Registration Dossier
Registration Dossier
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EC number: 500-151-7 | CAS number: 61791-12-6 1 - 6.5 moles ethoxylated
Toxicity to reproduction
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
- 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
- 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
- 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.
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.
Data source
Reference
- Reference Type:
- other company data
- Title:
- Unnamed
- Year:
- 2 018
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
- 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
Constituent 1
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)
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)
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.
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