Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

Reproductive toxicity study

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

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Remarks:
Experimental data from various test chemicals
Justification for type of information:
Weight of evidence approach based on the available information from various test chemicals.
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Qualifier:
according to
Guideline:
other: As mentioned below
Principles of method if other than guideline:
WoE report is based on reproductive toxicity studies on rats
GLP compliance:
not specified
Limit test:
no
Justification for study design:
No data avaiable
Species:
rat
Strain:
Crj: CD(SD)
Details on species / strain selection:
No data avaiable
Sex:
male/female
Details on test animals and environmental conditions:
1.TEST ANIMALS
- Age at study initiation:9 weeks old

2.TEST ANIMALS
- Source: Charles River Japan Co., Ltd
- Females (if applicable) nulliparous and non-pregnant: [yes]
- Age at study initiation: 9 weeks
- Weight at study initiation: male : 309 to 355 g female: 206 to 232 g
- Fasting period before study:
- Housing: a cage made of stainless steel hanging type wire mesh is excluded for the period excluding pregnancy / nursing period, and made of polycarbonate with a floor covering for laboratory animals (beta chip, Nippon Charles River Co., Ltd.)
- Use of restrainers for preventing ingestion (if dermal): yes/no
- Diet (e.g. ad libitum):
- Water (e.g. ad libitum): tap water irradiated with ultraviolet rays after autoclave sterilized solid feed for laboratory animals (CRF-1, Oriental Yeast Industry Co., Ltd.) and filtering with a pore size of 5 μm.
- Acclimation period:6 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2 ° C.,
- Humidity (%):55 ± 15%
- Air changes (per hr): ventilation at about 12 times / hour,
- Photoperiod (hrs dark / hrs light): lighting 12 hours / day (7: 00-19: 00)
IN-LIFE DATES: From: To:
Route of administration:
oral: gavage
Type of inhalation exposure (if applicable):
not specified
Vehicle:
other: 1 w/v% Tween 80 solution 2.0.5 % Sodium carboxymethylcellulose mixed with 0.1 % Tween 80
Details on exposure:
1.PREPARATION OF DOSING SOLUTIONS: Test material dissolved in 1 w/v% Tween 80 solution

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

VEHICLE
- Justification for use and choice of vehicle (if other than water):
- Concentration in vehicle: 0, 40, 200, 1000 mg/kg
- Amount of vehicle (if gavage):
- Lot/batch no. (if required):

2.PREPARATION OF DOSING SOLUTIONS: test material dissolved in 0.5 % Sodium carboxymethylcellulose mixed with 0.1 % Tween 80
DIET PREPARATION
- Rate of preparation of diet (frequency):
- Mixing appropriate amounts with (Type of food):
- Storage temperature of food:

VEHICLE
- Justification for use and choice of vehicle (if other than water): 0.5 % Sodium carboxymethylcellulose mixed with 0.1 % Tween 80
- Concentration in vehicle: 0,100, 300, 1000 mg/kg
- Amount of vehicle (if gavage): 10ml/kg
- Lot/batch no. (if required):
- Purity:
- Purity:
Details on mating procedure:
2.- M/F ratio per cage:1:1
- Length of cohabitation: together day and night on the 14th day
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy: vaginal plug formation or sperm was observed in vaginal plaque specimens was taken as copulation formation, and that day was taken as the 0th day of pregnancy
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: [no / yes (explain)]
- After successful mating each pregnant female was caged (how):
- Any other deviations from standard protocol:
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data avaiable
Duration of treatment / exposure:
1.Male: 42 days
Female: 42 – 48 days (from 14 days before mating to day 4 of lactation)
2.Males, 37 days
Females, from 14 days before mating to day 4 of lactation
Frequency of treatment:
Daily
Details on study schedule:
Recovery period: Males, 14 days
Females (satellite), 14 days

Sacrifice : Males, day 43 of treatment and day 15 of recovery
Females, day 5 of lactation
Females (satellite), day 15 of recovery
Remarks:
1.Doses / Concentrations:
0, 40, 200, 1000 mg/kg
2.0 (vehicle), 100, 300, 1000 mg/kg
No. of animals per sex per dose:
1.
No of animals Total: 116
0 mg/kg bw/day:12 male , 12 female
40 mg/kg bw/day:12 male , 12 female
200 mg/kg bw/day:12 male , 12 female
1000 mg/kg bw/day:12 male , 12 female

Recovery:
0 mg/kg bw/day: 5 male , 5 female
1000 mg/kg bw/day: 5 male , 5 female
2.Total: 96
0 mg/kg bw/day: 12 male, 12 female
100 mg/kg bw/day: 12 male, 12 female
300 mg/kg bw/day: 12 male, 12 female
1000 mg/kg bw/day: 12 male, 12 female

Control animals:
yes, concurrent vehicle
Details on study design:
No data avaialble
Positive control:
No data avaialble
Parental animals: Observations and examinations:
Clinical signs, FOB, Body weight, Food consumption, Urinalysis, Hematology and clinical chemistry were observed.
Oestrous cyclicity (parental animals):
Estrous cycle, numbers of corpora lutea or Implantations were observed
Sperm parameters (parental animals):
No data avaialble
Litter observations:
Viability, Clinical signs and Body weight were observed
Postmortem examinations (parental animals):
Gross pathology and Histopathology were observed
Postmortem examinations (offspring):
Gross pathology and Histopathology were observed
Statistics:
Regarding the weighing data, parametric data was tested for equal variance by the Bartlett method, and one-way ANOVA was performed when variance was equal. Where the variances are not equal and nonparametric data were tested by Kruskal-Wallis. When significant difference was observed between groups, multiple comparisons of Dunnett method or Dunnett type were performed. Pathological findings in counting data were examined by χ 2 for a × b . When significant difference was observed , comparison was made between control group and each test substance administered group by Armitage χ 2 test. Other counting data were tested by Fisher's direct stochastic method. The significance level of each test was 5%. For the data on newborn babies, the average value calculated for each mother was set as a sample unit
Reproductive indices:
Copulation index, fertility index, delivery index, gestation length, implantation index and gestation index were observed
Offspring viability indices:
Viability on day 4 were observed.
Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not specified
Mortality:
not specified
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
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
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed
Description (incidence and severity):
No effects on mating index, fertility index, numbers of corpora lutea or implantations, implantation index, delivery index, gestation index, gestation length, parturition or maternal behavior of treated rats were observed.
Clinical signs: No clinical signs of toxicity was observed in treated rats.

Body weight: No effect on body weight of treated rats was observed as compared to control.

Reproductive function: estrous cycle: No effects estrous cycle, numbers of corpora lutea or Implantations were observed in treated rats as compared to control.

Reproductive performance: No effects on copulation index, fertility index, delivery index, gestation length, implantation index and gestation index were observed in treated rats as compared to control.

Organ weights : No effect on organ weight of treated rats were in treated rats as compared to control.

Gross pathology: No gross pathological changes were observed in treatd rats as compared to control.

Histopathology: No histopathological changes were observed in treatd rats as compared to control.

other findings No effect on food consumption, hematology, blood chemistry, urinalysis of treated rats were observed as compared to contorl.
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No effect on Clinical signs, FOB, Body weight, Food consumption, Urinalysis, Hematology, Blood chemistry, organ weights, reproductive performance and Histopathology
Remarks on result:
other: overall no effects on reproductive parameters
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:
no effects observed
Description (incidence and severity):
1.No clinical signs of toxicity were observed in offspring as compared to cotnrol.
Dermal irritation (if dermal study):
not specified
Mortality / viability:
no mortality observed
Description (incidence and severity):
2.No significant differences in numbers of offspring or live offspring were observed as compared to cotnrol.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
2.No effect on body weight of offspring were observed as compared to cotnrol.
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):
2. No gorss pathological changes were observed in offspring as compared to cotnrol.
Histopathological findings:
no effects observed
Other effects:
not specified
Behaviour (functional findings):
not specified
Developmental immunotoxicity:
not specified
Viability: No effect on viability on day 4 were observed in offsprings to treated rats.

Clinical signs: No clinical signs of toxicity was observed in treated rats

Body weight: No effect on body weight of treated rats was observed in offsprings to treated rats as compared to control.

Gross pathology: No gross pathological changes were observed in offsprings of treated rats as compared to control.

Histopathology: No histopathological changes were observed in offsprings of treated rats as compared to control.

other findings: No effect on number of offspring or live offspring at birth, sex ratio and live birth index of offsprings of treated rats as compared to control.
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No effect on number of offspring or live offspring at birth, sex ratio, live birth index, or viability index , gross pathology and Histopathology
Remarks on result:
other: overall no effects on developmental parameters
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:
NOAEL was considered to be 1000 mg/kg bw/day for P and F1 generation when Crl:CD (SD) male and female rats were treated with test chemical orally by gavage for 42 days.
Executive summary:

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

Study 1

In combined repeated dose toxicity study with reproduction and developmental screening, Crj:CD(SD)IGS male and female rats were treated with test chemical in the concentration of 0, 40, 200 and 1000 mg/kg bw/day 1 w/v% Tween 80 solution orally by gavage for male 42 days and females from 14 days before mating to day 4 of lactation (Females (satellite), 42 days).All animals were observed for clinical sign , body weights, food consumption. Males were sacrificed on day 43 of treatment and day 15 of recovery while Females were sacrificed on day 5 of lactation Females (satellite), day 15 of recovery and Offspring on day 4 after birth.

No effect on clinical sign, body weights, food consumption, haematology, clinical chemistry, urinalysis, organ weights, gross pathology and histopathological of treated rats as compared to control. Similarly no effect on estrous cycle, copulation index, fertility index, delivery index, gestation length, numbers of corpora lutea or implantations, implantation index, gestation index, number of offspring or live offspring at birth, sex ratio, live birth index, or viability index on day 4 of offspring were observed as compared to control. In addition, no effect on clinical signs, body weights, gross pathology and histopathology of treated offspings were observed as compared to control. Therfore, NOAEL was considered to be 1000 mg/kg bw/day for P and F1 generation when  Crl:CD (SD) male and female rats were treated with test chemical orally by gavage for 42 days.

Study 2

In a combined repeated dose toxicity study with reproduction and developmental screening, Crj:CD(SD)IGS male and female rats were treated with test chemical in the concentration of 0, 100, 300, 1000 mg/kg bw/day in 0.5 % Sodium carboxymethylcellulose mixed with 0.1 % Tween 80 orally by gavage.The dosing period is from 42 to 47 days for a total of 37 days before mating by mating and 4 days before breeding and the day before necropsy, for females for 14 days before mating, a mating period, a gestation period and delivery until 4 nursing days did. The non-delivering animal was taken until the day before necropsy. At the time of administration, it was administered by gavage once a day using the teflon stomach probe, in the morning. The volume of the solution to be administered was 10 mL / kg, and it was calculated based on the body weight measured on the nearest day. Female vaginal plaque was collected daily in the morning from the start of administration to the start of the mating, the sexual cycle was examined, and the mean cycle duration was calculated. After the administration period before mating, pairs of males and females 1 were established within each group and allowed to live together day and night on the 14th day. Mating confirmation was done every morning, and cases where vaginal plug formation or sperm was observed in vaginal plaque specimens was taken as copulation formation, and that day was taken as the 0th day of pregnancy. Mating pairs were separated from male and female and submitted for further examination. Body weight was measured on both the male and female on the administration start date, 3, 7 and 14 days after the start of administration, once a week for females, females with mating completed on 0, 7, 14, 20 gestation days and 0 and 4 days of pregnancy It was measured

No effect on clinical sign, body weight, food consumption, haematology and clinical chemistry of treated rats as compared to control. Similarly, no significant effect on mating index, fertility index, numbers of corpora lutea or implantations, implantation index, delivery index, gestation index, gestation length, parturition or maternal behaviour were observed in treated rats. Increase in liver weight was observed in male and female rats. No gross pathological and histopathological changes were observed in treated rats. In addition, no significant effect on mating index, fertility index, numbers of corpora lutea or implantations implantation index, delivery index, gestation index, gestation length, parturition or maternal behaviour and numbers of offspring or live offspring, sex ratio, live birth index, viability index or body weights of offspring were observed. No gross pathological changes were observed in offspring as compared to control. Therefore, NOAEL was considered to be 1000 mg/kg bw/day when Crj:CD(SD)IGS male and female rats were treated with test chemical orally by gavage.

Based on the data available from different studies, test material did not showed reproductive toxicity at dose concentration 1000 mg/kg body weight/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 not likely to classify as reproductive toxicant.

 

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:

Study 1

In combined repeated dose toxicity study with reproduction and developmental screening, Crj:CD(SD)IGS male and female rats were treated with test chemical in the concentration of 0, 40, 200 and 1000 mg/kg bw/day 1 w/v% Tween 80 solution orally by gavage for male 42 days and females from 14 days before mating to day 4 of lactation (Females (satellite), 42 days).All animals were observed for clinical sign , body weights, food consumption. Males were sacrificed on day 43 of treatment and day 15 of recovery while Females were sacrificed on day 5 of lactation Females (satellite), day 15 of recovery and Offspring on day 4 after birth.

No effect on clinical sign, body weights, food consumption, haematology, clinical chemistry, urinalysis, organ weights, gross pathology and histopathological of treated rats as compared to control. Similarly no effect on estrous cycle, copulation index, fertility index, delivery index, gestation length, numbers of corpora lutea or implantations, implantation index, gestation index, number of offspring or live offspring at birth, sex ratio, live birth index, or viability index on day 4 of offspring were observed as compared to control. In addition, no effect on clinical signs, body weights, gross pathology and histopathology of treated offspings were observed as compared to control. Therfore, NOAEL was considered to be 1000 mg/kg bw/day for P and F1 generation when  Crl:CD (SD) male and female rats were treated with test chemical orally by gavage for 42 days.

Study 2

In a combined repeated dose toxicity study with reproduction and developmental screening, Crj:CD(SD)IGS male and female rats were treated with test chemical in the concentration of 0, 100, 300, 1000 mg/kg bw/day in 0.5 % Sodium carboxymethylcellulose mixed with 0.1 % Tween 80 orally by gavage.The dosing period is from 42 to 47 days for a total of 37 days before mating by mating and 4 days before breeding and the day before necropsy, for females for 14 days before mating, a mating period, a gestation period and delivery until 4 nursing days did. The non-delivering animal was taken until the day before necropsy. At the time of administration, it was administered by gavage once a day using the teflon stomach probe, in the morning. The volume of the solution to be administered was 10 mL / kg, and it was calculated based on the body weight measured on the nearest day. Female vaginal plaque was collected daily in the morning from the start of administration to the start of the mating, the sexual cycle was examined, and the mean cycle duration was calculated. After the administration period before mating, pairs of males and females 1 were established within each group and allowed to live together day and night on the 14th day. Mating confirmation was done every morning, and cases where vaginal plug formation or sperm was observed in vaginal plaque specimens was taken as copulation formation, and that day was taken as the 0th day of pregnancy. Mating pairs were separated from male and female and submitted for further examination. Body weight was measured on both the male and female on the administration start date, 3, 7 and 14 days after the start of administration, once a week for females, females with mating completed on 0, 7, 14, 20 gestation days and 0 and 4 days of pregnancy It was measured

No effect on clinical sign, body weight, food consumption, haematology and clinical chemistry of treated rats as compared to control. Similarly, no significant effect on mating index, fertility index, numbers of corpora lutea or implantations, implantation index, delivery index, gestation index, gestation length, parturition or maternal behaviour were observed in treated rats. Increase in liver weight was observed in male and female rats. No gross pathological and histopathological changes were observed in treated rats. In addition, no significant effect on mating index, fertility index, numbers of corpora lutea or implantations implantation index, delivery index, gestation index, gestation length, parturition or maternal behaviour and numbers of offspring or live offspring, sex ratio, live birth index, viability index or body weights of offspring were observed. No gross pathological changes were observed in offspring as compared to control. Therefore, NOAEL was considered to be 1000 mg/kg bw/day when Crj:CD(SD)IGS male and female rats were treated with test chemical orally by gavage.

Based on the data available from different studies, test material did not showed reproductive toxicity at dose concentration 1000 mg/kg body weight/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 not likely to classify as reproductive toxicant.

 

Effects on developmental toxicity

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

Justification for classification or non-classification

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