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Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
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
Justification for type of information:
Weight of evidence approach based on the available information from various test chemicals.
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
read-across source
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
Data from peer reviewed journal
Qualifier:
equivalent or similar to guideline
Guideline:
other: As mentioned below
Principles of method if other than guideline:
Test material was tested for reproductive effects in a feeding study with NMRI mice for days 6 to 15 of gestation study period.
GLP compliance:
not specified
Limit test:
no
Justification for study design:
No data available
Species:
mouse
Strain:
NMRI
Details on species / strain selection:
No data available
Sex:
female
Details on test animals or test system and environmental conditions:
No data available
Route of administration:
oral: feed
Type of inhalation exposure (if applicable):
not specified
Vehicle:
other: diet
Details on exposure:
1) Two groups of pregnant rats, 25 in one group and 31 in the other were fed diets containing test substance.
2) Two control groups of 26 and 28 rats were fed untreated feed.
Details on mating procedure:
N/A
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
6 to 15 days of gestation
Frequency of treatment:
Daily
Details on study schedule:
No data available
Remarks:
Doses / Concentrations:
Controls : 0 mg/kg (plain diet) Group 1: 5000 mg/kg Group 2 : 10000 mg/kg
Basis:

No. of animals per sex per dose:
1st group: 25 pregnant mice.
2nd group: 31 pregnant mice.
1st control group: 26 pregnant mice.
2nd control group : 28 pregnant mice.
Control animals:
yes, concurrent vehicle
Details on study design:
No data available
Positive control:
No data available
Parental animals: Observations and examinations:
Yes examined for toxicity
Oestrous cyclicity (parental animals):
No data available
Sperm parameters (parental animals):
No data available
Litter observations:
Yes examined for malformation
Postmortem examinations (parental animals):
No data available
Postmortem examinations (offspring):
No data available
Statistics:
No data available
Reproductive indices:
No data available
Offspring viability indices:
No data available
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
Histopathological findings: non-neoplastic:
not examined
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
No evidence of maternal toxicity.
Dose descriptor:
NOAEL
Effect level:
5 000 mg/kg bw/day
Based on:
test mat.
Sex:
female
Basis for effect level:
other: Effects: Negative maternal toxicity was observed in pregnant mouse.
Remarks on result:
other: No 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
Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality / viability:
no mortality observed
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
The few malformations observed among the fetuses which is not significant.
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
5 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
gross pathology
Remarks on result:
other: No developmental toxic effects 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:
The no observed adversed effect level (NOAEL) for reproductive toxicity is considered to be 5000 mg/kg bw/day.When female mice treated with test material orally.
Executive summary:

A reproductive study was conducted to evaluate the maternal toxicity effects by test material in mouse orally. In first group25 pregnant mice and in second group31 pregnant micewere fed diets containing test substance and in first control group 26pregnant mice and in second control group 28pregnant mic ewere fed untreated feed on daily basis for 6 to 15 days of gestation. During study period test animals were given 0(vehicle), 5000, 10000 mg/kg bw/day.Test material does not show any maternal toxicity. The few malformations observed among the fetuses which is not significant.Hence the no observed adversed effect level (NOAEL) for reproductive toxicity is considered to be 5000 mg/kg bw/day.When female mice treated with test material orally.

Reason / purpose for cross-reference:
read-across source
Reference
Endpoint:
reproductive toxicity, other
Remarks:
chronic toxicity study
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
Data from NTP study report
Qualifier:
equivalent or similar to guideline
Guideline:
other: As mentioned below
Principles of method if other than guideline:
Reproductive toxicity study of test material was performed on rats.
GLP compliance:
not specified
Limit test:
no
Justification for study design:
No data available
Species:
rat
Strain:
other: F344/N
Details on species / strain selection:
No data available
Sex:
male/female
Details on test animals or test system and environmental conditions:
Details on test animals and env. conditions
TEST ANIMALS
- Source: Simonsen Laboratories
(Gilroy, CA)
- Age at study initiation: 6 wk
- 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: Polycarbonate cages lined with
heat-treated hardwood chips and covered with polyester filter sheets, Rats were housed 5 per cage
- Use of restrainers for preventing ingestion (if dermal): yes/no
- Diet (e.g. ad libitum): NIH 07; Feed available ad libitum
- Water (e.g. ad libitum): Water available ad libitum
- Acclimation period: 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24.4°C
- Humidity (%):relative humidity ranged from 42% to 72%.
- Air changes (per hr): 10 times per hour.
- Photoperiod (hrs dark / hrs light): A controlled light cycle of 12 hours of daylight and 12 hours of darkness was maintained.

Route of administration:
oral: gavage
Vehicle:
not specified
Details on exposure:
DIET PREPARATION
Formulated diets were prepared by blending the appropriate amount of test material with a small quantity of feed to prepare a premix. The premix then was layered between the required amount
of feed in a twin-shell blender and blended for 15 minutes to achieve a uniform mix. Formulated diets were stored for no longer than 3 weeks at 5°C; feed hoppers in the animal cages were changed twice weekly.
Analytical verification of doses or concentrations:
yes
Remarks:
HPLC
Duration of treatment / exposure:
13 weeks.
Frequency of treatment:
daily
Details on study schedule:
No data available
Remarks:
0, 620, 1250, 2500, 5000, 10000mg/kg ( 0, 0.62%, 1.25%, 2.5%, 5.0% or 10%)
No. of animals per sex per dose:
Total:120
0 mg/kg : 10 male and 10 female
620mg/kg : 10 male and 10 female
1250mg/kg : 10 male and 10 female
2500mg/kg : 10 male and 10 female
5000mg/kg : 10 male and 10 female
10000mg/kg : 10 male and 10 female
Control animals:
yes, plain diet
Details on study design:
No data available
Positive control:
No data available
Parental animals: Observations and examinations:
Parental animals observation and examinations
CAGE SIDE OBSERVATIONS: yes

DETAILED CLINICAL OBSERVATIONS: Yes

Time schedule: Twice daily


BODY WEIGHT: Yes
Time schedule for examinations: Body weights were recorded initially and every week thereafter.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data: No data available


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

Oestrous cyclicity (parental animals):
yes
Sperm parameters (parental animals):
yes
Litter observations:
No data available
Postmortem examinations (parental animals):
Postmortem examinations (Parent Animal)
SACRIFICE: animals were euthanized by CO2 anaesthesia On days 21.

GROSS NECROPSY: yes ,complete necropsies were performed
HISTOPATHOLOGY / ORGAN WEIGHTS: yes Complete histopathology examinations were conducted on all rats from the control and 10% dose groups.

Livers were examined from male rats in all other dose groups; histologic sections of gross lesions were examined from all rats. Organ
weights were determined to the nearest milligram for the liver, right kidney, right testicle, heart, thymus, and lungs. All tissues were preserved in 10% neutral buffered formalin.

Postmortem examinations (offspring):
No data available
Statistics:
Body weight and organ weight data were statistically analyzed within each sex by one-way Analysis of Variance tests, followed by Dunnett's t-test if pair-wise comparisons were indicated (p < 0.05)(Dunnett, 1955).
Reproductive indices:
No data available
Offspring viability indices:
No data available
Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Group mean body weights of male rats did not differ significantly from controls, Mean body weights of exposed female rats were slightly lower than the mean body weights of controls but the differences were not dose-related.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No significant differences in average food consumption among each sex were observed, although food consumption of male and female rats in 10000mg/kg dose group was slightly lower than that of controls.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Description (incidence and severity):
Haematological effects were not considered biologically significant.
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):
Histopathologic examination revealed an absence of compound-related lesions in any organ or tissue of rats exposed to test material.
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
No effects on estrous cycle
Reproductive function: sperm measures:
no effects observed
Description (incidence and severity):
No effects on sperm parameters
Reproductive performance:
not specified
Dose descriptor:
NOAEL
Effect level:
10 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
mortality
body weight and weight gain
food consumption and compound intake
haematology
organ weights and organ / body weight ratios
gross pathology
histopathology: non-neoplastic
reproductive function (oestrous cycle)
reproductive function (sperm measures)
Remarks on result:
other: No 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
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:
not measured/tested
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

Reproductive System Data for F344/N rats in the 13-Week Feed Studies of test material

 

 

Percent in Feed

MALE (a)

0

2.5

5

10

Left caudal weight (mg)

151± 3

153± 7

145 ±4

153± 5

Left epididymal weight (mg)

502± 11

498± 10

464± 10*

476± 7

Left testis (mg)

1539± 21

1550± 31

1463± 53

1492 ±29

Sperm count (x106)/gram testis

72.8± 0.5

65.9 ±0.5

71.7± .5

77.5± 0.7

Sperm motility (percent)

73.6± 2.3

65.9± 5.6

72.1 ±4.1

69.8± 2.3

FEMALE (b)

 

 

 

 

Estrous stage (percent)

 

 

 

 

Proestrus

12.5

14.2

15.8

16.7

Estrous

28.3

32.5

25.8

25.8

Metestrous

18.3

19.2

18.3

19.2

Diestrous

40.8

34.2

39.2

38.3

Not clear or no cells observed

0.0

0.0

0.0

0.0

Cycle Length (days)

5.00 ±0.0

5.1 ±0.1

5.2 ±0.1

5.1 ±0.1

(a) Mean ± standard error for groups of 10 animals; no significant difference vs. the controls by Dunn's test (Dunn,

1964).

(b) Mean for groups of 10 animals unless otherwise specified

* Significantly different from control groups by Shirley's test (Shirley, 1977); p < 0.05.

 

 

Survival and Average Food and Compound Consumption of F344/N rats in the 13-Week

Feed Studies of test material

Dose (% in feed )

Survival

Mean body weight (gm)

Final weight relative to control (%)

Feed consumption (b)

Compound consumption(C)

Initial

Final

change

Male

 

 

 

 

 

 

 

0

10/10

132

364

233

 

65

0

0.62

10/10

130

346

216

95.0

65

404

1.25

10/10

126

359

233

98.6

65

809

2.5

10/10

131

356

226

97.8

63

1583

5.0

10/10

131

351

220

96.4

61

3067

10

10/10

129

353

224

97.0

58

5835

Female

 

 

 

 

 

 

 

0

10/10

108

208

100

 

64

0

0.62

10/10

108

202

95

97.1

65

401

1.25

10/10

107

205

97

98.6

64

797

2.5

10/10

109

202

93

97.1

63

1569

5.0

10/10

110

206

96

99.0

61

3045

10

10/10

108

197

89

97.7

57

5725

 

(a) Number surviving/number initially in group.

(b) Average grams food consumed per kg body weight per day.

(c) Average mg compound consumed per kg body weight per day.

Conclusions:
No Observed Adverse Effect Level (NOAEL) for reproductive toxicity was considered to be 10000mg/kg, When male and female rats were treated with test material orally over 13 weeks.
Executive summary:

13 weeks toxicity study of test material was performed on male and femaleF344/N rats. Animalswere quarantined and acclimated to laboratory conditions for 14 days prior to study start.10 rats /sex/ group were received receiving diets containing0, 620, 1250, 2500, 5000, 10000mg/kg (0, 0.62%, 1.25%, 2.5%, 5.0% or 10%) test material continuously for 13 weeks. Formulated diets were prepared by blending the appropriate amount of test material with a small quantity of feed to prepare a premix. The premix then was layered between the required amounts of feed in a twin-shell blender and blended for 15 minutes to achieve a uniform mix. Formulated diets were stored for no longer than 3 weeks at 5°C; feed hoppers in the animal cages were changed twice weekly. All the animals were observed twice daily for clinical signs.Body weights were recordedinitially and every week thereafter.At the study termination, all animals were euthanized by CO2 anesthesia, and complete necropsies were performed. Complete histopathology examinations were conducted on all rats. Sperm motility and morphology were evaluated at necropsy, and vaginal cytology was evaluated.No mortality observed.No significant differences in average food consumption among each sex were observed, although food consumption of male and female rats in 10000mg/kg dose group was slightly lower than that of controls. Group mean body weights of male rats did not differ significantly from controls, Mean body weights of exposed female rats were slightly lower than the mean body weights of controls but the differences were not dose-related. Haematological effects were not considered biologically significant. Absolute liver weights and the liver-to-body-weight ratio were increased in male rats in 10000mg/kg dose group. Using light microscopy, it was determined there were no morphologic changes associated with the slight differences in organ weights between groups. In male rats, there was a slight decrease in epididymal weight (6-7%) which occurred in the 5000 and 10000 mg/kg dose groups, but this was not dose-related. There were no effects on any other male rat reproductive endpoint, or on any female rat reproductive endpoint. Although there was some variation in epididymal weights, their small magnitude and the absence of changes in other endpoints suggested that there was little or no evidence of any reproductive toxicity associated test material. Histopathology examination revealed an absence of compound-related lesions in any organ or tissue of rats exposed to test material. HenceNo Observed Adverse Effect Level (NOAEL) for reproductive toxicity was considered to be 10000mg/kg, whenmale and femalerats were treated withtest material orallyover 13 weeks.

 

Data source

Reference
Reference Type:
other company data
Title:
Unnamed
Year:
2018

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
other: As mentioned below
Principles of method if other than guideline:
WoE report is based on two reproductive toxicity studies on rats or mice
Test material was tested for reproductive effects in a feeding study with NMRI mice for days 6 to 15 of gestation study period.
GLP compliance:
not specified
Limit test:
no
Justification for study design:
No data available

Test material

Constituent 1
Chemical structure
Reference substance name:
Castor oil, ethoxylated
EC Number:
500-151-7
EC Name:
Castor oil, ethoxylated
Cas Number:
61791-12-6
Molecular formula:
C57H104O9(CH2CH2O)n
IUPAC Name:
Castor oil, ethoxylated
Test material form:
liquid
Details on test material:
- IUPAC Name: Castor Oil, ethoxylated
- Smiles: CCCCCCC(CC=CCCCCCCCC(=O)OCC(C(=O)OCCCCCCCC=CCC(O)CCCCCC)OC(=O)CCCCCCC=CCC(O)CCCCCC)OCCOCCOCCOCCOCCO
- Molecular formula:C65H120O14
- Substance type:Organic
- Physical state:Liquid

Test animals

Species:
other: 1.mouse 2.rats
Strain:
other: 1.NMRI 2.F344/N
Details on species / strain selection:
No data available
Sex:
male/female
Details on test animals or test system and environmental conditions:
No data available

Administration / exposure

Route of administration:
other: 1.oral: feed 2.oral: gavage
Type of inhalation exposure (if applicable):
not specified
Vehicle:
other: diet
Details on exposure:
Study 1.
1) Two groups of pregnant rats, 25 in one group and 31 in the other were fed diets containing test substance.
2) Two control groups of 26 and 28 rats were fed untreated feed.
Study 2.
DIET PREPARATION
Formulated diets were prepared by blending the appropriate amount of test material with a small quantity of feed to prepare a premix. The premix then was layered between the required amount
of feed in a twin-shell blender and blended for 15 minutes to achieve a uniform mix. Formulated diets were stored for no longer than 3 weeks at 5°C; feed hoppers in the animal cages were changed twice weekly.

Details on mating procedure:
N/A
Analytical verification of doses or concentrations:
yes
Remarks:
HPLC
Duration of treatment / exposure:
Study 1.6 to 15 days of gestation
Study 2.13 weeks.
Frequency of treatment:
Daily
Details on study schedule:
No data available
Doses / concentrations
Remarks:
Doses / Concentrations:
Study 1.
Controls : 0 mg/kg (plain diet) Group 1: 5000 mg/kg Group 2 : 10000 mg/kg
Basis:

Study 2.
0, 620, 1250, 2500, 5000, 10000mg/kg ( 0, 0.62%, 1.25%, 2.5%, 5.0% or 10%)
No. of animals per sex per dose:
Study 1.
1st group: 25 pregnant mice.
2nd group: 31 pregnant mice.
1st control group: 26 pregnant mice.
2nd control group : 28 pregnant mice.
Study 2.
Total:120
0 mg/kg : 10 male and 10 female
620mg/kg : 10 male and 10 female
1250mg/kg : 10 male and 10 female
2500mg/kg : 10 male and 10 female
5000mg/kg : 10 male and 10 female
10000mg/kg : 10 male and 10 female

Control animals:
yes, concurrent vehicle
Details on study design:
No data available
Positive control:
No data available

Examinations

Parental animals: Observations and examinations:
Study 1.
Yes examined for toxicity
Study 2.
arental animals observation and examinations
CAGE SIDE OBSERVATIONS: yes

DETAILED CLINICAL OBSERVATIONS: Yes

Time schedule: Twice daily


BODY WEIGHT: Yes
Time schedule for examinations: Body weights were recorded initially and every week thereafter.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data: No data available


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

Oestrous cyclicity (parental animals):
No data available
Sperm parameters (parental animals):
No data available
Litter observations:
Study 1.
Yes examined for malformation
Postmortem examinations (parental animals):
Study 2.
Postmortem examinations (Parent Animal)
SACRIFICE: animals were euthanized by CO2 anaesthesia On days 21.

GROSS NECROPSY: yes ,complete necropsies were performed
HISTOPATHOLOGY / ORGAN WEIGHTS: yes Complete histopathology examinations were conducted on all rats from the control and 10% dose groups.

Livers were examined from male rats in all other dose groups; histologic sections of gross lesions were examined from all rats. Organ
weights were determined to the nearest milligram for the liver, right kidney, right testicle, heart, thymus, and lungs. All tissues were preserved in 10% neutral buffered formalin.

Postmortem examinations (offspring):
No data available
Statistics:
Study 2.
Body weight and organ weight data were statistically analyzed within each sex by one-way Analysis of Variance tests, followed by Dunnett's t-test if pair-wise comparisons were indicated (p < 0.05)(Dunnett, 1955).
Reproductive indices:
No data available
Offspring viability indices:
No data available

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality:
not specified
Body weight and weight changes:
no effects observed
Description (incidence and severity):
2.Group mean body weights of male rats did not differ significantly from controls, Mean body weights of exposed female rats were slightly lower than the mean body weights of controls but the differences were not dose-related.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
2.No significant differences in average food consumption among each sex were observed, although food consumption of male and female rats in 10000mg/kg dose group was slightly lower than that of controls.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Description (incidence and severity):
Haematological effects were not considered biologically significant.
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):
Histopathologic examination revealed an absence of compound-related lesions in any organ or tissue of rats exposed to test material.
Histopathological findings: neoplastic:
not specified
Other effects:
not specified

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
No effects on estrous cycle
Reproductive function: sperm measures:
no effects observed
Description (incidence and severity):
No effects on sperm parameters
Reproductive performance:
not specified

Details on results (P0)

Study 1.No evidence of maternal toxicity.

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
> 5 000 - <= 10 000 mg/kg bw/day
Based on:
test mat.
Sex:
female
Basis for effect level:
clinical signs
body weight and weight gain
food consumption and compound intake
haematology
organ weights and organ / body weight ratios
gross pathology
histopathology: non-neoplastic
reproductive function (oestrous cycle)
reproductive function (sperm measures)
other: Effects: Negative maternal toxicity was observed in pregnant mouse.
Remarks on result:
other: No toxic effects observed

Target system / organ toxicity (P0)

Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified

Results: F1 generation

General toxicity (F1)

Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality / viability:
no mortality observed
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

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not specified

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not specified

Details on results (F1)

Study 1.The few malformations observed among the fetuses which is not significant.

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
5 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
gross pathology
Remarks on result:
other: No developmental toxic effects observed

Target system / organ toxicity (F1)

Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified

Overall reproductive toxicity

Reproductive effects observed:
not specified
Treatment related:
not specified

Applicant's summary and conclusion

Conclusions:
The no observed adversed effect level (NOAEL) for reproductive toxicity is considered to be 5000 mg/kg bw/day.When female mice treated with test material orally.
Executive summary:

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

Study 1.

A reproductive study was conducted to evaluate the maternal toxicity effects by test material in mouse orally. In first group25 pregnant mice and in second group31 pregnant micewere fed diets containing test substance and in first control group 26pregnant mice and in second control group 28pregnant mic ewere fed untreated feed on daily basis for 6 to 15 days of gestation. During study period test animals were given 0(vehicle), 5000, 10000 mg/kg bw/day.Test material does not show any maternal toxicity. The few malformations observed among the fetuses which is not significant.Hence the no observed adversed effect level (NOAEL) for reproductive toxicity is considered to be 5000 mg/kg bw/day.When female mice treated with test material orally.

Study 2.

13 weeks toxicity study of test material was performed on male and femaleF344/N rats. Animalswere quarantined and acclimated to laboratory conditions for 14 days prior to study start.10 rats /sex/ group were received receiving diets containing0, 620, 1250, 2500, 5000, 10000mg/kg (0, 0.62%, 1.25%, 2.5%, 5.0% or 10%) test material continuously for 13 weeks. Formulated diets were prepared by blending the appropriate amount of test material with a small quantity of feed to prepare a premix. The premix then was layered between the required amounts of feed in a twin-shell blender and blended for 15 minutes to achieve a uniform mix. Formulated diets were stored for no longer than 3 weeks at 5°C; feed hoppers in the animal cages were changed twice weekly. All the animals were observed twice daily for clinical signs.Body weights were recordedinitially and every week thereafter.At the study termination, all animals were euthanized by CO2 anesthesia, and complete necropsies were performed. Complete histopathology examinations were conducted on all rats. Sperm motility and morphology were evaluated at necropsy, and vaginal cytology was evaluated.No mortality observed.No significant differences in average food consumption among each sex were observed, although food consumption of male and female rats in 10000mg/kg dose group was slightly lower than that of controls. Group mean body weights of male rats did not differ significantly from controls, Mean body weights of exposed female rats were slightly lower than the mean body weights of controls but the differences were not dose-related. Haematological effects were not considered biologically significant. Absolute liver weights and the liver-to-body-weight ratio were increased in male rats in 10000mg/kg dose group. Using light microscopy, it was determined there were no morphologic changes associated with the slight differences in organ weights between groups. In male rats, there was a slight decrease in epididymal weight (6-7%) which occurred in the 5000 and 10000 mg/kg dose groups, but this was not dose-related. There were no effects on any other male rat reproductive endpoint, or on any female rat reproductive endpoint. Although there was some variation in epididymal weights, their small magnitude and the absence of changes in other endpoints suggested that there was little or no evidence of any reproductive toxicity associated test material. Histopathology examination revealed an absence of compound-related lesions in any organ or tissue of rats exposed to test material. HenceNo Observed Adverse Effect Level (NOAEL) for reproductive toxicity was considered to be 10000mg/kg, whenmale and femalerats were treated withtest material orallyover 13 weeks.

 

Based on the data available from different studies test chemical did not showedreproductive toxicityat dose concentration 1000mg/kg bw/day by oral route.Hence the test chemical is not likely to classify as a reproductive toxicant as per the criteria mentioned in CLP regulation.