Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

Reproductive toxicity study

The data available for test chemicals was reviewed to determine the reproductive toxicity. The NOAEL for reproductive toxicity was considered to be in between 1000-1500 mg/kg bw as No effects on reproductive parameters were observed.When male and female rats or mice were treated with test chemical .Thus, comparing this value with the criteria of CLP regulation test chemical 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 of read across substances
Justification for type of information:
Weight of evidence approach based on structurally similar chemicals
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 two reproductive toxicity studies on rats or mice
1.Reproductive and developmental toxicity study of test material was performed on rats.
2.Reproductive toxicity study of test material was performed in mice by repeated dermal application for 18 months.
GLP compliance:
not specified
Limit test:
no
Justification for study design:
No data available
Specific details on test material used for the study:
No data available
Species:
other: 1.rat 2.mice
Strain:
other: 1.Tif:RAI f (SPF) hybrid 2.Swiss Webster
Details on species / strain selection:
No data available
Sex:
female
Details on test animals and environmental conditions:
Study 1
.TEST ANIMALS
- Source:
- Age at study initiation:9 weeks
- Weight at study initiation:
- Fasting period before study: Females were caged individually in Macrolon cages containing standardized soft wood bedding material.
- Housing:
- Diet (e.g. ad libitum): standard pelleted rat food (Nafag No. 890; Gossau, Switzerland) ad libitum
- Water (e.g. ad libitum):water ad libitum
- Acclimation period:7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20±3 °C
- Humidity (%):30-70%,
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): daily cycle of 12 hours light

Study 2.
TEST ANIMALS
- Source: No data available
- Age at study initiation: (P) : No data available
- Weight at study initiation: (P) : 17 to 25 g
- Fasting period before study: No data available
- Housing: Animals of sex were housed five per cage
- Diet (e.g. ad libitum): Purina Laboratory Chow , ad libitum
- Water (e.g. ad libitum): Fresh water, ad libitum
- Acclimation period: No data available




Route of administration:
other: 1.oral: gavage 2.dermal
Vehicle:
other: Study 1.aqueous solution of carboxymethylcellulose (0.5% w/w). Study 2.0.1 % solution of sodium lauryl sulfate
Details on exposure:
Study 1.
Details on exposure
Test material dissolved in aqueous solution of carboxymethylcellulose (0.5% w/w).
VEHICLE
- Justification for use and choice of vehicle (if other than water): Test material dissolved in aqueous solution of carboxymethylcellulose (0.5% w/w).
- Concentration in vehicle:0,1000mg/kg bw/day
- Amount of vehicle (if gavage): 20ml/kg
- Lot/batch no. (if required): No data available
- Purity: No data available

Study 2.
PREPARATION OF DOSING SOLUTIONS:
The test material diluted in 0.1 % solution of sodium lauryl sulfate
DIET PREPARATION
- Rate of preparation of diet (frequency):No data available
- Mixing appropriate amounts with (Type of food): No data available
- Storage temperature of food:No data available

VEHICLE
- Justification for use and choice of vehicle (if other than water): The test material dissolved in 0.1 % solution of sodium lauryl sulfate
- Concentration in vehicle: 1.0 % (1500 mg/kg bw/day)
- Amount of vehicle (if gavage): No data available
- Lot/batch no. (if required): No data available
- Purity:No data available
Details on mating procedure:
Study 1.
- M/F ratio per cage:one male rat was housed with 3 females
- Length of cohabitation: No data available
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy:vaginal lavage showed spermatozoa or a vaginal plug was observed; this was designated as gestation day zero
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: [no / yes (explain)]No data available
- After successful mating each pregnant female was caged (how): an individual
- Any other deviations from standard protocol:No data available
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Study 1.
10 days (6 through day 15 of gestation)
Study 2.
18 months
Frequency of treatment:
1.Daily
2.Twice weekly
Details on study schedule:
No data available
Remarks:
Study 1.
0, 1000mg/kg bw/day
Study 2.
1.0 % (1500 mg/kg bw/day)
No. of animals per sex per dose:
Study 1.
Total :48
0 mg/kg :24 female
1000mg/kg:24 female
Study 2.
Total: 300
0 mg/kg/bw/day : 100 males and 100 females
1500 mg/kg bw/day: 50 males and 50 females
Control animals:
yes, concurrent vehicle
Details on study design:
No data available
Positive control:
No data available
Parental animals: Observations and examinations:
Study 1.
CAGE SIDE OBSERVATIONS: Yes
- Time schedule:
- Cage side observations checked in table [No.?] were included.

DETAILED CLINICAL OBSERVATIONS: Yes / No / No data
- Time schedule:

BODY WEIGHT: Yes
- Time 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 / No / No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data

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

Study 2.
CAGE SIDE OBSERVATIONS: Yes
- Time schedule:
- Cage side observations checked in table [No.?] were included.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule:

BODY WEIGHT: Yes
- Time schedule for examinations:Mean body weight was determined at 3,6, 9, 12, 15, and 18 months;

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 / No / No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data

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

OTHER:Survival ,visible or palable growth and behavior were examined.
Oestrous cyclicity (parental animals):
No data available
Sperm parameters (parental animals):
No data available
Litter observations:
No data available
Postmortem examinations (parental animals):
Study 1.
SACRIFICE
All animals survived to necropsy on gestation day 21
GROSS NECROPSY
- 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.

Study 2.
SACRIFICE: yes after 18 months
- 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
Organs were fixed in 10% formalin solution after recording any gross pathological findings


HISTOPATHOLOGY / ORGAN WEIGHTS: yes
The tissues indicated in Table [#] were prepared for microscopic examination and weighed, respectively.
Postmortem examinations (offspring):
Study 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
- Gross necropsy consisted of [external and internal examinations including the cervical, thoracic, and abdominal viscera.]

HISTOPATHOLOGY / ORGAN WEIGTHS
About one-half of each litter was taken for visceral evaluation by the Wilson slicing technique after fixation. The remaining fetuses from each litter were fixed, cleared with KOH solution and then treated with alizarin red S for examination of skeletal features.
Statistics:
No data available
Reproductive indices:
No data available
Offspring viability indices:
No data available
Clinical signs:
no effects observed
Description (incidence and severity):
Study 1.
There were no remarkable cage-side observations during the study.
Study 2.
No abnormalities were observed in treated mice as compared to control.
Dermal irritation (if dermal study):
not specified
Mortality:
no mortality observed
Description (incidence):
Study 1.
No effect on survival of treated rats were observed as compared to control.
Study 2.
No effect on survival of treated mice were obserevd as compared to control.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Study 1.
No effect on body weight of treated rats was observed as compared to control.
Study 2.
No significant effect was observed on body weight of treated mice as compared to control.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Study 1.
No effect on food consumption of treated rats was observed as compared to control.
Study 2.
No significant effect was observed on food consumption of treated mice 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:
not specified
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
Study 1.
All animals survived to necropsy on gestation day 21, except for one dam from the treated group, found dead on gestation day 15. Necropsy revealed no pathological findings. Necropsy of all other animals did not reveal adverse effects or abnormal findings.

Study 2.
All grades Malignant lymphoma and Variation in nuclear morphology in Liver, Infarction, Malignant and Myeloid metaplasia, Leukocytic aggregations in Spleen, all grades Malignant lymphoma , Leukemic and round cell infiltration and Leukocytic aggregation in Kidneys , Malignant lymphoma in Lymph Nodes, Malignant lymphoma, Inflammation, pneumonitis, bronchitis, Necrotic changes in Lungs and all grades Malignant lymphoma in Thymus were observed in male and female treated miceNo significant difference in the incidence of this lesion were observed as compared to control and considered to be not treatment related.
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):
Study 1.
The number of implantation sites and preimplantation losses were comparable in the two groups. Early resorption rate was not affected by treatment, and there were no late resorptions, abortions or dead fetuses. Thus, the number of viable fetuses was comparable in the two groups. Statistical analysis of these endpoints did not show significant differences from the control group.
There was no evidence for an impairment of reproductive functions in animals
Dose descriptor:
NOAEL
Effect level:
> 1 000 - <= 1 500 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
clinical signs
mortality
body weight and weight gain
food consumption and compound intake
histopathology: non-neoplastic
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. body weights were not affected by treatment.
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.
The findings observed during fetal examinations were of equal frequency in the control and treated groups; thus, treatment-related effects on fetal external, visceral, or skeletal development did not occur in this study.
Histopathological findings:
not specified
Other effects:
no effects observed
Description (incidence and severity):
Study 1.Fetal sex ratios were not affected by treatment.
Behaviour (functional findings):
not specified
Developmental immunotoxicity:
not examined
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
viability
mortality
body weight and weight gain
gross pathology
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:
In reproductive and developmental toxicity study , NOAEL was considered to be 1000- 1500mg/kg bw/day as no effects on reproductive and developmental parameters were observed . When female rats were treated wtih test chemical orally.
Executive summary:

Study 1.

In reproductive and developmental toxicity study , femaleTif:RAI f (SPF) hybrid ratsrats were treated wtih test material in dose concentration 0,1000mg/kg orallyfrom day 6 through day 15 of gestation, inclusive.Test materialwas administered by gavage in an aqueous solution of carboxymethylcellulose (0.5% w/w). The control group received the vehicle solution. The dose volume in both groups was 20 ml/kg body weight, based on the daily body weight.24 females in each group, a proven fertile male rat of the same strain was placed in a mating cage with 3 females each. The female was removed and indicated as pregnant if vaginal lavage showed spermatozoa or a vaginal plug was observed; this was designated as gestation day zero.All the animals observed for body weight ,food consumption and mortality. There were no remarkable cage-side observations during the study. Maternal body weights and food consumption were not affected by treatment. All animals survived to necropsy on gestation day 21, except for one dam from the treated group, found dead on gestation day 15. Necropsy revealed no pathological findings. Necropsy of all other animals did not reveal adverse effects or abnormal findings.Three animals in the control group were not pregnant, and one in the treated group died on gestation day15. Thus, the number of pregnant animals with viable fetuses at necropsy was 21 and 23 for the control and treated group, respectively.

The number of implantation sites and preimplantation losses were comparable with the control groups. Early resorption rate was not affected by treatment, and there were no late resorptions, abortions or dead fetuses. Thus, the number of viable fetuses was comparable with control groups. Statistical analysis of these endpoints did not show significant differences from the control group.Fetal sex ratios and body weights were not affected by treatment. The findings observed during fetal examinations were of equal frequency in the control and treated groups; thus, treatment-related effects on fetal external, visceral, or skeletal development did not occur in this study.Hence,NOAEL was considered to be 1000mg/kg bw/day as no effects on reproductive and developmental parameters were observed. When female rats were treated wtih test material orally.

Study 2.

The reproductive toxicity study was considered on the bases of a repeated dose dermal toxicity study, Swiss-Webster male and female mice were treated with test material in the concentration of 1500 mg/kg bw/day in 0.1 % solution of sodium lauryl sulfate applied twice weekly on 6 cm2dorsal area of skin for 18 months. No effect was observed on survival, clinical sign and body weight of treated male and female mice as compared to control. Similarly, lesion in Mammary Gland and Subcutaneous papillary were observed gross pathologically in treated mice, but the observed effect was similar to control. In addition, All grades Malignant lymphoma and Variation in nuclear morphology in Liver, Infarction, Malignant and Myeloid metaplasia, Leukocytic aggregations in Spleen, all grades Malignant lymphoma , Leukemic and round cell infiltration and Leukocytic aggregation in Kidneys , Malignant lymphoma in Lymph Nodes, Malignant lymphoma, Inflammation, pneumonitis, bronchitis and Necrotic changes in Lungs and all grades Malignant lymphoma in Thymus were observed in male and female treated mice. No significant difference in the incidence of this lesion were observed as compared to control and considered to be not treatment related. No effects were observed on male and female reproductive organ. Therefore, NOAEL was considered to be 1500 mg/kg bw/day when Swiss-Webster male and female mice were treated with test material by dermal application.

 

 

 

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 test chemical. The studies are as mentioned below.

 

Study1.

In reproductive and developmental toxicity study , female Tif:RAI f (SPF) hybrid rats rats were treated with test material in dose concentration 0,1000mg/kg orally from day 6 through day 15 of gestation, inclusive. Test material was administered by gavage in an aqueous solution of carboxymethylcellulose (0.5% w/w). The control group received the vehicle solution. The dose volume in both groups was 20 ml/kg body weight, based on the daily body weight.24 females in each group; a proven fertile male rat of the same strain was placed in a mating cage with 3 females each. The female was removed and indicated as pregnant if vaginal lavage showed spermatozoa or a vaginal plug was observed; this was designated as gestation day zero. All the animals observed for body weight, food consumption and mortality. There were no remarkable cage-side observations during the study. Maternal body weights and food consumption were not affected by treatment. All animals survived to necropsy on gestation day 21, except for one dam from the treated group, found dead on gestation day 15. Necropsy revealed no pathological findings. Necropsy of all other animals did not reveal adverse effects or abnormal findings. Three animals in the control group were not pregnant, and one in the treated group died on gestation day15. Thus, the number of pregnant animals with viable fetuses at necropsy was 21 and 23 for the control and treated group, respectively.

The number of implantation sites and preimplantation losses were comparable with the control groups. Early resorption rate was not affected by treatment, and there were no late resorptions, abortions or dead fetuses. Thus, the number of viable fetuses was comparable with control groups. Statistical analysis of these endpoints did not show significant differences from the control group. Fetal sex ratios and body weights were not affected by treatment. The findings observed during fetal examinations were of equal frequency in the control and treated groups; thus, treatment-related effects on fetal external, visceral, or skeletal development did not occur in this study. Hence, NOAEL was considered to be 1000mg/kg bw/day as no effects on reproductive and developmental parameters were observed. When female rats were treated with test material orally.

Study2.

The reproductive toxicity study was considered on the bases of a repeated dose dermal toxicity study, Swiss-Webster male and female mice were treated with test material in the concentration of 1500 mg/kg bw/day in 0.1 % solution of sodium lauryl sulfate applied twice weekly on 6 cm2dorsal area of skin for 18 months. No effect was observed on survival, clinical sign and body weight of treated male and female mice as compared to control. Similarly, lesion in Mammary Gland and Subcutaneous papillary were observed gross pathologically in treated mice, but the observed effect was similar to control. In addition, All grades Malignant lymphoma and Variation in nuclear morphology in Liver, Infarction, Malignant and Myeloid metaplasia, Leukocytic aggregations in Spleen, all grades Malignant lymphoma , Leukemic and round cell infiltration and Leukocytic aggregation in Kidneys , Malignant lymphoma in Lymph Nodes, Malignant lymphoma, Inflammation, pneumonitis, bronchitis and Necrotic changes in Lungs and all grades Malignant lymphoma in Thymus were observed in male and female treated mice. No significant difference in the incidence of this lesion were observed as compared to control and considered to be not treatment related. No effects were observed on male and female reproductive organ. Therefore, NOAEL was considered to be 1500 mg/kg bw/day when Swiss-Webster male and female mice were treated with test material by dermal application.

Based on the data available from different studies, test chemical did not showed reproductive toxicity at dose concentration between  1000-1500mg/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 test chemical is not likely to classify as reproductive toxicant.