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 studiesNOAEL was considered to be in range of 125 -146.3mg/kg bw for male rats or mice and NOAEL was considered to be in range of 125 -178.0mg/kg bw for female ratsor mice when male and female rats or mice were exposed daily to the test chemical by oral route. 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:
no
Limit test:
no
Species:
other: 1. rats 2.mouse
Strain:
other: 1.Sprague-Dawley 2.Crj: CD(SD)
Details on species / strain selection:
No Data Available
Sex:
male/female
Details on test animals and environmental conditions:
1.- Source: Central Animal Facility (CAF), NIPER, Sector-67, S.A.S. Nagar, Punjab, India
- Age at study initiation: 7 to 8 weeks old
- Weight at study initiation: Male 184.38-234.56 g, Female 176.90-208.56 g
- Fasting period before study: No data available
- Housing: Four rats per sex per cage were housed in sterilized solid bottom polypropylene cages with stainless steel grill tops with bedding of clean paddy husk. The cages were suspended on stainless steel racks in a controlled environment.
- Diet (e.g. ad libitum): Standard laboratory sterile extruded pelleted rodent feed (Provimi Animal Nutrition India Pvt. Ltd, Bangalore, India), ad libitum
- Water (e.g. ad libitum): Potable tap water filtered through Reviva Reverse Osmosis System (water filter cum purifier), adlibitum
- Acclimatization period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3°C
- Humidity (%):30-70 %
- Air changes (per hr): 25 ± 5 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours dark/12 hours light

IN-LIFE DATES: From: 11.04.2014 (Male), 13.04.2014 (Female); To: 17.05.2014 (Male), 19.05.2014 (Female)
2.Details on test animal
TEST ANIMALS
- Source: Charles River Japan, Inc. (Kanagawa, Japan)
- Age at study initiation: (P) x wks; 4weeks
(F1) x wks
- Weight at study initiation: (P) Males: x-x g; Females: x-x g; (F1) Males: x-x g; Females: x-x g
- Fasting period before study:
- Housing: The mice were housed individually in plastic cages with cedar chip bedding
- Diet (e.g. ad libitum): CE-2 (CLEA Japan,Tokyo) diet ad libter
- Water (e.g. ad libitum): Water was provided ad libter
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24–25 °C
- Humidity (%):50–60%
- Air changes (per hr): ventilation of ten air changes per hour
- Photoperiod (hrs dark / hrs light): 12:12 h light: dark cycle

Route of administration:
other: 1.oral: gavage 2.oral: feed
Type of inhalation exposure (if applicable):
not specified
Vehicle:
other: 1. Groundnut oil.
Details on exposure:
Details on exposure

PREPARATION OF DOSING SOLUTIONS:

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): Groundnut oil
- Concentration in vehicle: 0, 125, 250 or 500 mg/kg body weight/day
- Amount of vehicle (if gavage): 5 ml/kg body weight
- Lot/batch no. (if required): No data available
- Purity: No data available 98.66%

Details on mating procedure:
No data available
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No Data Available
Duration of treatment / exposure:
Study 1
28 days
Study 2
78 weeks
Frequency of treatment:
Daily
Remarks:
Study 1
0.0,125,250,500mg/kg bw
Study 2
0.031, 0.125 and 0.5% (33.2, 146.3 and 605 mg/kg body weight per day in males and 40.0, 178.8 and 615 mg/kg body weight)
No. of animals per sex per dose:
Study 1
Total animals: 56
Control: 7 males, 7 females
125 mg/kg/day: 7males, 7 females
250 mg/kg/day: 7 males, 7 females
500 mg/kg/day: 7 males, 7 females
Study 2
Total number of animals;200
0%; 50 male anf female
0.031%; 50 male anf female
0.125%; 50 male anf female
714%; 50 male anf female
Control animals:
yes, concurrent vehicle
Details on study design:
No Data Available
Positive control:
No Data Available
Parental animals: Observations and examinations:
1.The mortality and changes in body weight, food consumption and water consumption were recorded.
2.Clinical sign; The mice were observed daily
Mortality : The mice were observed daily
Body weight and food intake was measured weekly up to 4 weeks and monthly thereafter. The measurements of body weight and food intake were performed on 20 of 50 mice. Total intake of test chemical in each of the dosed groups was calculated from food intakes.

Hematology ; At the end of administration, Blood for hematology
of 20 mice of each group was collected into tubes treated with ethylenediamine-tetraacetic acid dipotassium salt (EDTA-2K). Red blood cellcount (RBC), hemoglobin concentration (Hb), packed cell volume (PCV), mean corpuscular volume(MCV), mean corpuscular hemoglobin(MCH), mean corpuscular hemoglobin concentration
(MCHC), white blood cell count (WBC) and platelet count (Pl) were measured by an automated hematology analyzer Sysmex E-4000 (TOA Medical Electronics Co. Ltd., Kobe, Japan).
Oestrous cyclicity (parental animals):
No data available
Sperm parameters (parental animals):
No data available
Litter observations:
No data available
Postmortem examinations (parental animals):
1.The testes, ovaries and uterus were pathologically examined after termination. Examinations also included weight of brain, testes and ovaries (incl. paired ovaries and uterus, including cervix).
2.All mice were necropsied and tumors and nonneoplastic lesions were examined. The spleen, heart, lung, liver, kidney, bladder, testis, ovary,
uterus and brain were weighed and the organ– body weight ratios were calculated. The fluid in the kidney with hydronephrosis was drained and then the kidney was weighed. These and other organs (skin, mammary gland, Harderian gland, salivary gland, bone, skeletal muscle, bone marrow, thymus, pancreas, esophagus, stomach, intestine, caecum, prostate gland, epididymis, preputial gland, seminal vesicle, pituitary gland,
adrenal gland and thyroid with parathyroid glands) were fixed in 10% neutral buffered formalin (NBF), embedded in paraffin wax, sectioned at
4 m and stained with hematoxylin and eosin. The bladder was drained of urine and infused with NBF. After 7 days, the bladder was cut longitudinally and was weighed without formalin and calculi. After gross examination, the bladder was prepared for microscopic examination.
Postmortem examinations (offspring):
No data available
Statistics:
1.Statistical analysis was carried out by using Microsoft Excel and IBM SPSS statistics version -20. All analyses and comparisons were evaluated at the 5 % level, statistically significant differences (p>0.05) indicated by appropriate notation. PAIRED T-Testing procedure was used to check the significance between above mentioned groups. For multiple comparisons Turkey’s HSD test was applied.
2.Statistical evaluation of equality of means in control and treated groups was assessed using Scheffe’s test for multiple comparisons (Gad and Weil, 1982). Mortality data was determined by Kaplan and Meier’s test. Fisher’s exact probability test was used for the analysis of data on
histopathology.
Reproductive indices:
No data available
Offspring viability indices:
No data available
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
1.Abnormalities such as nasal discharge, red crust around the nostrils was observed in all treatment groups. In addition, a few cases of snuffling, eye lid swelling and hunched back posture were also observed in the treated groups.
2.Treated mice were slightly less active and had ruffled fur then control.But the test result was negative for such changes.
Dermal irritation (if dermal study):
not specified
Mortality:
mortality observed, non-treatment-related
Description (incidence):
1.All animals except two animals of high dose group survived throughout the treatment period.
2.There were no statistically significant differences in mortality between control and treated groups.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
1.Treatment with 500 mg/kg body weight/day showed a significant reduction in body weights in male rats on the first, second and fourth week of treatment. In female rats, a significant decrease in body weight was observed on the first, second and third week of treatment.
2.Statistically significant changes were observed in the 178 mg/kg/day group of treated male compare to control.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No difference was observed among the groups.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
no effects observed
Description (incidence and severity):
1.No difference in water consumption was observed among the groups.
Ophthalmological findings:
no effects observed
Description (incidence and severity):
1.No difference in opthalmological changes was observed among the groups.
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
1.In male rats, significant increase in the platelet count was observed along with decrease in MCV and MCH levels at 125 mg/kg body weight/day.
Treatment with 250 mg/kg body weight/day showed significantly decreased values of hemoglobin and MCHC in male rats. The level of MCHC was also found to be significantly decreased when treated with 500 mg/kg body weight/day.

In female rats, treatment with 125 mg/kg body weight/day showed significant alterations in platelet count and MCV. At 250 mg/kg body weight/day, a significant decrease was noticed in neutrophils along with altered values of MCV in female rats.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
1.In female animals, the level of total bile acid was decreased at 250 mg/kg body weight/day. A significant increase was noticed in the level of estrogen in the same group. A similar trend was also noticed at 125 and 500 mg/kg body weight/day, but was statistically non-significant.

At 250 and 500 mg/kg body weight/day the levels of potassium and albumin were found to be significantly increased. The cholesterol level in the 250 mg/kg body weight/day group was noticed to be significantly elevated in the mid-dose group.

In male rats, the level of testosterone was significantly increased after treatment with 500 mg/kg body weight/day.
Urinalysis findings:
not specified
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
1.No statistically significant difference was observed in the motor activity scores for any dose group when compared with the control animals.
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
1.The absolute organ weight of ovaries from all treated groups was found to be decreased significantly in female rats. Significant increase in the relative weights of heart and testes was also noticed at 500 mg/kg body weight/day. In female rats, at all dose levels, the relative weight of ovaries was decreased in comparison to the control group animals. The relative weight of uterus was also decreased in the 125 or 250 mg/kg body weight/day groups. The weight of uterus was found to be significantly decreased in 250 or 500 mg/kg body weight/day-treated male and female rats. The weight of spleen was decreased in the 250 mg/kg body weight/day groups while treatment with 500 mg/kg body weight/day resulted in the decreased weight of kidney in both female and male rats. However, the a solute organ weight of male animals does not show any significant difference.
In male rats, the relative weight of liver was noticed to be increased at 125 mg/kg body weight/day. At 250 mg/kg body weight/day, the relative weights of brain and heart were significantly decreased in females. A significant decrease in the relative weight of spleen was observed at 250 or 500 mg/kg body weight/day.
2.Statistically significant changes were observed in the relative weight of testes at 605 mg/kg/day group of treated male compare to control.
Statistically significant changes were observed in the absolute and relative weight of ovaries and uterus at 146.3 and 615 mg/kg/day group of treated female compare to control.
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
1.Nasal discharge, red crust around nostril, perineum wet, bloated stomach, viscous oily secretion was found inside the thoracic cavity.
Small white solid mass slightly firm in consistency floating inside the urinary bladder was observed. However, due to adaptive metabolic and physiological changes, anoxic/ hypoxic conditions during anesthesia and terminal sacrifice, these findings were considered to be of no toxicological significance.
2.Gross findings in treated mice included the renal atrophy, hydronephrosis, calculi in renal pelvis and/or bladder and ovarian atrophy at 605 mg/kg/day groupof male and 615 mg/kg/day in female mice of treated group compare to control.
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
1.No remarkable changes observed in control and the 500 mg/kg body weight/day-treated animals.A few microscopic findings observed in 500 mg/kg body weight/day-treated animals included collapsed lung with focal inflammation, focal fatty change and excess of lymphocytes in liver, inflammation in small intestine, reactive spleen and excess of mucous in colon. However, these findings were also observed in the control animals.
2.In the seminal vesicle, a dose-dependent decrease of the cystic dilatation was observed and the incidence in the 605 mg/kg/day group was significantly lower than that of the control group. In the preputial gland, a dose-dependent decrease of the glandular atrophy was observed and the incidences in the 178 and 605 mg/kg/day group groups were significantly lower than that of the control group. In the ovary, the atrophy was observed in the 615 mg/kg/day group with a statistical significance. The ovarian cyst was significantly decreased in the 615 mg/kg/day group. In the uterus, the incidence of severe cystic endometrial hyperplasia was decreased in a dose-dependent manner. In the pituitary gland, cyst or cystic degeneration was observed in both male and female mice of only treated groups; however, the differences were not significant compared to the controls.
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
not specified
Dose descriptor:
NOAEL
Effect level:
> 125 - <= 146.3 mg/kg bw/day
Based on:
test mat.
Sex:
male
Basis for effect level:
clinical signs
mortality
body weight and weight gain
food consumption and compound intake
water consumption and compound intake
ophthalmological examination
haematology
clinical biochemistry
organ weights and organ / body weight ratios
gross pathology
histopathology: non-neoplastic
other: No effect observed
Remarks on result:
other: No effects on reproductive organ
Dose descriptor:
NOAEL
Effect level:
> 125 - <= 178 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
ophthalmological examination
haematology
clinical biochemistry
urinalysis
organ weights and organ / body weight ratios
gross pathology
histopathology: non-neoplastic
Remarks on result:
other: No effects on reproductive organ
Critical effects observed:
not specified
System:
other: not specified
Organ:
ovary
not specified
Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality / viability:
not specified
Body weight and weight changes:
not specified
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:
not specified
Other effects:
not specified
Behaviour (functional findings):
not specified
Developmental immunotoxicity:
not specified
Dose descriptor:
other: not specified
Generation:
other: not specified
Based on:
not specified
Sex:
not specified
Basis for effect level:
other: not specified
Remarks on result:
other: not specified
Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Reproductive effects observed:
not specified
Treatment related:
not specified
Conclusions:
NOAEL was considered to be in range of 125 -146.3mg/kg bw for male rats or mice and NOAEL was considered to be in range of 125 -178.0mg/kg bw for female rats or mice when male and female rats or mice were exposed daily to the test chemical by oral route.
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 a 28 days repeated dose toxicity study, the effect of the test chemical was evaluated in male and female Sprague Dawley rats. The test chemical was administered by oral gavage in the concentration of 0, 125, 250 or 500 mg/kg body weight/day. The results showed that the test chemical significantly increased the level of testosterone in the 500 mg/kg body weight/day group as well as it significantly increased the level of estrogen in the 250 mg/kg body weight/day group .The relative and absolute organ weight of ovaries decreased when treated with 125, 250 or 500 mg/kg body weight/day. In similarity, the relative and absolute organ weight of uterus decreased in the 125 or 500 mg/kg body weight/day groups.No significant changes in were detected in hematology,clinical biochemistry,mortality ororgan weight, and no effects were observed in water consumption,opthalmoscopic examination or locomotor activity. In male rats, the relative organ weights of the testes and epididymides increased when rats were treated with 500 mg/kg body weight/day. Histopathology performed on reproductive organs after treatment with 500 mg/kg body weight/day did not reveal any toxic lesions as compared to control. Hence, NOAEL was considered to be 250 mg/kg bw for male rats and LOAEL was considered to be 125 mg/kg body weight/day for female when Sprague Dawley male and female rats were exposed daily to the test chemical by oral route for 28 days.

Study 2

In a chronic study Male and female CD-1 mice were administered test chemical in diet at levels of 0 (control), 0.031, 0.125 and 0.5% (33.2, 146.3 and 605 mg/kg body weight per day in males and 40.0, 178.8 and 615 mg/kg body weight )for 78 weeks.The animals were observed for clinical sign,mortality,body weight ,food intake, hematology,gross and histopathology There were no significant differences in mortality between the control and treated groups. Mean body weights of high-dose groups showed significant decreases compared with the controls. The bladder weights of male and female mice of the 605 or 615 mg/kg/day group were significantly higher than those of the control mice. Gross findings in treated mice included the renal atrophy, hydronephrosis, calculi in renal pelvis and/or bladder and ovarian atrophy. Microscopic findings in the kidneys of treated mice included the nephrosis, hydronephrosis or hyperplasia of transitional epithelium of renal pelvis or papilla. In the bladder of treated mice, hyperplasia or squamous metaplasia of transitional epithelium and one transitional cell papilloma were observed. Dose-dependent decreases in the incidence of spontaneous lesion in the male or female reproductive system were recognized. Therefore NOAEL was considered to be 178 mg/kg/day for female 146.3 mg/kg/day for male respectivley .When test chemical was exposed to the Crj:CD-1 (ICR) male and female mice by oral feed for 78 weeks.

Based on the data available from different studiesNOAEL was considered to be in range of 125 -146.3mg/kg bw for male rats or mice and NOAEL was considered to be in range of 125 -178.0mg/kg bw for female ratsor mice when male and female rats or mice were exposed daily to the test chemical by oral route.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
125 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Data is Klimicsh 2 and from authoritative database

Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Reproductive toxicity study

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

Study 1

In a 28 days repeated dose toxicity study, the effect of the test chemical was evaluated in male and female Sprague Dawley rats. The test chemical was administered by oral gavage in the concentration of 0, 125, 250 or 500 mg/kg body weight/day. The results showed that the test chemical significantly increased the level of testosterone in the 500 mg/kg body weight/day group as well as it significantly increased the level of estrogen in the 250 mg/kg body weight/day group .The relative and absolute organ weight of ovaries decreased when treated with 125, 250 or 500 mg/kg body weight/day. In similarity, the relative and absolute organ weight of uterus decreased in the 125 or 500 mg/kg body weight/day groups.No significant changes in were detected in hematology,clinical biochemistry,mortality ororgan weight, and no effects were observed in water consumption,opthalmoscopic examination or locomotor activity. In male rats, the relative organ weights of the testes and epididymides increased when rats were treated with 500 mg/kg body weight/day. Histopathology performed on reproductive organs after treatment with 500 mg/kg body weight/day did not reveal any toxic lesions as compared to control. Hence, NOAEL was considered to be 250 mg/kg bw for male rats and LOAEL was considered to be 125 mg/kg body weight/day for female when Sprague Dawley male and female rats were exposed daily to the test chemical by oral route for 28 days.

Study 2

In a chronic study Male and female CD-1 mice were administered test chemical in diet at levels of 0 (control), 0.031, 0.125 and 0.5% (33.2, 146.3 and 605 mg/kg body weight per day in males and 40.0, 178.8 and 615 mg/kg body weight )for 78 weeks.The animals were observed for clinical sign,mortality,body weight ,food intake, hematology,gross and histopathology There were no significant differences in mortality between the control and treated groups. Mean body weights of high-dose groups showed significant decreases compared with the controls. The bladder weights of male and female mice of the 605 or 615 mg/kg/day group were significantly higher than those of the control mice. Gross findings in treated mice included the renal atrophy, hydronephrosis, calculi in renal pelvis and/or bladder and ovarian atrophy. Microscopic findings in the kidneys of treated mice included the nephrosis, hydronephrosis or hyperplasia of transitional epithelium of renal pelvis or papilla. In the bladder of treated mice, hyperplasia or squamous metaplasia of transitional epithelium and one transitional cell papilloma were observed. Dose-dependent decreases in the incidence of spontaneous lesion in the male or female reproductive system were recognized. Therefore NOAEL was considered to be 178 mg/kg/day for female 146.3 mg/kg/day for male respectivley .When test chemical was exposed to the Crj:CD-1 (ICR) male and female mice by oral feed for 78 weeks.

Based on the data available from different studiesNOAEL was considered to be in range of 125 -146.3mg/kg bw for male rats or mice and NOAEL was considered to be in range of 125 -178.0mg/kg bw for female ratsor mice when male and female rats or mice were exposed daily to the test chemical by oral route.Thus, comparing this value with the criteria of CLP regulation test material is not 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, NOAEL for test chemical was considered to be in range of  53 -120 mg/kg bw.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:
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 developmental toxicity studies on rats

GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Wistar
Details on test animals and environmental conditions:
1.Sex: Female
2.TEST ANIMALS
- Source: Woodlyn Farms, Guelph, Ontario
- Weight at study initiation: 175- 250 g
- Housing: The mated females were caged individually.
- Diet (e.g. ad libitum): Food (Purina cubes); ad libitum.
- Water (e.g. ad libitum): Water; ad libitum.
Route of administration:
other: orally by stomach intubation
Type of inhalation exposure (if applicable):
not specified
Vehicle:
corn oil
Details on exposure:
VEHICLE
- Justification for use and choice of vehicle (if other than water): corn oil
- Concentration in vehicle: 5 ml/kg
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data
Details on mating procedure:
1.pregnant female rat were used
2.- Impregnation procedure: cohoused
- If cohoused:
- Length of cohabitation: overnight
- Further matings after two unsuccessful attempts: no
- Verification of same strain and source of both sexes: no
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 1] of pregnancy
Duration of treatment / exposure:
Study 1
5 days (gestation day 8 through day 12)
Study 2
12 or 13 of gestation
Frequency of treatment:
Daily
Duration of test:
12 days
Study 2
Day 22 of gestation
Dose / conc.:
53 mg/kg bw/day
Remarks:
upto
Remarks:
Study 1
53 mg/kg bw/day
Study 2
120 mg/kg bw/day
No. of animals per sex per dose:
Five to 10 mated females were assigned.
Control animals:
not specified
Maternal examinations:
No data
Ovaries and uterine content:
2.The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Number of deciduomas and corpora lutea: Yes
Fetal examinations:
1.Fetal weight and gross pathology were examined.
2.- Individual litter weight, and litter size determined.
- Visceral examinations: Yes
- Skeletal examinations: Yes
Statistics:
No data
Indices:
No data
Historical control data:
No data
Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality:
not specified
Body weight and weight changes:
not specified
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
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:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Number of abortions:
not specified
Pre- and post-implantation loss:
not specified
Total litter losses by resorption:
not specified
Early or late resorptions:
not specified
Dead fetuses:
not specified
Changes in pregnancy duration:
not specified
Changes in number of pregnant:
not specified
Other effects:
no effects observed
Details on maternal toxic effects:
No effect on fetal growth were observed in trearted rats
Dose descriptor:
NOAEL
Effect level:
> 53 - <= 120 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: No effect on No effect on fetal growth
Remarks on result:
other: No toxic effect were observed
Abnormalities:
not specified
Fetal body weight changes:
no effects observed
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:
effects observed, treatment-related
Description (incidence and severity):
All anomalies in fetuseswere minor, such as nonfusion of 5th sternebra, wavy ribs, retarded ossification, and 14th rib.
Visceral malformations:
not specified
Other effects:
not specified
Dose descriptor:
NOAEL
Effect level:
> 53 - <= 120 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
fetal/pup body weight changes
external malformations
Remarks on result:
other: No toxic effect were observed
Abnormalities:
not specified
Developmental effects observed:
not specified
Treatment related:
not specified
Conclusions:
NOAEL was considered to be in range of 53 -120 mg/kg bw for F1 generation when pregnant female rat were treated with test chemical orally.
Executive summary:

Study 1

In a developmental toxicity study, pregnant female rat were treated with test chemical orally upto 53 mg/kg bw on day 8 through 12. No effect on fetal growth nor malformation were observed in treated female rats. Therefore, NOAEL was considered to be 53 mg/kg bw for F1 generation when pregnant female rat were treated with test chemical orally.

Study 2

In order to investigate teratogenic potential of test chemical, the female wistar rats were given a single dosage of 120 mg/kg of the test chemica orally by stomach intubation on day 12 or 13 (because higher dosages killed some pregnant females). Females were killed on day 22 of gestation and individual litter weight, litter size, and number of deciduomas and corpora lutea determined. Approximately two thirds of the fetuses were processed for skeleton examination and the remainder for visceral examination. Thetest chemical did not displayed any teratogenic potential at the maternally tolerated dosages (120 mg/kg). All anomalies in fetuses to test chemical were minor, such as nonfusion of 5th sternebra, wavy ribs, retarded ossification, and 14th rib. Thus, under the conditions of the present study, the no observed adverse effect level (NOAEL) of test chemical for teratogenicity was considered to be 120 mg/kg.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
53 mg/kg bw/day
Study duration:
subacute
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

In a developmental toxicity study, pregnant female rat were treated with test chemical orally upto 53 mg/kg bw on day 8 through 12. No effect on fetal growth nor malformation were observed in treated female rats. Therefore, NOAEL was considered to be 53 mg/kg bw for F1 generation when pregnant female rat were treated with test chemical orally.

Study 2

In order to investigate teratogenic potential of test chemical, the female wistar rats were given a single dosage of 120 mg/kg of the test chemica orally by stomach intubation on day 12 or 13 (because higher dosages killed some pregnant females). Females were killed on day 22 of gestation and individual litter weight, litter size, and number of deciduomas and corpora lutea determined. Approximately two thirds of the fetuses were processed for skeleton examination and the remainder for visceral examination. Thetest chemical did not displayed any teratogenic potential at the maternally tolerated dosages (120 mg/kg). All anomalies in fetuses to test chemical were minor, such as nonfusion of 5th sternebra, wavy ribs, retarded ossification, and 14th rib. Thus, under the conditions of the present study, the no observed adverse effect level (NOAEL) of test chemical for teratogenicity was considered to be 120 mg/kg.

Based on the various studies available for the test chemical were reviewed to determine the developmental toxicity, NOAELfor test chemical was considered to bein range of  53 -120 mg/kg bw.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.

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.