Reaction mass of 3H-Indolium, 2-[[2-(4-methoxyphenyl)-2-methylhydrazinylidene]methyl]-1,3,3-trimethyl- and acetate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Reproductive toxicity study

The data available for Reaction mass of 3H-​Indolium, 2-​[[2-​(4-​methoxyphenyl)​-​2-​methylhydrazinyliden​e]​methyl]​-​1,​3,​3-​trimethyl-​ & acetate andstructurally similarread across chemicals was reviewed to determine thereproductive toxicity .The NOAEL for reproductive toxicity was considered to be above 215-500 mg/kg bw/day as No effects on reproductive parameters were observed .When female rats or mice were treated withReaction mass of 3H-​Indolium, 2-​[[2-​(4-​methoxyphenyl)​-​2-​methylhydrazinyliden​e]​methyl]​-​1,​3,​3-​trimethyl-​ & acetate .Thus, comparing this value with the criteria of CLP regulation Reaction mass of 3H-​Indolium, 2-​[[2-​(4-​methoxyphenyl)​-​2-​methylhydrazinyliden​e]​methyl]​-​1,​3,​3-​trimethyl-​ & acetatenot 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 of read across substances

Justification for type of information:

Weight of evidence approach based on structurally similar chemicals

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Qualifier:

equivalent or similar to guideline

Guideline:

other: As mentioned below

Principles of method if other than guideline:

WoE report is based on two reproductive toxicity studies on rats 1.Reproductive and developmental toxicity study of test material was performed on Sprague Dawley rats. 2.Long term toxicity and carcinogenicity study of test material was performed in mice.

GLP compliance:

not specified

Limit test:

no

Justification for study design:

No data available

Species:

other: rats and mice

Strain:

other: 1.Sprague-Dawley 2.B6C3F1

Details on species / strain selection:

No data available

Sex:

female

Details on test animals or test system and environmental conditions:

Study 2- Source:Cumberland View Farms- Age at study initiation: 7 dyas - Weight at study initiation: 10-19 gms Fasting period before study:- Housing: Animals were 6 mice to a cage. 2160 mice couli be housed in each room.- Diet (e.g. ad libitum): food , ad libitum- Water (e.g. ad libitum): water, ad libitum - Acclimation period:ENVIRONMENTAL CONDITIONS- Temperature (°C):- Humidity (%):- Air changes (per hr): A dual duct high velocity sy~tem was used for heating, ventilation and air conditioning.Unidirectional air-flow minimized room to room contamination with absolute filtration of all incoming air to remove particulate matter of 0.3 micron diameter or greater.- Photoperiod (hrs dark / hrs light):

Route of administration:

other: 1.oral : gavage 2.oral administration by stomach tube and after dose is administer through diet.

Vehicle:

other: 1.corn oil 2.Diet(ground feed) and 0.5% gelatin

Details on exposure:

Study 1.Details on exposurePREPARATION OF DOSING SOLUTIONS: Test material 73.5% test material & 26.5% biphenyl mixed in corn oil.DIET PREPARATION- Rate of preparation of diet (frequency):No data available- Mixing appropriate amounts with (Type of food )- Storage temperature of food: No data availableVEHICLE- Justification for use and choice of vehicle (if other than water): corn oil - Concentration in vehicle: 50, 200, 500 mg/kg/day - Amount of vehicle (if gavage): 5ml/kg - Lot/batch no. (if required): No data available- Purity: No data availableStudy 2.oral administration by stomach tube from day 7 to 28 and after dose is administered through diet for 18 months

Details on mating procedure:

No data available

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Study1.10 days ( on gestation days 6-15)Study2.18 months

Frequency of treatment:

daily

Details on study schedule:

No data available

Remarks:

Study1.0,50, 200, 500 mg/kg/day Study2.0 and 215 mg/kg bw/day

No. of animals per sex per dose:

Study 1.Total:960 mg/kg bw/day:2450mg/kg bw/day:24200mg/kg bw/day:24500mg/kg bw/day:24Study2.Total: 1500 mg/kg bw :18 Females0 mg/kg bw :18 Females215 mg/kg bw :18 FemalesPositive controlEthyl carbamate: 24 FemalesAmitrol: 18 FemalesE:thylene imine: 18 FemalesAramite: 18 FemalesDihydrosafrole: 18 FemalesSafrole: 18 Females

Control animals:

yes, concurrent vehicle

Details on study design:

No data available

Positive control:

Study 2.Ethyl carbamate, Amitrol, E:thylene imine, Aramite, Dihydrosafrole and Safrole were used as positive control.

Parental animals: Observations and examinations:

Study1.Parental animals observation and examinationsCAGE SIDE OBSERVATIONS: yes DETAILED CLINICAL OBSERVATIONS: Yes Time schedule: BODY WEIGHT: YesTime schedule for examinations: FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes 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 availableWATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data Time schedule for examinations: Study2.CAGE SIDE OBSERVATIONS: Yes - Time schedule:Daily - Cage side observations checked in table [No.?] were included: Mortality and morbidity were observed. DETAILED CLINICAL OBSERVATIONS: Yes - Time schedule: palpated weekly at time of weighing for enlargement of liv,~r and spleen, or any subcutaneous tumor. BODY WEIGHT: Yes - Time schedule for examinations: six animals in each cage were weighed once a week.

Oestrous cyclicity (parental animals):

No data available

Sperm parameters (parental animals):

No data available

Litter observations:

No data available

Postmortem examinations (parental animals):

Study1and 2SACRIFICE- Maternal animals: yes GROSS NECROPSY: yes - Gross necropsy consisted of [external and internal examinations including the cervical, thoracic, and abdominal viscera.] HISTOPATHOLOGY / ORGAN WEIGHTS The tissues indicated in Table [#] were prepared for microscopic examination and weighed, respectively.

Postmortem examinations (offspring):

Study1GROSS NECROPSY: yes - Approximately 1/2 of the fetuses in each litter were processed for soft-tissue evaluations while the other half for skeletal evaluations

Statistics:

Study 1Statistical evaluation of equality of means was made by the appropriate one-way analysis of variance technique (ANOVA) for parametric procedures and Kruskal-Wallis test for nonparametric procedures were used after applying Bartlett's test for determination of equal variance. Statistical tests for trend, using either standard regression techniques (parametric cases) or Jonckheere's test in nonparametric cases. Levels of statistical significance used were either p<0.05 or p<0.01. Study 2.Chi square test &Yates Correction were used

Reproductive indices:

No data available

Offspring viability indices:

No data available

Clinical signs:

effects observed, non-treatment-related

Description (incidence and severity):

Study1.Excessive alopecia, salivation and/or anogenital staining was observed but no pattern of treatment relationship could be determined.

Dermal irritation (if dermal study):

not specified

Mortality:

mortality observed, treatment-related

Description (incidence):

Study1.2 deaths occurred at 500 mg/kgStudy2. No effect on survival of treated female mice were observed as compared to control.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Study1.Statistically reduced maternal weight gain were observed at 200 and 500 mg/kg/d.Study2.Body weight gain was observed with the increase in duration of treatment.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Study1.Statistically reduced food consumption were observed at 200 and 500 mg/kg/d.

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

Histopathological findings: non-neoplastic:

not specified

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):

Study1.No effects observed on fetal resorptions, fetal viability, postimplantation loss or total implantationsStudy 2.Not Disrupted sexual function

Dose descriptor:

NOAEL

Effect level:

> 215 - <= 500 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

reproductive performance

Remarks on result:

other: No effects on reproductive performance

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:

not specified

Body weight and weight changes:

no effects observed

Description (incidence and severity):

Study 1.Mean litter weights in treated and control groups were similar

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):

Study 1.No increases were observed in incidence of malformations or variations at any treatment level.

Histopathological findings:

not specified

Other effects:

not specified

Behaviour (functional findings):

not specified

Developmental immunotoxicity:

not specified

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

500 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

not specified

Basis for effect level:

gross pathology

Remarks on result:

other: No developmental toxic effects were seen up to the highest dose of 500 mg/kg bw.

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Treatment related:

not specified

Dose response relationship:

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 be above 215-500mg/kg/day, and No indications of any influence on reproductive parameters or damage to reproductive organs were found and No developmental toxic effects were seen up to the highest dose of 500 mg/kg bw .When female rats or mice were treated with Reaction mass of 3H-​Indolium, 2-​[[2-​(4-​methoxyphenyl)​-​2-​methylhydrazinyliden​e]​methyl]​-​1,​3,​3-​trimethyl-​ & acetate orally.

Executive summary:

Data available from different studies were reviewed to determine thereproductive toxicityof  Reaction mass of 3H-​Indolium, 2-​[[2-​(4-​methoxyphenyl)​-​2-​methylhydrazinyliden​e]​methyl]​-​1,​3,​3-​trimethyl-​ & acetate.The studies are as mentioned below:

Study 1

Reproductive and development toxicity study of test material was performed on mated female Sprague Dawley rats according to OECD Test Guideline 414. The test material73.5% test material & 26.5% biphenyl mixed in corn oil at volume of 5 ml/kg were administered in dose concentration 0,50, 200, 500 mg/kg/day on gestation days 6-15by oral gavage route. .96 rats were divided as 24 rats /dose group. Animals were checked daily for clinical signs. Food consumption and body weight were recorded; the dams were sacrificed and subjected to a macroscopic examination. Approximately 1/2 of the fetuses in each litter were processed for soft-tissue evaluations while the other half for skeletal evaluations. Statistical evaluation of equality of means was made by the appropriate one-way analysis of variance technique (ANOVA) for parametric procedures and Kruskal-Wallis test for nonparametric procedures were used after applying Bartlett's test for determination of equal variance. Statistical tests for trend, using either standard regression techniques (parametric cases) or Jonckheere's test in nonparametric cases. Levels of statistical significance used were either p<0.05 or p<0.01. Two deaths occurred at 500 mg/kg. Statistically reduced maternal weight gain and food consumption were observed at 200 and 500 mg/kg/d. Excessive alopecia, salivation and/or anogenital staining was observed but no pattern of treatment relationship could be determined. No effects observed on fetal resorptions, fetal viability, postimplantation loss or total implantations. Mean litter weights in treated and control groups were similar. No significant increases were observed in incidence of malformations or variations at any treatment level. Therefore No Observed Adverse Effect Level (NOAEL) for maternal toxicity was considered to be 50 mg/kg/day, and No indications of any influence on reproductive parameters or damage to reproductive organs were foundand No developmental toxic effects were seen up to the highest dose of 500 mg/kg bw. Hence the dose-level of 500 mg/kg/day was considered to be the NOAEL for embryo-foetal toxicity and reproductive toxicity .When female Sprague Dawley rats were treated with test material orally.

Study 2

In a reproductive toxicity study, B6C3F1 female mice were treated with test material in the concentration of 0 and 215 mg/kg bw/day in 0.5% gelatin for 7 to 28 day and after dose is administer through diet at 560 ppm for 18 months. Body weight gain was observed with the increase in duration of treatment. No gross pathological changes were observed in treated female mice. In addition, no fibroadenoma and carcinoma mammary gland were observed in treated female mice as compared to control. Therefore, NOAEL was considered to be > 215 mg/kg bw when B6C3F1 female mice by using test material for 18 months.

Based on the data available from different studies,Reaction mass of 3H-​Indolium, 2-​[[2-​(4-​methoxyphenyl)​-​2-​methylhydrazinyliden​e]​methyl]​-​1,​3,​3-​trimethyl-​ & acetatedid not showedreproductive toxicityat dose concentration above 215-500mg/kg bw/day . Hence the test chemical is not likely to classify as a reproductive toxicant as per the criteria mentioned in CLP regulation.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

500 mg/kg bw/day

Study duration:

chronic

Species:

other: rats or mice

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 thereproductive toxicityof  Reaction mass of 3H-​Indolium, 2-​[[2-​(4-​methoxyphenyl)​-​2-​methylhydrazinyliden​e]​methyl]​-​1,​3,​3-​trimethyl-​ & acetate.The studies are as mentioned below:

Study 1

Reproductive and development toxicity study of test material was performed on mated female Sprague Dawley rats according to OECD Test Guideline 414. The test material73.5% test material & 26.5% biphenyl mixed in corn oil at volume of 5 ml/kg were administered in dose concentration 0,50, 200, 500 mg/kg/day on gestation days 6-15by oral gavage route. .96 rats were divided as 24 rats /dose group. Animals were checked daily for clinical signs. Food consumption and body weight were recorded; the dams were sacrificed and subjected to a macroscopic examination. Approximately 1/2 of the fetuses in each litter were processed for soft-tissue evaluations while the other half for skeletal evaluations. Statistical evaluation of equality of means was made by the appropriate one-way analysis of variance technique (ANOVA) for parametric procedures and Kruskal-Wallis test for nonparametric procedures were used after applying Bartlett's test for determination of equal variance. Statistical tests for trend, using either standard regression techniques (parametric cases) or Jonckheere's test in nonparametric cases. Levels of statistical significance used were either p<0.05 or p<0.01. Two deaths occurred at 500 mg/kg. Statistically reduced maternal weight gain and food consumption were observed at 200 and 500 mg/kg/d. Excessive alopecia, salivation and/or anogenital staining was observed but no pattern of treatment relationship could be determined. No effects observed on fetal resorptions, fetal viability, postimplantation loss or total implantations. Mean litter weights in treated and control groups were similar. No significant increases were observed in incidence of malformations or variations at any treatment level. Therefore No Observed Adverse Effect Level (NOAEL) for maternal toxicity was considered to be 50 mg/kg/day, and No indications of any influence on reproductive parameters or damage to reproductive organs were foundand No developmental toxic effects were seen up to the highest dose of 500 mg/kg bw. Hence the dose-level of 500 mg/kg/day was considered to be the NOAEL for embryo-foetal toxicity and reproductive toxicity .When female Sprague Dawley rats were treated with test material orally.

Study 2

In a reproductive toxicity study, B6C3F1 female mice were treated with test material in the concentration of 0 and 215 mg/kg bw/day in 0.5% gelatin for 7 to 28 day and after dose is administer through diet at 560 ppm for 18 months. Body weight gain was observed with the increase in duration of treatment. No gross pathological changes were observed in treated female mice. In addition, no fibroadenoma and carcinoma mammary gland were observed in treated female mice as compared to control. Therefore, NOAEL was considered to be > 215 mg/kg bw when B6C3F1 female mice by using test material for 18 months.

Based on the data available from different studies,Reaction mass of 3H-​Indolium, 2-​[[2-​(4-​methoxyphenyl)​-​2-​methylhydrazinyliden​e]​methyl]​-​1,​3,​3-​trimethyl-​ & acetatedid not showedreproductive toxicityat dose concentration above 215-500mg/kg bw/day . Hence the test chemical is not likely to classify as a reproductive toxicant as per the criteria mentioned in CLP regulation.

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 Reaction mass of 3H-​Indolium, 2-​[[2-​(4-​methoxyphenyl)​-​2-​methylhydrazinyliden​e]​methyl]​-​1,​3,​3-​trimethyl-​ & acetatenot likely to classify as reproductive toxicant.