoplastic

Remarks on result:

other: Pups exhibited reduced body weights per litter on days 21 (weaning) and 28 (postweaning) at 2000 ppm. F1 pup body weight gains were reduced for lactation days 14 - 21 and 21 - 28 (postweaning).

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality / viability:

no mortality observed

Description (incidence and severity):

Perinatal deaths and lactational survival were unaffected by treatment.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Pup body weights per litter were reduced at 2000 ppm at postnatal day 28 (postweaning). Pup weight gains per litter also were reduced at 2000 ppm for lactational days 14 - 21 (preweaning) and for days 21 - 28 (postweaning).

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:

not specified

Histopathological findings:

no effects observed

Description (incidence and severity):

There were no treatment-related lesions observed in the necropsy of F2 pups that died during lactation or of randomly selected F2 pups
(10/sex/group)

Other effects:

not specified

Behaviour (functional findings):

not specified

Developmental immunotoxicity:

not specified

Dose descriptor:

NOAEL

Generation:

F2

Effect level:

73 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

not specified

Basis for effect level:

viability

mortality

body weight and weight gain

histopathology: non-neoplastic

Remarks on result:

other: No developmental toxic effects observed

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Reproductive effects observed:

not specified

Treatment related:

not specified

Relation to other toxic effects:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Conclusions:

No Observed Adverse Effect Level (NOAEL) for reproductive toxicity was considered to beapproximately 145 mg/kg/day (2000ppm)and for developmental toxicity considered to be approximately 73mg/kg /day(1000ppm). When male and female SpragueDawley rats were treated with test material orally.

Executive summary:

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

Study 1

The two generation reproductive toxicity of test material was performed on male and female SpragueDawley rats. The test material mixed with feed in dose concentration 300, 1000 and 2000 ppm (approximately 22.5, 72.6 and 145.5 mg/kg/day base on Mean consumption for the males and females throughout the study). A total of 28 male and 28 female rats were evaluated at each dose level. After a 10-week pre-breed period rats were mated (one male to one female) for three weeks to produce the F1 generation. Exposures continued through mating, gestation, parturition and lactation. At weaning, 28 F1 weanlings/sex/group were selected to produce the F2 generation, and were then exposed to the same dietary concentrations of test material as their parents for 10 weeks. After their pre-breed exposure, F1 animals were paired as described above. All procedures during mating, gestation, and lactation of the F1 parents and selected F2 weanlings were performed as described above. All F0 and F1 parental animals were necropsied and examined for gross lesions; selected reproductive tissues from the high dose and control groups were examined histologically as were other tissues with gross lesions. Ten F1 and F2 weanlings/sex/group were randomly selected and examined for gross lesions. Remaining nonselected F1 and F2 pups at weaning were euthanized and discarded after the necropsy of the selected pups.

After 10 weeks Premating Exposure for paraents males exhibited no reduction in body weight. Females at 2000 ppm had reductions in body weight for weeks 5, 6, 9 and 10 of treatment. Body weight gain was reduced at 2000 ppm for one week during the prebreed treatment. Food consumption in F0 females at 2000 ppm was reduced for the first four exposure weeks. While Reproductive parameters were unaffected by treatment. Females in the 2000 ppm group showedsignificant reductions in body weights on day 0 of gestation, but no body weight gain reductions.Body weight gains throughout lactation and body weights on lactation day 21 were increased in thefemales in the 2000 ppm group. Food consumption during gestation and lactation was unaffected bytest substance treatment during gestation and lactation period in F0 Female. After postmortem .No treatment-related lesions were observed in the necropsy of F0 males and females. No treatment-related lesions were observed in the histopathologic examination of selected organs from F0 males and females at 2000 ppm.

F1 males at 2000 ppm exhibited no reduction in body weights but did have reduced weight gain in the second treatment week. Food consumption was reduced for F1 males at 2000 ppm for two of the 10 treatment weeks. There were no significant effects on F1 females. Reproductive parameters were unaffected by treatment. Maternal body weights at 2000 ppm were unaffected during the gestational and lactational periods. Gestational food consumption was reduced for days 7 - 11 and 14- 17 at2000 ppm. After postmortem in F1 male and female .No treatment-related lesions were observed in the necropsy of F1 males and females. There were no treatment-related lesions observed in the histopathologic examination of selected organs from the 2000 ppm group. There were no apparenttreatment-related deaths of adult animals on study.

In F1 litter,Pups exhibited reduced body weights per litter on days 21 (weaning) and 28 (postweaning) at 2000 ppm. F1 pup body weight gains were reduced for lactation days 14 - 21 and 21 – 28 (postweaning). No effects of treatment on postnatal deaths (postnatal days 0 - 28) were observed. No treatment-related lesions were observed in the necropsy of F1 pups that died during lactation or of randomly selected F1 pups (10/sex/dose).While in F2 Litters,Pup body weights per litter were reduced at 2000 ppm at postnatal day 28 (postweaning). Pup weight gains per litter also were reduced at 2000 ppm for lactational days 14 - 21 (preweaning) and for days 21 - 28 (postweaning). Perinatal deaths and lactational survival were unaffected by treatment. There were no treatment-related lesions observed in the necropsy of F2 pups that died during lactation or of randomly selected F2 pups (10/sex/group).

Exposure of rats to the test substance in the diet for two generations resulted in parental toxicityat the target dose level of 145mg/kg bw/day (2000 ppm): perinatal toxicity was concomitant with parental toxicity, being well-defined at 145mg/kg bw/day (2000 ppm.There were notreatment-related reproductive effects observed in this study. The A/D ratio (the dose level at which there were no observable effects in adults/the dose level at which there were no observable effects on offspring) is 1 (1000 ppm/1000 ppm) indicating no increased risk to the offspring in the absence of indications of adult toxicity. HenceNo Observed Adverse Effect Level (NOAEL) for reproductive toxicity was considered to beapproximately 145 mg/kg/day (2000ppm)and for developmental toxicity considered to be approximately 73mg/kg /day(1000ppm). When male and femaleSpragueDawley rats were treated withtest materialorally.

 Study 2.

The reproductive and developmental toxicity of test material was performed ontimed-pregnant female Sprague-Dawley rats. The test material was dissolved in Milli-Q water in dose concentration 10, 30 and 100 mg/kg/day and adminstered in dose volume 5 ml/kg orally by gavage from Days 6 through 15 of gestation. The dose concentration selected on the bases of dose range finding atconcentrations of 25, 50, 100, 200 or 400 mg/kg/day by oral gavage on gestation days (GD) 6 through 15.study.In main study,three groups of 25 timed-pregnant female rats each were dosed group while a control group of 25 timed-pregnant rats received water. Administered dose volumes of water or aqueous solutions of test material were based on the individual dam’s body weight on GD 6 and a constant volume of 5 ml/kg/day. Concentrations were adjusted for percentactive ingredient. Throughout the study, (GD 0 - 21), female rats were observed for mortality twice daily, clinical signs of toxicity daily (twice daily during dosing) and maternal body weights and food consumption were measured at varying intervals. At scheduled sacrifice on GD 21, a gross necropsy was performed on all dams. In addition, the dams were evaluated for body weight, liver and gravid uterine weight, number of corpora lutea, and number and status of implantation sites. All live fetuseswere dissected from the uterus weighed and examined for external malformation and variations and gender determinations. Approximately one-half of the live fetuses in each litter were examined for thoracic and abdominal visceral abnormalities. These fetuses were decapitated and their heads were fixed in Bouin’s solution for examination of craniofacial structures by serial sectioning. Intactfetuses (approximately one-half) were processed for skeletal staining with alizarin red S and examined for skeletal malformations and variations.

Treatment-related clinical signs included perioral wetness in 67% of dams in the 100 mg/kg group. Audible respiration during and subsequent to the treatment period also was observed in three dams in the 100 mg/kg group. One dam in this group exhibited dehydration, unkempt appearance, loose feces, urine stains and perioral wetness. Audible respiration was observed in two dams in the 30 mg/kg group. One of these dams also exhibited urine stains, gasping, perinasal encrustation, loose feces and perioral wetness. No treatment-related clinical signs were observed in animals in the 10 mg/kg group during or subsequent to treatment. Food consumption was reduced for days 6 - 9 of gestation in the 30 and 100 mg/kg groups. There were no effects of treatment on gestational bodyweight and weight gain, corrected body weight or gravid uterine weight. Pregnancy rate was equivalent among groups and ranged from 84 to 100%. Twenty-one to 25 live litters were available for evaluation from each group. There were no statistically significant differences between treated and control animals in gestational parameters (including total number of implantations, number of viable and nonviable implants per litter). There were no statistically significant differences betweentreated and control fetal body weights per litter or in the incidences of external, visceral or skeletal malformations or variations.HenceNo Observed Adverse Effect Level (NOAEL) for reproductive and developmental toxicity was considered to be 100mg/kg bw/day. When femaleSpragueDawley rats were treated with test material orally.

Study 3.

The reproductive and developmental toxicity study of test material was performed on femaleWistar derived albino rats.The study was carried out in a manner similar to OECD Guideline 414. The test material in dose concentration 0, 5, 15 and 50 mg/kg/day were administered orally using gavage once daily on days 6 through 15 of gestation. In positive control group aspirin, 250 mg/kg/day were administered. 22-37 pregnant rats/group were treated. The dams were sacrificed at day 20 and the foetuses were examined for visceral and skeletal variations and malformations.

There were no clinical signs reported. There were 3 deaths of dames in the 50 mg/kg/day test group. however, this finding was not statistically significant.There were no effects of treatment on gestational body weight. Effects on gestation were not noted in any treatment group. Twelve females in the positive control group resorbed their uterine contents. There were no treatment-related effects related to bodyweight. Decreased weights were observed in the positive control group. There were no malformations or gross finding at necropsy. There were no treatment-related variations or malformations with respect to skeletal or visceral findings.HenceNo Observed Adverse Effect Level (NOAEL) for reproductive and developmental toxicity was considered to be above 50mg/kg bw/day. When female SpragueDawley rats were treated with test material orally.

Based on the data available from different studies ,test material did not showedreproductive toxicityat dose concentration 50 mg/kg bw/day.When rats were treated with test material orally.,Thus, comparing this value with the criteria ofCLP regulation test material is likely to classify as reproductive toxicant.

 

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

50 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 test chemical.The studies are as mentioned below:

Study 1

The two generation reproductive toxicity of test material was performed on male and female SpragueDawley rats. The test material mixed with feed in dose concentration 300, 1000 and 2000 ppm (approximately 22.5, 72.6 and 145.5 mg/kg/day base on Mean consumption for the males and females throughout the study). A total of 28 male and 28 female rats were evaluated at each dose level. After a 10-week pre-breed period rats were mated (one male to one female) for three weeks to produce the F1 generation. Exposures continued through mating, gestation, parturition and lactation. At weaning, 28 F1 weanlings/sex/group were selected to produce the F2 generation, and were then exposed to the same dietary concentrations of test material as their parents for 10 weeks. After their pre-breed exposure, F1 animals were paired as described above. All procedures during mating, gestation, and lactation of the F1 parents and selected F2 weanlings were performed as described above. All F0 and F1 parental animals were necropsied and examined for gross lesions; selected reproductive tissues from the high dose and control groups were examined histologically as were other tissues with gross lesions. Ten F1 and F2 weanlings/sex/group were randomly selected and examined for gross lesions. Remaining nonselected F1 and F2 pups at weaning were euthanized and discarded after the necropsy of the selected pups.

After 10 weeks Premating Exposure for paraents males exhibited no reduction in body weight. Females at 2000 ppm had reductions in body weight for weeks 5, 6, 9 and 10 of treatment. Body weight gain was reduced at 2000 ppm for one week during the prebreed treatment. Food consumption in F0 females at 2000 ppm was reduced for the first four exposure weeks. While Reproductive parameters were unaffected by treatment. Females in the 2000 ppm group showedsignificant reductions in body weights on day 0 of gestation, but no body weight gain reductions.Body weight gains throughout lactation and body weights on lactation day 21 were increased in thefemales in the 2000 ppm group. Food consumption during gestation and lactation was unaffected bytest substance treatment during gestation and lactation period in F0 Female. After postmortem .No treatment-related lesions were observed in the necropsy of F0 males and females. No treatment-related lesions were observed in the histopathologic examination of selected organs from F0 males and females at 2000 ppm.

F1 males at 2000 ppm exhibited no reduction in body weights but did have reduced weight gain in the second treatment week. Food consumption was reduced for F1 males at 2000 ppm for two of the 10 treatment weeks. There were no significant effects on F1 females. Reproductive parameters were unaffected by treatment. Maternal body weights at 2000 ppm were unaffected during the gestational and lactational periods. Gestational food consumption was reduced for days 7 - 11 and 14- 17 at2000 ppm. After postmortem in F1 male and female .No treatment-related lesions were observed in the necropsy of F1 males and females. There were no treatment-related lesions observed in the histopathologic examination of selected organs from the 2000 ppm group. There were no apparenttreatment-related deaths of adult animals on study.

In F1 litter,Pups exhibited reduced body weights per litter on days 21 (weaning) and 28 (postweaning) at 2000 ppm. F1 pup body weight gains were reduced for lactation days 14 - 21 and 21 – 28 (postweaning). No effects of treatment on postnatal deaths (postnatal days 0 - 28) were observed. No treatment-related lesions were observed in the necropsy of F1 pups that died during lactation or of randomly selected F1 pups (10/sex/dose).While in F2 Litters,Pup body weights per litter were reduced at 2000 ppm at postnatal day 28 (postweaning). Pup weight gains per litter also were reduced at 2000 ppm for lactational days 14 - 21 (preweaning) and for days 21 - 28 (postweaning). Perinatal deaths and lactational survival were unaffected by treatment. There were no treatment-related lesions observed in the necropsy of F2 pups that died during lactation or of randomly selected F2 pups (10/sex/group).

Exposure of rats to the test substance in the diet for two generations resulted in parental toxicityat the target dose level of 145mg/kg bw/day (2000 ppm): perinatal toxicity was concomitant with parental toxicity, being well-defined at 145mg/kg bw/day (2000 ppm.There were notreatment-related reproductive effects observed in this study. The A/D ratio (the dose level at which there were no observable effects in adults/the dose level at which there were no observable effects on offspring) is 1 (1000 ppm/1000 ppm) indicating no increased risk to the offspring in the absence of indications of adult toxicity. HenceNo Observed Adverse Effect Level (NOAEL) for reproductive toxicity was considered to beapproximately 145 mg/kg/day (2000ppm)and for developmental toxicity considered to be approximately 73mg/kg /day(1000ppm). When male and femaleSpragueDawley rats were treated withtest materialorally.

 Study 2.

The reproductive and developmental toxicity of test material was performed ontimed-pregnant female Sprague-Dawley rats. The test material was dissolved in Milli-Q water in dose concentration 10, 30 and 100 mg/kg/day and adminstered in dose volume 5 ml/kg orally by gavage from Days 6 through 15 of gestation. The dose concentration selected on the bases of dose range finding atconcentrations of 25, 50, 100, 200 or 400 mg/kg/day by oral gavage on gestation days (GD) 6 through 15.study.In main study,three groups of 25 timed-pregnant female rats each were dosed group while a control group of 25 timed-pregnant rats received water. Administered dose volumes of water or aqueous solutions of test material were based on the individual dam’s body weight on GD 6 and a constant volume of 5 ml/kg/day. Concentrations were adjusted for percentactive ingredient. Throughout the study, (GD 0 - 21), female rats were observed for mortality twice daily, clinical signs of toxicity daily (twice daily during dosing) and maternal body weights and food consumption were measured at varying intervals. At scheduled sacrifice on GD 21, a gross necropsy was performed on all dams. In addition, the dams were evaluated for body weight, liver and gravid uterine weight, number of corpora lutea, and number and status of implantation sites. All live fetuseswere dissected from the uterus weighed and examined for external malformation and variations and gender determinations. Approximately one-half of the live fetuses in each litter were examined for thoracic and abdominal visceral abnormalities. These fetuses were decapitated and their heads were fixed in Bouin’s solution for examination of craniofacial structures by serial sectioning. Intactfetuses (approximately one-half) were processed for skeletal staining with alizarin red S and examined for skeletal malformations and variations.

Treatment-related clinical signs included perioral wetness in 67% of dams in the 100 mg/kg group. Audible respiration during and subsequent to the treatment period also was observed in three dams in the 100 mg/kg group. One dam in this group exhibited dehydration, unkempt appearance, loose feces, urine stains and perioral wetness. Audible respiration was observed in two dams in the 30 mg/kg group. One of these dams also exhibited urine stains, gasping, perinasal encrustation, loose feces and perioral wetness. No treatment-related clinical signs were observed in animals in the 10 mg/kg group during or subsequent to treatment. Food consumption was reduced for days 6 - 9 of gestation in the 30 and 100 mg/kg groups. There were no effects of treatment on gestational bodyweight and weight gain, corrected body weight or gravid uterine weight. Pregnancy rate was equivalent among groups and ranged from 84 to 100%. Twenty-one to 25 live litters were available for evaluation from each group. There were no statistically significant differences between treated and control animals in gestational parameters (including total number of implantations, number of viable and nonviable implants per litter). There were no statistically significant differences betweentreated and control fetal body weights per litter or in the incidences of external, visceral or skeletal malformations or variations.HenceNo Observed Adverse Effect Level (NOAEL) for reproductive and developmental toxicity was considered to be 100mg/kg bw/day. When femaleSpragueDawley rats were treated with test material orally.

Study 3.

The reproductive and developmental toxicity study of test material was performed on femaleWistar derived albino rats.The study was carried out in a manner similar to OECD Guideline 414. The test material in dose concentration 0, 5, 15 and 50 mg/kg/day were administered orally using gavage once daily on days 6 through 15 of gestation. In positive control group aspirin, 250 mg/kg/day were administered. 22-37 pregnant rats/group were treated. The dams were sacrificed at day 20 and the foetuses were examined for visceral and skeletal variations and malformations.

There were no clinical signs reported. There were 3 deaths of dames in the 50 mg/kg/day test group. however, this finding was not statistically significant.There were no effects of treatment on gestational body weight. Effects on gestation were not noted in any treatment group. Twelve females in the positive control group resorbed their uterine contents. There were no treatment-related effects related to bodyweight. Decreased weights were observed in the positive control group. There were no malformations or gross finding at necropsy. There were no treatment-related variations or malformations with respect to skeletal or visceral findings.HenceNo Observed Adverse Effect Level (NOAEL) for reproductive and developmental toxicity was considered to be above 50mg/kg bw/day. When female Sprague Dawley rats were treated with test material orally.

Based on the data available from different studies ,test material did not showed reproductive toxicity at dose concentration 50 mg/kg bw/day.When rats were treated with test material orally.,Thus, comparing this value with the criteria of CLP regulation test material is likely to classify as reproductive toxicant.

 

Effects on developmental toxicity

Description of key information

Developmental toxicity study

Based on the various studies available for the test chemical were reviewed to determine the developmental toxicity, NOAELfor test chemical was considered to be 50 mg /kg bw/day .When rats were treated with test chemical orally. Thus, comparing this value with the criteria of CLP regulation test chemical is not likely to classify as reproductive and developmental toxicant.

Link to relevant study records

Reference

Endpoint:

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 for cross-reference:

read-across: supporting information

Reason / purpose for cross-reference:

read-across: supporting information

Qualifier:

equivalent or similar to guideline

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.Sprague-Dawley 2.Wistar derived albino

Details on test animals or test system and environmental conditions:

No data available

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

Details on exposure
PREPARATION OF DOSING SOLUTIONS: test material dissolved in Milli-Q water

DIET PREPARATION
- Rate of preparation of diet (frequency):No data available
- Mixing appropriate amounts with (Type of food)
- Storage temperature of food: No data available
VEHICLE
- Justification for use and choice of vehicle (if other than water):
- Concentration in vehicle:10, 30 and 100 mg/kg/day
- Amount of vehicle (if gavage): 5 ml/kg/day.

- Lot/batch no. (if required): No data available
- Purity: No data available

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

timed-pregnant female rats

Duration of treatment / exposure:

10 days (Days 6 through 15 of gestation)

Frequency of treatment:

Daily

Duration of test:

Day 21 of gestation

Remarks:

1.
0,10, 30 and 100 mg/kg/day
2.0,5, 15 and 50 mg/kg/day

No. of animals per sex per dose:

1.Total:100
0 mg/kg/day:25 female
10 mg/kg/day:25 female
30 mg/kg/day:25 female
100mg/kg/day:25 female
2.Total:88-148
0 mg/kg/day:22-37 pregnant rats
5 mg/kg/day:22-37 pregnant rats
15 mg/kg/day:22-37 pregnant rats
50mg/kg/day:22-37 pregnant rats
concurrent positive (aspirin, 250 mg/kg/day)

Control animals:

yes

Details on study design:

- Dose selection rationale: A range-finding study was conducted to determine dose levels for the definitive developmental toxicity study. Five groups of five timedpregnant female rats each were dosed with test material at concentrations of 25, 50, 100, 200 or 400 mg/kg/day by oral gavage on gestation days (GD) 6 through 15.

Maternal examinations:

1.Parental animals observation and examinations
CAGE SIDE OBSERVATIONS: yes

DETAILED CLINICAL OBSERVATIONS: Yes

Time schedule: female rats were observed for mortality twice daily, clinical
signs of toxicity daily (twice daily during dosing)


BODY WEIGHT: Yes
Time schedule for examinations: maternal body weights and food consumption were
measured at varying intervals.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes Food consumption was determined weekly.

Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data: No data available


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
Time schedule for examinations:

2.Parental animals observation and examinations
CAGE SIDE OBSERVATIONS: yes

DETAILED CLINICAL OBSERVATIONS: Yes

Time schedule:

BODY WEIGHT: Yes
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):

Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day:
Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data: No data available


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
Time schedule for examinations

Ovaries and uterine content:

1&2.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:

1&2.- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: No data

Statistics:

1.Quantitative continuous variables were compared for the three treatment groups and the control group by use of Levene’s test for equality of variances, analysis of variance (ANOVA), and t-tests. Nonparametric data were evaluated using the Kruskal-Wallis test, followed by the Mann- Whitney U test when appropriate. Incidence data were compared using the Fisher’s Exact Test.
2.Confidence Belts for proportions with a confidence coefficient of 0.95 was used to compare the experimental and control groups. If the significance was not clearly definable, the probability of the occurrence was determined by the computation of exact probabilities.

Indices:

No data available

Historical control data:

No data available

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

1.Treatment-related clinical signs included perioral wetness in 67% of dams in the 100 mg/kg group. Audible respiration during and subsequent to the treatment period also was observed in three dams in the 100 mg/kg group.
One dam in this group exhibited dehydration, unkempt appearance, loose feces, urine stains and perioral wetness. Audible respiration was observed in two dams in the 30 mg/kg group. One of these dams also exhibited urine stains, gasping, perinasal encrustation, loose feces and perioral wetness. No treatment-related clinical signs were observed in animals in the 10 mg/kg group during or subsequent to treatment.
2.There were no clinical signs reported

Dermal irritation (if dermal study):

not specified

Mortality:

mortality observed, treatment-related

Description (incidence):

There were 3 deaths of dames in the 50 mg/kg/day test group.Increased mortality was observed at 50 mg/kg/day; however, this finding was not statistically significant

Body weight and weight changes:

no effects observed

Description (incidence and severity):

1.There were no effects of treatment on gestational body weight and weight gain, corrected body weight.
2.There were no effects of treatment on gestational body weight

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Food consumption was reduced for days 6 - 9 of gestation in the 30 and 100 mg/kg groups.

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:

no effects observed

Description (incidence and severity):

1.There were no effects of treatment on gravid uterine weight.

Gross pathological findings:

not specified

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Number of abortions:

not specified

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:

not specified

Changes in pregnancy duration:

not specified

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

Other effects:

not specified

Details on maternal toxic effects:

Pregnancy rate was equivalent among groups and ranged from 84 to 100%. Twenty-one to 25 live litters were available for evaluation from each group. There were no statistically significant differences between treated and control animals in gestational parameters
(including total number of implantations, number of viable and nonviable implants per litter).

Dose descriptor:

NOAEL

Effect level:

100 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

body weight and weight gain

changes in number of pregnant

clinical signs

early or late resorptions

food consumption and compound intake

maternal abnormalities

number of abortions

pre and post implantation loss

total litter losses by resorption

Remarks on result:

other: No effects observed

Abnormalities:

not specified

Localisation:

not specified

Fetal body weight changes:

no effects observed

Description (incidence and severity):

1.There were no statistically significant differences between treated and control fetal body weights per litter
2.There were no treatment-related effects related to bodyweight.

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:

not specified

Changes in sex ratio:

not specified

Changes in litter size and weights:

not specified

Changes in postnatal survival:

not specified

External malformations:

no effects observed

Skeletal malformations:

no effects observed

Visceral malformations:

no effects observed

Other effects:

not specified

Dose descriptor:

NOAEL

Effect level:

50 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

not specified

Basis for effect level:

fetal/pup body weight changes

external malformations

skeletal malformations

visceral malformations

Remarks on result:

other: No developmental toxic effects were observed

Abnormalities:

not specified

Localisation:

other: not specified

Developmental effects observed:

not specified

Treatment related:

not specified

Relation to maternal toxicity:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Conclusions:

No Observed Adverse Effect Level (NOAEL) for reproductive and developmental toxicity was considered to be 100mg/kg bw/day. When female SpragueDawley rats were treated with test material orally.

Executive summary:

Data available from different studies for test chemicals were reviewed to determine the developmental toxicity of test chemical. The studies are as mentioned below:

Study 1

The reproductive and developmental toxicity of test material was performed ontimed-pregnant female Sprague-Dawley rats. The test material was dissolved in Milli-Q water in dose concentration 10, 30 and 100 mg/kg/day and adminstered in dose volume 5 ml/kg orally by gavage from Days 6 through 15 of gestation. The dose concentration selected on the bases of dose range finding atconcentrations of 25, 50, 100, 200 or 400 mg/kg/day by oral gavage on gestation days (GD) 6 through 15.study.In main study,three groups of 25 timed-pregnant female rats each were dosed group while a control group of 25 timed-pregnant rats received water. Administered dose volumes of water or aqueous solutions of test material were based on the individual dam’s body weight on GD 6 and a constant volume of 5 ml/kg/day. Concentrations were adjusted for percentactive ingredient. Throughout the study, (GD 0 - 21), female rats were observed for mortality twice daily, clinical signs of toxicity daily (twice daily during dosing) and maternal body weights and food consumption were measured at varying intervals. At scheduled sacrifice on GD 21, a gross necropsy was performed on all dams. In addition, the dams were evaluated for body weight, liver and gravid uterine weight, number of corpora lutea, and number and status of implantation sites. All live fetuseswere dissected from the uterus weighed and examined for external malformation and variations and gender determinations. Approximately one-half of the live fetuses in each litter were examined for thoracic and abdominal visceral abnormalities. These fetuses were decapitated and their heads were fixed in Bouin’s solution for examination of craniofacial structures by serial sectioning. Intactfetuses (approximately one-half) were processed for skeletal staining with alizarin red S and examined for skeletal malformations and variations.

Treatment-related clinical signs included perioral wetness in 67% of dams in the 100 mg/kg group. Audible respiration during and subsequent to the treatment period also was observed in three dams in the 100 mg/kg group. One dam in this group exhibited dehydration, unkempt appearance, loose feces, urine stains and perioral wetness. Audible respiration was observed in two dams in the 30 mg/kg group. One of these dams also exhibited urine stains, gasping, perinasal encrustation, loose feces and perioral wetness. No treatment-related clinical signs were observed in animals in the 10 mg/kg group during or subsequent to treatment. Food consumption was reduced for days 6 - 9 of gestation in the 30 and 100 mg/kg groups. There were no effects of treatment on gestational bodyweight and weight gain, corrected body weight or gravid uterine weight. Pregnancy rate was equivalent among groups and ranged from 84 to 100%. Twenty-one to 25 live litters were available for evaluation from each group. There were no statistically significant differences between treated and control animals in gestational parameters (including total number of implantations, number of viable and nonviable implants per litter). There were no statistically significant differences betweentreated and control fetal body weights per litter or in the incidences of external, visceral or skeletal malformations or variations.HenceNo Observed Adverse Effect Level (NOAEL) for reproductive and developmental toxicity was considered to be 100mg/kg bw/day. When female Sprague Dawley rats were treated with test material orally.

 Study 2.

The reproductive and developmental toxicity study of test material was performed on femaleWistar derived albino rats.The study was carried out in a manner similar to OECD Guideline 414. The test material in dose concentration 0, 5, 15 and 50 mg/kg/day were administered orally using gavage once daily on days 6 through 15 of gestation. In positive control group aspirin, 250 mg/kg/day were administered. 22-37 pregnant rats/group were treated. The dams were sacrificed at day 20 and the foetuses were examined for visceral and skeletal variations and malformations.

There were no clinical signs reported. There were 3 deaths of dames in the 50 mg/kg/day test group. however, this finding was not statistically significant.There were no effects of treatment on gestational body weight. Effects on gestation were not noted in any treatment group. Twelve females in the positive control group resorbed their uterine contents. There were no treatment-related effects related to bodyweight. Decreased weights were observed in the positive control group. There were no malformations or gross finding at necropsy. There were no treatment-related variations or malformations with respect to skeletal or visceral findings.HenceNo Observed Adverse Effect Level (NOAEL) for reproductive and developmental toxicity was considered to be above 50mg/kg bw/day. When femaleSpragueDawley rats were treated withtest materialorally.

Thus, based on the data available fortest chemical,No Observed Adverse Effect Level (NOAEL) was considered to be 50mg /kg bw .When rats were treated with test chemical orally. Thus, comparing this value with the criteria of CLP regulationtest chemicalis not likely to classify as reproductive and developmental toxicant.

 

 

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

50 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Data is Klimicsh 2 and from authoritative database

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

Developmental toxicity study

Data available from different studies for test chemicals were reviewed to determine the developmental toxicity of test chemical. The studies are as mentioned below:

Study 1

The reproductive and developmental toxicity of test material was performed ontimed-pregnant female Sprague-Dawley rats. The test material was dissolved in Milli-Q water in dose concentration 10, 30 and 100 mg/kg/day and adminstered in dose volume 5 ml/kg orally by gavage from Days 6 through 15 of gestation. The dose concentration selected on the bases of dose range finding atconcentrations of 25, 50, 100, 200 or 400 mg/kg/day by oral gavage on gestation days (GD) 6 through 15.study.In main study,three groups of 25 timed-pregnant female rats each were dosed group while a control group of 25 timed-pregnant rats received water. Administered dose volumes of water or aqueous solutions of test material were based on the individual dam’s body weight on GD 6 and a constant volume of 5 ml/kg/day. Concentrations were adjusted for percentactive ingredient. Throughout the study, (GD 0 - 21), female rats were observed for mortality twice daily, clinical signs of toxicity daily (twice daily during dosing) and maternal body weights and food consumption were measured at varying intervals. At scheduled sacrifice on GD 21, a gross necropsy was performed on all dams. In addition, the dams were evaluated for body weight, liver and gravid uterine weight, number of corpora lutea, and number and status of implantation sites. All live fetuseswere dissected from the uterus weighed and examined for external malformation and variations and gender determinations. Approximately one-half of the live fetuses in each litter were examined for thoracic and abdominal visceral abnormalities. These fetuses were decapitated and their heads were fixed in Bouin’s solution for examination of craniofacial structures by serial sectioning. Intactfetuses (approximately one-half) were processed for skeletal staining with alizarin red S and examined for skeletal malformations and variations.

Treatment-related clinical signs included perioral wetness in 67% of dams in the 100 mg/kg group. Audible respiration during and subsequent to the treatment period also was observed in three dams in the 100 mg/kg group. One dam in this group exhibited dehydration, unkempt appearance, loose feces, urine stains and perioral wetness. Audible respiration was observed in two dams in the 30 mg/kg group. One of these dams also exhibited urine stains, gasping, perinasal encrustation, loose feces and perioral wetness. No treatment-related clinical signs were observed in animals in the 10 mg/kg group during or subsequent to treatment. Food consumption was reduced for days 6 - 9 of gestation in the 30 and 100 mg/kg groups. There were no effects of treatment on gestational bodyweight and weight gain, corrected body weight or gravid uterine weight. Pregnancy rate was equivalent among groups and ranged from 84 to 100%. Twenty-one to 25 live litters were available for evaluation from each group. There were no statistically significant differences between treated and control animals in gestational parameters (including total number of implantations, number of viable and nonviable implants per litter). There were no statistically significant differences betweentreated and control fetal body weights per litter or in the incidences of external, visceral or skeletal malformations or variations.HenceNo Observed Adverse Effect Level (NOAEL) for reproductive and developmental toxicity was considered to be 100mg/kg bw/day. When femaleSprague Dawley rats were treated with test material orally.

 Study 2.

The reproductive and developmental toxicity study of test material was performed on femaleWistar derived albino rats.The study was carried out in a manner similar to OECD Guideline 414. The test material in dose concentration 0, 5, 15 and 50 mg/kg/day were administered orally using gavage once daily on days 6 through 15 of gestation. In positive control group aspirin, 250 mg/kg/day were administered. 22-37 pregnant rats/group were treated. The dams were sacrificed at day 20 and the foetuses were examined for visceral and skeletal variations and malformations.

There were no clinical signs reported. There were 3 deaths of dames in the 50 mg/kg/day test group. however, this finding was not statistically significant.There were no effects of treatment on gestational body weight. Effects on gestation were not noted in any treatment group. Twelve females in the positive control group resorbed their uterine contents. There were no treatment-related effects related to bodyweight. Decreased weights were observed in the positive control group. There were no malformations or gross finding at necropsy. There were no treatment-related variations or malformations with respect to skeletal or visceral findings.HenceNo Observed Adverse Effect Level (NOAEL) for reproductive and developmental toxicity was considered to be above 50mg/kg bw/day. When femaleSpragueDawley rats were treated withtest materialorally.

Thus, based on the data available fortest chemical,No Observed Adverse Effect Level (NOAEL) was considered to be 50mg /kg bw .When rats were treated with test chemical orally. Thus, comparing this value with the criteria of CLP regulationtest chemicalis not likely to classify as reproductive and developmental toxicant.

 

 

Justification for classification or non-classification

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