Registration Dossier

Administrative data

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Effects on fertility

Description of key information

Reproductive Toxicity

Based on the data available from different studies, the No Observed Adverse Effect Level (NOAEL) was considered to be 1000 mg/kg/day for reproductive toxicity, when rodents 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 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 data of the read-across chemicals.
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Qualifier:
according to guideline
Guideline:
other: As mentioned below
Principles of method if other than guideline:
WoE report is based on 2 reproductive toxicity studies i.e. WoE-2 and WoE-3.
GLP compliance:
not specified
Limit test:
no
Justification for study design:
not specified
Species:
rat
Strain:
other: 2. Osborne-Mendel 3. Virgin female albino rats bred (COBS)3
Sex:
male/female
Details on test animals or test system and environmental conditions:
2. Rats were caged individually.
3. No Data Available
Route of administration:
other: 2. oral: feed 3. oral: gavage
Type of inhalation exposure (if applicable):
not specified
Vehicle:
other: 2. Commercial Laboratory Chow diet 3. water
Details on exposure:
2. PREPARATION OF DOSING SOLUTIONS:
DIET PREPARATION
The test chemical was mixed into a commercial laboratory chow diet for each feeding study.
3. PREPARATION OF DOSING SOLUTIONS: No Data Available

VEHICLE
- Justification for use and choice of vehicle (if other than water): Water was used as a vehicle.
- Concentration in vehicle: 15, 50 and 150 mg/kg bw
- Amount of vehicle (if gavage): 10 ml
- Lot/batch no. (if required): No Data Available
- Purity: No Data Available
Details on mating procedure:
2. Mating was not performed
3. - M/F ratio per cage: No Data Available
- Length of cohabitation: No Data Available
- Proof of pregnancy: Mating was confirmed by sperm-positive results of vaginal examinations. The day of insemination was considered day 0 of the gestation period.
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility: No Data Available
- Further matings after two unsuccessful attempts: [no / yes (explain)]: No Data Available
- After successful mating each pregnant female was caged (how): No Data Available
- Any other deviations from standard protocol: No Data Available
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
2. two-years
3. Gestation Day 6 to 15.
Frequency of treatment:
Once Daily
Details on study schedule:
No Data Available
Remarks:
2. 0, 500, 1000 mg/kg bw/day
3. 0, 15, 50, 150 mg/kg bw/day
No. of animals per sex per dose:
2. control - 200(100/ sex)
500 mg/kgbw/day - 100 (50/sex)
1000 mg/kgbw/day - 100 (50/sex)
3. 16 to 22 pregnant rats per group.
Control animals:
yes, concurrent vehicle
Details on study design:
2. Two-year tests were run in which 400 rats were distributed into various treatment groups. The test chemical was mixed into a commercial laboratory chow diet for each feeding study.Rats were individually caged. Each animal received in the Pathology Laboratory was given a careful gross examination, and all lesions were recorded. Of those not received, most were discarded because of advanced postmortem autolysis. So far as can be determined, none of the discarded animals had tumors. Lesions which could not clearly be identified as neoplastic or nonneoplastic, and tumors, the type of which was uncertain or uncommon, were also sectioned and examined microscopically. Tissues sectioned include the following: liver, lung, heart, spleen, pancreas, stomach, small intestine, colon, kidney, adrenal, thyroid, testis (or ovary and uterus), leg muscles, leg bones with included marrow, and any tumor or other unusual condition.Sections of the mamary glands were also observed for tumours.
3. No Data Available
Positive control:
2. no data available
3. 2 positive control groups were treated with 200 mg/kg/day of sodium salicylate.
Parental animals: Observations and examinations:
2. no data available
3. No Data Available
Oestrous cyclicity (parental animals):
2. no data available
3. No Data Available
Sperm parameters (parental animals):
2. no data available
3. No Data Available
Litter observations:
2. no data available
3. Fetuses were removed and sacrificed for examination. An external examination of all fetuses was conducted to detect any gross abnormalities. Two-thirds of all fetuses of each sex from each litter were examined for skeletal development using the alizarin staining method. Internal development was evaluated in the remaining fetuses by freehand razor blade sectioning technique.
Postmortem examinations (parental animals):
2. Each animal received in the Pathology Laboratory was given a careful gross examination, and all lesions were recorded. Of those not received, most were discarded because of advanced postmortem autolysis. So far as can be determined, none of the discarded animals had tumors. Lesions which could not clearly be identified as neoplastic or nonneoplastic, and tumors, the type of which was uncertain or uncommon, were also sectioned and examined microscopically.
Tissues sectioned include the following: liver, lung, heart, spleen, pancreas, stomach, small intestine, colon, kidney, adrenal, thyroid, testis (or ovary and uterus), leg muscles, leg bones with included marrow, and any tumor or other unusual condition.Sections of the mamary glands were also observed for tumours.
3. All females were sacrificed on day 20 of gestation. Fetal swellings, implantation and resorption sites and any uterine abnormalities were noted and the number of viable fetuses present in the uterus was determined.
Postmortem examinations (offspring):
2. no data available
3. Two-thirds of all fetuses of each sex from each litter were examined for skeletal development using the alizarin staining method. Internal development was evaluated in the remaining fetuses by freehand razor blade sectioning technique.
Statistics:
2. no data available
3. Fetal viability data were subjected to 2 types of statistical analysis. First, in a chi-square analysis, the number of resorption sites per implantation site of each test animal was compared to the expected incidence. The expected incidence was calculated from data obtained from the 3 untreated control groups. The second analysis utilized the ranking method of Weil (1970). For this analysis the individual viability indices of each test group were ranked with individual viability indices of each control group.
Reproductive indices:
2. no data available
3. No Data Available
Offspring viability indices:
2. no data available
3. No Data Available
Clinical signs:
no effects observed
Description (incidence and severity):
2. no effects observed - The ingestion of the test chemical had no effect on survival, growth, or weights at autopsy of heart, liver, kidney, spleen, or testes in the test animals
3. no effects observed - No untoward reactions of the test chemical was observed.
Dermal irritation (if dermal study):
not specified
Mortality:
no mortality observed
Description (incidence):
2. no mortality observed - The ingestion of the test chemical had no effect on survival, growth, or weights at autopsy of heart, liver, kidney, spleen, or testes in the test animals
3. no mortality observed - No deaths at any dose groups were observed due to administration of the test chemical.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
2. no effects observed - The ingestion of the test chemical had no effect on survival, growth, or weights at autopsy of heart, liver, kidney, spleen, or testes in the test animals
3. no effects observed - No effects on the maternal body weight was observed due to administration of the test chemical. The mean maternal weight gain from day 0 to 20 of gestation were 146, 134, 144, 137 and 145 g.
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:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
2. no effects observed - Findings, such as liver enlargement, abscesses, distendedurinary bladders, ovarian cysts, distended uteri, enlarged parathyroids, enlargement of seminal vesicles and other miscellaneous changes, were present in approximately equal incidence and degree in test and control rats. No effect due to ingestion of the test chemical on either tumor incidence or tumor type was noted in Osborne Mendel strain on this two-year experiment.
3. not specified
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
2. no effects observed - No effect due to ingestion of the test chemical on either tumor incidence or tumor type was noted in Osborne Mendel rats on this two-year experiment. Rats of the Osborne- Mendel strain had more tumors (especially mammary).Incidence of tumor formation in mammary glands were found to be in control and treatment groups. Thus, they are considered to be incidemtal and non treatment related in nature and strain specific.
3. 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):
2. not specified
3. no effects observed - The test chemical had no effect upon the incidence of resorptions or upon fetal viability. The ncidence of resorptions was increased in 1 of the 2 groups of dams treated with the positive control.
No untoward reactions of the test chemical was observed. No effects on the maternal body weight was observed due to administration of the test chemical. The mean maternal weight gain from day 0 to 20 of gestation were 146, 134, 144, 137 and 145 g. The test chemical had no effect upon the incidence of resorptions or upon fetal viability. The ncidence of resorptions was increased in 1 of the 2 groups of dams treated with the positive control.
Dose descriptor:
NOAEL
Remarks:
2
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
gross pathology
histopathology: non-neoplastic
histopathology: neoplastic
Remarks on result:
not determinable due to absence of adverse toxic effects
Dose descriptor:
NOAEL
Remarks:
3
Effect level:
150 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
clinical signs
mortality
body weight and weight gain
reproductive performance
Critical effects observed:
not specified
Remarks on result:
not measured/tested
Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality / viability:
no mortality observed
Description (incidence and severity):
No effect on fetal mortality or viability was observed, after administration of the test chemical.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Fetal body weights and sex distribution were unaffected by any treatment. Mean body weights were 3.9, 3.5, 4.3, 4.4 and 4.2 g for males and 3.7, 3.3, 4.0, 4.1 and 4.1 g for females from all 3 vehicle control, the 2 positive control and the 15, 50 and 150 mg/kg test groups, respectively.
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:
no effects observed
Description (incidence and severity):
The distribution of sexes was 283 males and 266 females (51.5% males) for the 3 vehicle control groups, 177 males and 196 females (47.8% males) for the 2 positive control groups, 110 males and 113 females (49.3 % males) for the 15 mg/kg test group, 103 males and 101 females (50.5 % males) for the 15 mg/kg test group and 97 males and 81 females (54.5 % males) for the 150 mg/kg test group.
Anogenital distance (AGD):
not specified
Nipple retention in male pups:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings:
no effects observed
Description (incidence and severity):
External abnormalities were somewhat more numerous among pups from animals treated with sodium salicylate. These abnormalities included runt, craniorachischisis, gastroschisis, spiraled caudia and talipes. The numbers of fetuses with external abnormalities from dams treated with the test chemical did not differ from those of controls.
Other effects:
not specified
Behaviour (functional findings):
not specified
Developmental immunotoxicity:
not specified
No effect on fetal mortality or viability was observed, after administration of the test chemical. Fetal body weights and sex distribution were unaffected by any treatment. Mean body weights were 3.9, 3.5, 4.3, 4.4 and 4.2 g for males and 3.7, 3.3, 4.0, 4.1 and 4.1 g for females from all 3 vehicle control, the 2 positive control and the 15, 50 and 150 mg/kg test groups, respectively. The distribution of sexes was 283 males and 266 females (51.5% males) for the 3 vehicle control groups, 177 males and 196 females (47.8% males) for the 2 positive control groups, 110 males and 113 females (49.3 % males) for the 15 mg/kg test group, 103 males and 101 females (50.5 % males) for the 15 mg/kg test group and 97 males and 81 females (54.5 % males) for the 150 mg/kg test group. External abnormalities were somewhat more numerous among pups from animals treated with sodium salicylate. These abnormalities included runt, craniorachischisis, gastroschisis, spiraled caudia and talipes. The numbers of fetuses with external abnormalities from dams treated with the test chemical did not differ from those of controls.
Remarks on result:
not measured/tested
Remarks:
2
Dose descriptor:
NOAEL
Remarks:
3
Generation:
F1
Effect level:
150 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
viability
sexual maturation
mortality
histopathology: non-neoplastic
Critical effects observed:
not specified
Remarks on result:
not measured/tested
Reproductive effects observed:
no
Treatment related:
no

2.

Lesions observed in the 2 year feeding study

Parameter

Control

1%

2%

Number of rats started

200

100

100

Number of survivors at 80 weeks

158

75

78

Number received by pathology

171

89

89

Number of males with tumors

25

9

10

Number of females with tumors

42

14

22

Total number of rats with tumors

67

23

32

Tumor type in each rat

 

 

 

Fibroadenoma, mammary                          

19

9

12

Adenocarcinoma

18

6

7

Lymphosarcoma

18

7

5

Lymphoblastoma

5

0

0

Fibrosacroma

0

0

4

Interstitial cell tumor

5

4

2

Endometrial sarcoma

3

1

0

Other tumors

10

1

5

Other pathology

 

 

 

Chronic pneumonia

34

18

16

Granular kidneys

49

23

23

Splenic enlargement

27

16

13

Splenic atrophy

17

16

9

Testicular atrophy

8

8

4

Adrenal enlargement

5

2

3

Chronic arteritis

2

2

0

Conclusions:
Based on the data available from different studies, the No Observed Adverse Effect Level (NOAEL) was considered to be 1000 mg/kg/day for reproductive toxicity, when rodents 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 toxicant.
Executive summary:

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

 

Combined Repeated Dose and Carcinogenicity was performed to determine the toxic nature of the test chemical in Osborne Mendel rats. Two-year tests were run in which 400 male and female Osborne Mendel rats were distributed into various treatment groups. The treatment groups were - 100 rats/dose (50/sex) and 100 rats/sex for controls. The test chemical (500 mg/kg bw/day, 1000 mg/kg bw/day) was mixed into a commercial laboratory chow diet for each feeding study. Rats were individually caged. Each animal received in the Pathology Laboratory was given a careful gross examination, and all lesions were recorded. Of those not received, most were discarded because of advanced postmortem autolysis. So far as can be determined, none of the discarded animals had tumors. Lesions which could not clearly be identified as neoplastic or non-neoplastic, and tumors, the type of which was uncertain or uncommon, were also sectioned and examined microscopically. Tissues sectioned include the following: liver, lung, heart, spleen, pancreas, stomach, small intestine, colon, kidney, adrenal, thyroid, testis (or ovary and uterus), leg muscles, leg bones with included marrow, and any tumor or other unusual condition. Sections of the mammary glands were also observed for tumors. Findings, such as liver enlargement, abscesses, distended urinary bladders, ovarian cysts, distended uteri, enlarged parathyroid, enlargement of seminal vesicles and other miscellaneous changes, were present in approximately equal incidence and degree in test and control rats. Rats of the Osborne- Mendel strain had more tumors (especially mammary).Incidence of tumor formation in mammary glands were found to be in control and treatment groups. Thus, they are considered to be incidental and non-treatment related in nature and strain specific. No effect due to ingestion of the test chemical on either tumor incidence or tumor type was noted in Osborne Mendel strain on this two-year experiment. Considering all the observations, the No Observed Adverse Effect Level was considered to be 1000 mg/kg bw/day in Osborne Mendel rats.

 

In supporting with the above result, another prenatal developmental toxicity study was performed using the test chemical in Virgin female albino rats (COBS). The animals were dosed with the test chemical during gestation day 6 to 15 to assess its teratogenic potential. The dose range selected for the study was 0, 15, 50 and 150 mg/kg bw as control, low dose, mid dose and high dose groups, respectively. Eight groups, ranging in size from 16 to 22 pregnant animals each, were studied: 3 control groups received vehicle alone, 2 positive control groups were treated with 200 mg/kg/day of sodium salicylate4 3 test groups received 15,50 or 150 mg/kg/day of the test chemical. The vehicle employed was 1.5 % aqueous methylcellulose, and the concentrations of test material were such that all animals received equivalent volumes of vehicle or test suspension per unit of body weight. Food and water were available ad libitum. After the administration, the effects on the pregnant females were observed. No untoward reactions of the test chemical was observed. No effects on the maternal body weight was observed due to administration of the test chemical. The mean maternal weight gain from day 0 to 20 of gestation were 146, 134, 144, 137 and 145 g. The test chemical had no effect upon the incidence of resorptions or upon fetal viability. The incidence of resorptions was increased in 1 of the 2 groups of dams treated with the positive control. No effect on fetal mortality or viability was observed, after administration of the test chemical. Fetal body weights and sex distribution were unaffected by any treatment. Mean body weights were 3.9, 3.5, 4.3, 4.4 and 4.2 g for males and 3.7, 3.3, 4.0, 4.1 and 4.1 g for females from all 3 vehicle control, the 2 positive control and the 15, 50 and 150 mg/kg test groups, respectively. The distribution of sexes was 283 males and 266 females (51.5% males) for the 3 vehicle control groups, 177 males and 196 females (47.8% males) for the 2 positive control groups, 110 males and 113 females (49.3 % males) for the 15 mg/kg test group, 103 males and 101 females (50.5 % males) for the 15 mg/kg test group and 97 males and 81 females (54.5 % males) for the 150 mg/kg test group. External abnormalities were somewhat more numerous among pups from animals treated with sodium salicylate. These abnormalities included runt, craniorachischisis, gastroschisis, spiraled caudia and talipes. The numbers of fetuses with external abnormalities from dams treated with the test chemical did not differ from those of controls. Thus, based on all the available data, and observations and results, it was concluded that the NOAEL for the test chemical was 150 mg/kg bw for maternal and fetal development.

 

Based on the data available from different studies, NOAEL was considered to be 1000 mg/kg/day for reproductive toxicity, when rodents were treated with test chemical orally. Thus, comparing this value and effects with the criteria of CLP regulation test chemical 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 handbook or collection of data.
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

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

 

Combined Repeated Dose and Carcinogenicity was performed to determine the toxic nature of the test chemical in Osborne Mendel rats. Two-year tests were run in which 400 male and female Osborne Mendel rats were distributed into various treatment groups. The treatment groups were - 100 rats/dose (50/sex) and 100 rats/sex for controls. The test chemical (500 mg/kg bw/day, 1000 mg/kg bw/day) was mixed into a commercial laboratory chow diet for each feeding study. Rats were individually caged. Each animal received in the Pathology Laboratory was given a careful gross examination, and all lesions were recorded. Of those not received, most were discarded because of advanced postmortem autolysis. So far as can be determined, none of the discarded animals had tumors. Lesions which could not clearly be identified as neoplastic or non-neoplastic, and tumors, the type of which was uncertain or uncommon, were also sectioned and examined microscopically. Tissues sectioned include the following: liver, lung, heart, spleen, pancreas, stomach, small intestine, colon, kidney, adrenal, thyroid, testis (or ovary and uterus), leg muscles, leg bones with included marrow, and any tumor or other unusual condition. Sections of the mammary glands were also observed for tumors. Findings, such as liver enlargement, abscesses, distended urinary bladders, ovarian cysts, distended uteri, enlarged parathyroid, enlargement of seminal vesicles and other miscellaneous changes, were present in approximately equal incidence and degree in test and control rats. Rats of the Osborne- Mendel strain had more tumors (especially mammary).Incidence of tumor formation in mammary glands were found to be in control and treatment groups. Thus, they are considered to be incidental and non-treatment related in nature and strain specific. No effect due to ingestion of the test chemical on either tumor incidence or tumor type was noted in Osborne Mendel strain on this two-year experiment. Considering all the observations, the No Observed Adverse Effect Level was considered to be 1000 mg/kg bw/day in Osborne Mendel rats.

 

In supporting with the above result, another prenatal developmental toxicity study was performed using the test chemical in Virgin female albino rats (COBS). The animals were dosed with the test chemical during gestation day 6 to 15 to assess its teratogenic potential. The dose range selected for the study was 0, 15, 50 and 150 mg/kg bw as control, low dose, mid dose and high dose groups, respectively. Eight groups, ranging in size from 16 to 22 pregnant animals each, were studied: 3 control groups received vehicle alone, 2 positive control groups were treated with 200 mg/kg/day of sodium salicylate4 3 test groups received 15,50 or 150 mg/kg/day of the test chemical. The vehicle employed was 1.5 % aqueous methylcellulose, and the concentrations of test material were such that all animals received equivalent volumes of vehicle or test suspension per unit of body weight. Food and water were available ad libitum. After the administration, the effects on the pregnant females were observed. No untoward reactions of the test chemical was observed. No effects on the maternal body weight was observed due to administration of the test chemical. The mean maternal weight gain from day 0 to 20 of gestation were 146, 134, 144, 137 and 145 g. The test chemical had no effect upon the incidence of resorptions or upon fetal viability. The incidence of resorptions was increased in 1 of the 2 groups of dams treated with the positive control. No effect on fetal mortality or viability was observed, after administration of the test chemical. Fetal body weights and sex distribution were unaffected by any treatment. Mean body weights were 3.9, 3.5, 4.3, 4.4 and 4.2 g for males and 3.7, 3.3, 4.0, 4.1 and 4.1 g for females from all 3 vehicle control, the 2 positive control and the 15, 50 and 150 mg/kg test groups, respectively. The distribution of sexes was 283 males and 266 females (51.5% males) for the 3 vehicle control groups, 177 males and 196 females (47.8% males) for the 2 positive control groups, 110 males and 113 females (49.3 % males) for the 15 mg/kg test group, 103 males and 101 females (50.5 % males) for the 15 mg/kg test group and 97 males and 81 females (54.5 % males) for the 150 mg/kg test group. External abnormalities were somewhat more numerous among pups from animals treated with sodium salicylate. These abnormalities included runt, craniorachischisis, gastroschisis, spiraled caudia and talipes. The numbers of fetuses with external abnormalities from dams treated with the test chemical did not differ from those of controls. Thus, based on all the available data, and observations and results, it was concluded that the NOAEL for the test chemical was 150 mg/kg bw for maternal and fetal development.

 

Based on the data available from different studies, NOAEL was considered to be 1000 mg/kg/day for reproductive toxicity, when rodents were treated with test chemical orally. Thus, comparing this value and effects with the criteria of CLP regulation test chemical 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

Comparing the NOAEL value and effects observed on rodents, with the criteria of CLP regulation the given test chemical is not likely to classify as reproductive toxicant.

Additional information