Registration Dossier
Registration Dossier
Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.
The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.
Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: 204-841-6 | CAS number: 127-41-3
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- 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
- Remarks:
- Experimental data from various test chemicals
- Justification for type of information:
- Data for the target chemical is summarized based on data from various test chemicals
Cross-referenceopen allclose all
- Reason / purpose for cross-reference:
- read-across source
Reference
- Endpoint:
- 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 is from peer reviewed journal
- Qualifier:
- according to guideline
- Guideline:
- other: Refer below principle
- Principles of method if other than guideline:
- Test chemical was evaluated for developmental toxicity in presumed pregnant Sprague-Dawley rats.
- GLP compliance:
- not specified
- Limit test:
- no
- Species:
- rat
- Strain:
- other: Crl:CD® (SD) IGS BR VAF®/Plus
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Raleigh, NC
- Age at study initiation: 6-8 weeks old
- Weight at study initiation: Females: 213 to 241 g,
- Fasting period before study: No data available
- Housing: Animals were housed individually in cage.
- Diet (e.g. ad libitum): Certified Rodent DietR 5002 (PMI Nutrition International, St. Louis, MO), ad libitum
- Water (e.g. ad libitum): reverse osmosis deionized water (with chlorine added to the processed water as a bacteriostat), ad libitum
- Acclimation period: acclimatizated for short period.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17.7 ± 26.11°C
- Humidity (%): 30% to 70%
- Air changes (per hr):at least 10 changes per hour of 100% fresh air passed through 99.97% HEPA filters.
- Photoperiod (hrs dark / hrs light): 12:12-h light-dark lighting cycle was used
IN-LIFE DATES: From: To: No data available - Route of administration:
- oral: gavage
- Type of inhalation exposure (if applicable):
- not specified
- Vehicle:
- corn oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
Dosing formulations were prepared daily from bulk materials. Samples from each concentration of the dosing suspensions (first and last days of treatment) were analyzed for the test chemical content.3 mg/ml conc.level was found to be stable for 10 days when stored at ambient conditions and protected from light.
DIET PREPARATION
- Rate of preparation of diet (frequency):Not applicable
- Mixing appropriate amounts with (Type of food): Not applicable
- Storage temperature of food: Not applicable
VEHICLE
- Justification for use and choice of vehicle (if other than water): corn oil
- Concentration in vehicle: 0, 3, 10 and 30 mg/kg/day
- Amount of vehicle (if gavage): 10 ml/kg
- Lot/batch no. (if required): 103K0107 and 074K0025
- Purity: Not available - Analytical verification of doses or concentrations:
- not specified
- Details on mating procedure:
- - M/F ratio per cage:1:1
- Length of cohabitation:5 days
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility:Not available
- Further matings after two unsuccessful attempts:Not available
- Verification of same strain and source of both sexes:Not available
- Proof of pregnancy: The presence of spermatozoa and/or a copulatory plug in situ was designated as gestational day 0 (GD 0).
- Any other deviations from standard protocol:Not available - Duration of treatment / exposure:
- 11 days (gestational days 7 to 17)
- Frequency of treatment:
- Daily
- Duration of test:
- gestational day 21
- Remarks:
- Doses / Concentrations:
0, 3, 10, or 30 mg/kg/day
Basis:
no data - No. of animals per sex per dose:
- Total:100
Control(0)-25 female pregnant rats
3 mg/kg/day-25 female pregnant rats
10 mg/kg/day-25 female pregnant rats
30 mg/kg/day-25 female pregnant rats - Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: Dosages were selected on the basis of range-finding study. dosages of 0, 1.25, 2.5, 5, or 10 mg/kg/day were administered daily to 8 rats/group on GDs 7 to 17. No adverse test chemical related clinical signs and food consumption observed. During the post dosage period, the body weight gains remained increased. All rats were pregnant and all caesarean sectioning and litter observations were comparable among the five groups. No fetal gross external alterations were observed. Based on these data, a dosage greater than 10 mg/kg/day AIM was recommended for the definitive developmental toxicity study in rats.
- Rationale for animal assignment (if not random): The healthy, mated female rats, weighing 213 to 241 g, were assigned to four dosage groups, 25 rats/group, using a computer-generated (weight-ordered) randomization procedure based on body weights recorded on initiation of study.
- Rationale for selecting satellite groups:No data avaiable
- Post-exposure recovery period in satellite groups: No data avaiable
- Section schedule rationale (if not random):No data avaiable - Maternal examinations:
- CAGE SIDE OBSERVATIONS: yes, survival observed. Animals were observed twice daily for viability and examined for abnormal clinical signs
DETAILED CLINICAL OBSERVATIONS: Yes
BODY WEIGHT: Yes, Body weights were recorded prior to the start of the study and daily during the dosage and postdosage periods.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes, Feed consumption was recorded on GDs 0, 7, 10, 12, 15, 18, and 21
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
POST-MORTEM EXAMINATIONS: Yes
POST-MORTEM EXAMINATIONS: Yes / No / No data
- Sacrifice on gestation day # On gestational day 21.
- Organs examined: Yes, Organ weight and gross pathology were examined.
OTHER: abortions and premature deliveries- - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes - Fetal examinations:
- - External examinations: Yes
- Soft tissue examinations: Yes
- Skeletal examinations: Yes
- Head examinations: No data - Statistics:
- Continuous data were analyzed by using Bartlett’s test of homogeneity of variances and the analysis of variance. Dunnett’s test was used to identify statistical significance of individual groups. If the analysis of variance was not appropriate, the Kruskal-Wallis test or Dunn’s method of multiple comparisons was used to identify the statistical significance of the individual groups. If there were greater than 75% ties, Fisher’s exact test was used to analyze the data.
- Indices:
- Dead or resorbed conceptuses indice and live male fetuses indice were examined.
- Historical control data:
- No data avaialble
- Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Chromorhinorrhea, excess salivation, sparse hair coat, localized alopecia, urine-stained abdominal fur, soft or liquid feces, or decreased activities were observed in a few animals from each group of rats. None of these clinical signs were attributed to treatment because the number of affected rats was not dosage related and did not significantly differ between control and treated groups.
- Dermal irritation (if dermal study):
- not specified
- Mortality:
- no mortality observed
- Description (incidence):
- No effect was observed on survival of treated female rats as compared to control.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- No effects were observed on body weight and body weight gain of treated female rat during dosing and post dosage period (GDs 18 to 21).
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- Absolute feed consumption was 101.0%, 102.1%, and 102.6% of the control value for 3, 10, and 30 mg/kg/day dose group.
No effect was observed on food consumption of treated female rats as compared to control. - Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- not specified
- Clinical biochemistry findings:
- not specified
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- not specified
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- No alterations were observed on litters with fetuses and % fetuses/litter in treated female rats as compared to control.
- Neuropathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- not specified
- Histopathological findings: neoplastic:
- not specified
- Other effects:
- not specified
- Number of abortions:
- not specified
- Pre- and post-implantation loss:
- not specified
- Total litter losses by resorption:
- no effects observed
- Description (incidence and severity):
- No significant effect were observed litter sizes, live fetuses, resorptions
- Early or late resorptions:
- no effects observed
- Description (incidence and severity):
- No significant effect were observed
- Dead fetuses:
- no effects observed
- Description (incidence and severity):
- No significant effect were observed percentage of live male fetuses of treated female rats as compared to control.
- Changes in pregnancy duration:
- no effects observed
- Changes in number of pregnant:
- not specified
- Other effects:
- not specified
- Details on maternal toxic effects:
- Maternal toxic effects:no effects
Details on maternal toxic effects:
Mortality: No effect was observed on survival of treated female rats as compared to control.
Clinical sing: Chromorhinorrhea, excess salivation, sparse hair coat, localized alopecia, urine-stained abdominal fur, soft or liquid feces, or decreased activities were observed in a few animals from each group of rats.
None of these clinical signs were attributed to treatment because the number of affected rats was not dosage related and did not significantly differ between control and treated groups.
Body weight and body weight gain: No effects were observed on body weight and body weight gain of treated female rat during dosing and post dosage period (GDs 18 to 21).
Food consumption: Absolute feed consumption was 101.0%, 102.1%, and 102.6% of the control value for 3, 10, and 30 mg/kg/day dose group.
No effect was observed on food consumption of treated female rats as compared to control.
Reproductive performence: No significant effect were observed on corpora lutea, implantations, litter sizes, live fetuses, resorptions, percentage of dead or resorbed conceptuses and percentage of live male fetuses of treated female rats as compared to control.
Gross pathology: No alterations were observed on litters with fetuses and % fetuses/litter in treated female rats as compared to control. - Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 30 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- clinical signs
- food efficiency
- gross pathology
- maternal abnormalities
- mortality
- Remarks on result:
- other: No toxic effects were observed
- Abnormalities:
- not specified
- Localisation:
- not specified
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- No effect was observed on fetus weight in treated groups as compared to control.
- Reduction in number of live offspring:
- no effects observed
- Description (incidence and severity):
- No effect was observed on number of live fetuses in treated groups as compared to control.
- Changes in sex ratio:
- not specified
- Changes in litter size and weights:
- not specified
- Changes in postnatal survival:
- not specified
- External malformations:
- not specified
- Skeletal malformations:
- effects observed, treatment-related
- Description (incidence and severity):
- Limited to infrequent incidences of skeletal variations as delayed ossification at various bone ossification centers (non–dose dependent) and the presence of cervical ribs at the 7th cervical vertebra in four foetuses of 30 mg/kg/day and in control.
- Visceral malformations:
- not specified
- Other effects:
- not specified
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:no effects
Details on embryotoxic / teratogenic effects:
Mortality: No effect was observed on number of live fetuses in treated groups as compared to control.
Fetus weight: No effect was observed on fetus weight in treated groups as compared to control.
Gross pathology: No gross external fetal alterations were observed in treated rats as compared to control.
Soft tissue malformations:
Limited to infrequent incidences of skeletal variations as delayed ossification at various bone ossification centers (non–dose dependent) and the presence of cervical ribs at the 7th cervical vertebra in four foetuses of 30 mg/kg/day and in control.
Folded retinas in seven foetuses and aberrant umbilical artery in two fetuses at 10 mg/kg/day
Slight dilation of the renal pelvis in one fetus at 3 mg/kg/day was observed.
All fetal gross external, soft tissue, or skeletal alterations (malformations or variations) were considered unrelated to test material
because (1) neither the fetal nor litter incidences were dosage dependent; (2) the incidences did not significantly differ from the control group values; and/or (3) the incidences were within the ranges observed historically at the Testing Facility. - Dose descriptor:
- NOAEL
- Effect level:
- >= 30 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- reduction in number of live offspring
- fetal/pup body weight changes
- changes in litter size and weights
- skeletal malformations
- Remarks on result:
- other: All fetal gross external, soft tissue, or skeletal alterations (malformations or variations) were considered unrelated to test material
- Key result
- Abnormalities:
- no effects observed
- Localisation:
- other: not specified
- Developmental effects observed:
- not specified
- Treatment related:
- not specified
- Conclusions:
- The no observed adverse effect level (NOAEL) was considered to be 30 mg/kg/day for F0 and F1 generation when Crl:CD® (SD) IGS BR VAF®/Plus female rats treated with test material.
- Executive summary:
Developmental study was initiated to study the toxicity of test material . In this study, Crl:CD® (SD) IGS BR VAF®/Plus male and female rats were mated for 5 days and the presence of spermatozoa and/or a copulatory plug in situ was designated as gestational day 0 (GD 0). The test material in a corn oil vehicle was administered orally via gavage to four groups of presumed pregnant rats on GDs 7 to 17 at dosages of 0, 3, 10, or 30 mg/kg/day. No effects were observed on survival, body weight and body weight gain and food consumption of treated female rats as compared to control. Chromorhinorrhea, excess salivation, sparse hair coat, localized alopecia, urine-stained abdominal fur, soft or liquid feces, or decreased activities were observed in a few animals from each group of rats. None of these clinical signs were attributed to treatment because the number of affected rats was not dosage related and did not significantly differ between control and treated groups. Similarly, No significant effect were observed on corpora lutea, implantations, litter sizes, live fetuses, resorptions, percentage of dead or resorbed conceptuses and percentage of live male fetuses and no alterations were observed on litters with fetuses and % fetuses/litter in treated female rats as compared to control. In addition, no effects were observed on number of live fetuses, fetus weight and on gross external fetal alterations in treated rats as compared to control. Limited to infrequent incidences of skeletal variations as delayed ossification at various bone ossification centers (non–dose dependent) and the presence of cervical ribs at the 7thcervical vertebra in four foetuses were observed in 30 mg/kg/day and in control. Folded retinas in seven foetuses and aberrant umbilical artery in two fetuses at 10 mg/kg/day and Slight dilation of the renal pelvis in one fetus at 3 mg/kg/day was observed. All fetal gross external, soft tissue, or skeletal alterations (malformations or variations) were considered unrelated to treatment because (1) neither the fetal nor litter incidences were dosage dependent; (2) the incidences did not significantly differ from the control group values; and/or (3) the incidences were within the ranges observed historically at the Testing Facility. Therefore, the no observed adverse effect level (NOAEL) was considered to be 30 mg/kg/day for F0 and F1 generation when Crl: CD® (SD) IGS BR VAF®/Plus female rats were treated with test material orally by gavage for 11 days.
- Reason / purpose for cross-reference:
- read-across source
Reference
- Endpoint:
- 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 is from peer reviewed publication
- Qualifier:
- according to guideline
- Guideline:
- other: Refer below principle
- Principles of method if other than guideline:
- The reproductive and embryotoxic effect of test material was evaluated in pregnant Wistar rats.
- GLP compliance:
- not specified
- Limit test:
- no
- Species:
- rat
- Strain:
- Wistar
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Center for Breeding of Laboratory Animals, Oswaldo Cruz Foundation
- Age at study initiation: No data available
- Weight at study initiation: approx. 220 g (200-250 g)
- Fasting period before study: No data available
- Housing: Animals were housed in standard plastic cages with stainless steel cover lids and wood shavings as bedding in a controlled environment.
- Diet (e.g. ad libitum): Nuvital diet, ad libitum
- Water (e.g. ad libitum): Tap water, ad libitum
- Acclimatization period: No data available
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23±1°C
- Humidity (%):70%
- Air changes (per hr): No data available
- Photoperiod (hrs dark / hrs light): 12-hr dark/12-hr light - Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: The test chemical was mixed with corn oil at dose level of 0, 500, 1000 and 1500 mg/kg body wt
DIET PREPARATION-Not available
VEHICLE
- Justification for use and choice of vehicle (if other than water): Corn oil
- Concentration in vehicle: 0,250, 500, 750 or 1000 mg/kg/day
- Amount of vehicle (if gavage): No data available
- Lot/batch no. (if required): No data available
- Purity: No data available - Analytical verification of doses or concentrations:
- not specified
- Details on mating procedure:
- - M/F ratio per cage: 1:2
- Length of cohabitation: 2 h
- Proof of pregnancy: Confirmed by the presence of sperm in the vaginal smear.The day on which spermatozoa were found in the smear was designated as day 0 ofpregnancy.
- After … days of unsuccessful pairing replacement of first male by another male with proven fertility:Not available
- Further matings after two unsuccessful attempts: [no / yes (explain)]: Not available
- After successful mating each pregnant female was caged (how): singly
- Any other deviations from standard protocol: Not available - Duration of treatment / exposure:
- Once (on Day 11 of pregnancy)
- Frequency of treatment:
- Once
- Duration of test:
- 21 days
- Remarks:
- Doses / Concentrations:
0, 250, 500, 750 or 1000 mg/kg bw
Basis:
actual ingested - No. of animals per sex per dose:
- Total: 65
0 mg/kg bw : 22 pregnant females
250 mg/kg/day: 12 pregnant females
500 mg/kg/day: 9 pregnant females
750 mg/kg/day: 12 pregnant females
1000 mg/kg/day: 10 pregnant females - Control animals:
- yes, concurrent vehicle
- Details on study design:
- Mating performed (8:00-10:00 h) for 2h.The rats were given single dose of beta-Ionone only on day 11 of pregnancy and on day 21 of gestation dams were anesthesized and killed by CO2 inhalation.
- Maternal examinations:
- Body weight gain: Yes
The rats were weighed on days 0, 11 and 21 of pregnancy. - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: No
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes - Fetal examinations:
- -Fetal body weight: Yes
- External examinations (incl. anomalies): Yes
- Head examinations: Yes
The living fetuses were weighed, numbered with a marker pen, examined for externally visible anomalies under a stereomicroscope and fixed in a 5% formalin solution.
The externally visible skull defects were scored for severity. - Statistics:
- The data were analysed by the one-way analysis of variance (ANOVA) followed by the Scheffe’s test for multiple comparisons or, alternatively, by the Kruskal-Wallis test followed by the Mann-Whitney U-test whenever the variable did not fit a normal distribution. Proportions were analyzed by the chi square -test or, alternatively, by the Fisher’s exact test.
- Indices:
- Not available
- Historical control data:
- Not available
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- No overt signs of maternal toxicity were observed as compared to control.
- Dermal irritation (if dermal study):
- not specified
- Mortality:
- not specified
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- No dose-related reduction of pregnancy weight gain were observed in treated rats.
- 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:
- effects observed, treatment-related
- Description (incidence and severity):
- Decreased gravid uterus weight were observed in dams exposed to 1000 mg/kg/day.
- Gross pathological findings:
- not specified
- Neuropathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- not specified
- Histopathological findings: neoplastic:
- not specified
- Other effects:
- not specified
- Number of abortions:
- not specified
- Pre- and post-implantation loss:
- not specified
- Total litter losses by resorption:
- not specified
- Early or late resorptions:
- effects observed, treatment-related
- Description (incidence and severity):
- When treated with 1000 mg/kg/day of test material the ratio of resorptions per implantations, and the percentage of resorptions per implantations per litter were substantially increased
- Dead fetuses:
- not specified
- Changes in pregnancy duration:
- not specified
- Changes in number of pregnant:
- not specified
- Other effects:
- not specified
- Details on maternal toxic effects:
- Maternal toxic effects:no effects. Remark: No dose related effects observed
Details on maternal toxic effects:
Clinical sign: No overt signs of maternal toxicity were observed as compared to control.
Body weight gain: No dose-related reduction of pregnancy weight gain were observed in treated rats.
Reproductive performance-When treated with 1000 mg/kg/day of BI the ratio of resorptions per implantations, and the percentage of resorptions per implantations per litter were substantially increased, while the ratio of live fetuses per implantations per litter was drastically decreased.
Organ weights-Decreased gravid uterus weight were observed in dams exposed to 1000 mg/kg/day. - Dose descriptor:
- NOAEL
- Effect level:
- 750 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: maternal toxicity
- Remarks on result:
- other: No toxic effects were observed
- Abnormalities:
- not specified
- Localisation:
- not specified
- Fetal body weight changes:
- not specified
- Reduction in number of live offspring:
- effects observed, treatment-related
- Description (incidence and severity):
- When treated with 1000 mg/kg/day of BI the ratio of live fetuses per implantations per litter was drastically decreased.
- Changes in sex ratio:
- not specified
- Changes in litter size and weights:
- not specified
- Changes in postnatal survival:
- not specified
- External malformations:
- no effects observed
- Description (incidence and severity):
- No externally-visible anomaly and skull defects were observed in fetuses of treated rats as compared to control.
- Skeletal malformations:
- not specified
- Visceral malformations:
- not specified
- Other effects:
- not specified
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:no effects
Details on embryotoxic / teratogenic effects:
Gross pathology:
No externally-visible anomaly and skull defects were observed in fetuses of treated rats as compared to control. - Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- not specified
- Basis for effect level:
- other: embryotoxicity
- Remarks on result:
- other: No externally-visible anomaly and skull defects were observed in fetuses of treated rats as compared to control.
- Abnormalities:
- not specified
- Developmental effects observed:
- not specified
- Treatment related:
- not specified
- Conclusions:
- The no observed adverse effect level (NOAEL) was considered to be 750 mg/kg bw for P generation and 1000 mg/kg bw for F1 generation when Wistar female rats were treated with test material once orally by gavage in corn oil.
- Executive summary:
In a teratogenicity study, Wistar female rats were treated with test material in the concentration of 250, 500, 750 and 1000 mg/kg body weight orally by gavage in corn oil at day 11 of pregnancy. No overt signs of maternal toxicity and effect on body weight gain were observed in treated rats as compared to control. Substantially increased in ratio of resorptions per implantations, and the percentage of resorptions per implantations per litter, while the ratio of live fetuses per implantations per litter was drastically decreased at 1000 mg/kg bw in treated rats as compared to control. Similarly, Decreased in gravid uterus weight were observed in dams treated with 1000 mg/kg/day. In addition, no significant effect on externally-visible anomaly and skull defects were observed in fetuses of treated rats as compared to control. Therefore, the no observed adverse effect level (NOAEL) was considered to be 750 mg/kg bw for P generation and 1000 mg/kg bw for F1 generation when Wistar female rats were treated with test material once orally by gavage in corn oil at day 11 of pregnancy.
Table 1:Maternal section data and caesarean section data of rats treated orally with test material only:
Sr.No. |
Parameters |
Dose (mg/kg bw) |
||||
|
|
0 |
250 |
500 |
750 |
1000 |
1. |
Pregnant females (N) |
22 |
12 |
9 |
12 |
10 |
2. |
Resorption of the whole litter (N) |
0 |
0 |
1 |
1 |
9 |
3. |
Gravid uterus weight (g ) |
66.99+-10.8 |
83 89+-11.9 |
61.69+-30.2 |
70.29+-30.0 |
4.69+-12.5 |
4. |
Maternal weight gain (Days 0 -21(minus uterus wt) |
45.99+-16.8 |
40.49+-14.4 |
64.99+-11.1 |
39.09+-19.2 |
49.09+-16.1 |
5. |
Implantation sites |
|
|
|
|
|
|
Total (N) |
267 |
173 |
121 |
159 |
120 |
|
Per litter (mean+-SD) |
12.19+-1.9 |
14.49+-1.4 |
13.49+-2.3 |
13.39+-3.6 |
12.09+-1.9 |
6. |
Resorptions |
|
|
|
|
|
|
Total (N) |
35 |
16 |
36 |
31 |
114 |
|
Per implantation sites (%) |
13.1 |
9.2 |
29.8 |
19.5 |
95.0 |
|
Per implantation per litter (%) |
9.2 |
6.4 |
11.1 |
11.8 |
100.0 |
7. |
Live fetuses Per implantation sites (%) |
86.9 |
90.8 |
70.2 |
80.5 |
5.0 |
8. |
Fetal body weight Per litter |
4.889+-0.36
|
4.829+-0.23 |
4.889+-0.18
|
4.969+-0.27 |
- |
Data source
Reference
- Reference Type:
- review article or handbook
- Title:
- WoE of developmental toxicity study for CAS no 127-41-3
- Author:
- Sustainability Support Services (Europe) AB
- Year:
- 2 019
- Bibliographic source:
- WoE report, Sustainability Support Services (Europe) AB, 2019
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- other: Refer below principle
- Principles of method if other than guideline:
- WoE for the target CAS is summarized based on data from various test chemicals
- GLP compliance:
- not specified
- Limit test:
- no
Test material
- Reference substance name:
- 3-methyl-4-(2,6,6-trimethyl-2-cyclohexen-1-yl)-3-buten-2-one
- EC Number:
- 204-846-3
- EC Name:
- 3-methyl-4-(2,6,6-trimethyl-2-cyclohexen-1-yl)-3-buten-2-one
- Cas Number:
- 127-51-5
- Molecular formula:
- C14-H22-O
- IUPAC Name:
- 3-methyl-4-(2,6,6-trimethyl-2-cyclohexen-1-yl)-3-buten-2-one
- Details on test material:
- - Name of test material: Alpha-iso-methylionone
- Molecular formula: C14H22O
- Molecular weight: 206.328 g/mol
- Substance type: Organic
- Physical state: Liquid
Constituent 1
Test animals
- Species:
- rat
- Strain:
- other: 2. Crl:CD® (SD) IGS BR VAF®/Plus; 3. Wistar
- Details on test animals or test system and environmental conditions:
- 2. TEST ANIMALS
- Source: Charles River Laboratories, Raleigh, NC
- Age at study initiation: 6-8 weeks old
- Weight at study initiation: Females: 213 to 241 g,
- Fasting period before study: No data available
- Housing: Animals were housed individually in cage.
- Diet (e.g. ad libitum): Certified Rodent DietR 5002 (PMI Nutrition International, St. Louis, MO), ad libitum
- Water (e.g. ad libitum): reverse osmosis deionized water (with chlorine added to the processed water as a bacteriostat), ad libitum
- Acclimation period: acclimatizated for short period.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17.7 ± 26.11°C
- Humidity (%): 30% to 70%
- Air changes (per hr):at least 10 changes per hour of 100% fresh air passed through 99.97% HEPA filters.
- Photoperiod (hrs dark / hrs light): 12:12-h light-dark lighting cycle was used
IN-LIFE DATES: From: To: No data available
3. TEST ANIMALS
- Source: Center for Breeding of Laboratory Animals, Oswaldo Cruz Foundation
- Age at study initiation: No data available
- Weight at study initiation: approx. 220 g (200-250 g)
- Fasting period before study: No data available
- Housing: Animals were housed in standard plastic cages with stainless steel cover lids and wood shavings as bedding in a controlled environment.
- Diet (e.g. ad libitum): Nuvital diet, ad libitum
- Water (e.g. ad libitum): Tap water, ad libitum
- Acclimatization period: No data available
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23±1°C
- Humidity (%):70%
- Air changes (per hr): No data available
- Photoperiod (hrs dark / hrs light): 12-hr dark/12-hr light
Administration / exposure
- Route of administration:
- oral: gavage
- Type of inhalation exposure (if applicable):
- not specified
- Vehicle:
- corn oil
- Details on exposure:
- 2. PREPARATION OF DOSING SOLUTIONS:
Dosing formulations were prepared daily from bulk materials. Samples from each concentration of the dosing suspensions (first and last days of treatment) were analyzed for the test chemical content.3 mg/ml conc.level was found to be stable for 10 days when stored at ambient conditions and protected from light.
DIET PREPARATION
- Rate of preparation of diet (frequency):Not applicable
- Mixing appropriate amounts with (Type of food): Not applicable
- Storage temperature of food: Not applicable
VEHICLE
- Justification for use and choice of vehicle (if other than water): corn oil
- Concentration in vehicle: 0, 3, 10 and 30 mg/kg/day
- Amount of vehicle (if gavage): 10 ml/kg
- Lot/batch no. (if required): 103K0107 and 074K0025
- Purity: Not available
3. PREPARATION OF DOSING SOLUTIONS: The test chemical was mixed with corn oil at dose level of 0, 500, 1000 and 1500 mg/kg body wt
DIET PREPARATION-Not available
VEHICLE
- Justification for use and choice of vehicle (if other than water): Corn oil
- Concentration in vehicle: 0,250, 500, 750 or 1000 mg/kg/day
- Amount of vehicle (if gavage): No data available
- Lot/batch no. (if required): No data available
- Purity: No data available - Analytical verification of doses or concentrations:
- not specified
- Details on mating procedure:
- 2. - M/F ratio per cage:1:1
- Length of cohabitation:5 days
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility:Not available
- Further matings after two unsuccessful attempts:Not available
- Verification of same strain and source of both sexes:Not available
- Proof of pregnancy: The presence of spermatozoa and/or a copulatory plug in situ was designated as gestational day 0 (GD 0).
- Any other deviations from standard protocol:Not available
3. - M/F ratio per cage: 1:2
- Length of cohabitation: 2 h
- Proof of pregnancy: Confirmed by the presence of sperm in the vaginal smear.The day on which spermatozoa were found in the smear was designated as day 0 of pregnancy.
- After … days of unsuccessful pairing replacement of first male by another male with proven fertility:Not available
- Further matings after two unsuccessful attempts: [no / yes (explain)]: Not available
- After successful mating each pregnant female was caged (how): singly
- Any other deviations from standard protocol: Not available - Duration of treatment / exposure:
- 2. 11 days (gestational days 7 to 17)
3. Once (on Day 11 of pregnancy) - Frequency of treatment:
- 2. Daily
3. Once - Duration of test:
- 2. gestational day 21
3. 21 days
Doses / concentrationsopen allclose all
- Remarks:
- Doses / Concentrations: / 2
0, 3, 10, or 30 mg/kg/day
Basis:
no data
- Remarks:
- Doses / Concentrations: / 3
0, 250, 500, 750 or 1000 mg/kg bw
Basis:
actual ingested
- No. of animals per sex per dose:
- 2. Total:100
Control(0)-25 female pregnant rats
3 mg/kg/day-25 female pregnant rats
10 mg/kg/day-25 female pregnant rats
30 mg/kg/day-25 female pregnant rats
3. Total: 65
0 mg/kg bw : 22 pregnant females
250 mg/kg/day: 12 pregnant females
500 mg/kg/day: 9 pregnant females
750 mg/kg/day: 12 pregnant females
1000 mg/kg/day: 10 pregnant females - Control animals:
- yes, concurrent vehicle
- Details on study design:
- 2. - Dose selection rationale: Dosages were selected on the basis of range-finding study. dosages of 0, 1.25, 2.5, 5, or 10 mg/kg/day were administered daily to 8 rats/group on GDs 7 to 17. No adverse test chemical related clinical signs and food consumption observed. During the post dosage period, the body weight gains remained increased. All rats were pregnant and all caesarean sectioning and litter observations were comparable among the five groups. No fetal gross external alterations were observed. Based on these data, a dosage greater than 10 mg/kg/day AIM was recommended for the definitive developmental toxicity study in rats.
- Rationale for animal assignment (if not random): The healthy, mated female rats, weighing 213 to 241 g, were assigned to four dosage groups, 25 rats/group, using a computer-generated (weight-ordered) randomization procedure based on body weights recorded on initiation of study.
- Rationale for selecting satellite groups:No data avaiable
- Post-exposure recovery period in satellite groups: No data avaiable
- Section schedule rationale (if not random):No data avaiable
3. Mating performed (8:00-10:00 h) for 2h.The rats were given single dose of beta-Ionone only on day 11 of pregnancy and on day 21 of gestation dams were anesthesized and killed by CO2 inhalation.
Examinations
- Maternal examinations:
- 2. CAGE SIDE OBSERVATIONS: yes, survival observed. Animals were observed twice daily for viability and examined for abnormal clinical signs
DETAILED CLINICAL OBSERVATIONS: Yes
BODY WEIGHT: Yes, Body weights were recorded prior to the start of the study and daily during the dosage and postdosage periods.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes, Feed consumption was recorded on GDs 0, 7, 10, 12, 15, 18, and 21
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
POST-MORTEM EXAMINATIONS: Yes
POST-MORTEM EXAMINATIONS: Yes / No / No data
- Sacrifice on gestation day # On gestational day 21.
- Organs examined: Yes, Organ weight and gross pathology were examined.
OTHER: abortions and premature deliveries-
3. Body weight gain: Yes
The rats were weighed on days 0, 11 and 21 of pregnancy. - Ovaries and uterine content:
- 2. The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
3. The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: No
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes - Fetal examinations:
- 2. - External examinations: Yes
- Soft tissue examinations: Yes
- Skeletal examinations: Yes
- Head examinations: No data
3. -Fetal body weight: Yes
- External examinations (incl. anomalies): Yes
- Head examinations: Yes
The living fetuses were weighed, numbered with a marker pen, examined for externally visible anomalies under a stereomicroscope and fixed in a 5% formalin solution.
The externally visible skull defects were scored for severity. - Statistics:
- 2. Continuous data were analyzed by using Bartlett’s test of homogeneity of variances and the analysis of variance. Dunnett’s test was used to identify statistical significance of individual groups. If the analysis of variance was not appropriate, the Kruskal-Wallis test or Dunn’s method of multiple comparisons was used to identify the statistical significance of the individual groups. If there were greater than 75% ties, Fisher’s exact test was used to analyze the data.
3. The data were analysed by the one-way analysis of variance (ANOVA) followed by the Scheffe’s test for multiple comparisons or, alternatively, by the Kruskal-Wallis test followed by the Mann-Whitney U-test whenever the variable did not fit a normal distribution. Proportions were analyzed by the chi square -test or, alternatively, by the Fisher’s exact test. - Indices:
- 2. Dead or resorbed conceptuses indice and live male fetuses indice were examined.
3. Not available - Historical control data:
- No data avaialble
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- 2. Chromorhinorrhea, excess salivation, sparse hair coat, localized alopecia, urine-stained abdominal fur, soft or liquid feces, or decreased activities were observed in a few animals from each group of rats. None of these clinical signs were attributed to treatment because the number of affected rats was not dosage related and did not significantly differ between control and treated groups.
3. No overt signs of maternal toxicity were observed as compared to control. - Dermal irritation (if dermal study):
- not specified
- Mortality:
- no mortality observed
- Description (incidence):
- No effect was observed on survival of treated female rats as compared to control.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- 2. No effects were observed on body weight and body weight gain of treated female rat during dosing and post dosage period (GDs 18 to 21).
3. No dose-related reduction of pregnancy weight gain were observed in treated rats. - Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- 2. Absolute feed consumption was 101.0%, 102.1%, and 102.6% of the control value for 3, 10, and 30 mg/kg/day dose group. No effect was observed on food consumption of treated female rats as compared to control.
- 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:
- effects observed, treatment-related
- Description (incidence and severity):
- 2. No data
3. Decreased gravid uterus weight were observed in dams exposed to 1000 mg/kg/day. - Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- 2. No alterations were observed on litters with fetuses and % fetuses/litter in treated female rats as compared to control.
- Neuropathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- not specified
- Histopathological findings: neoplastic:
- not specified
- Other effects:
- not specified
Maternal developmental toxicity
- Number of abortions:
- not specified
- Pre- and post-implantation loss:
- not specified
- Total litter losses by resorption:
- no effects observed
- Description (incidence and severity):
- No significant effect were observed litter sizes, live fetuses, resorptions
- Early or late resorptions:
- no effects observed
- Description (incidence and severity):
- 2. No significant effect were observed
3. When treated with 1000 mg/kg/day of test material the ratio of resorptions per implantations, and the percentage of resorptions per implantations per litter were substantially increased - Dead fetuses:
- no effects observed
- Description (incidence and severity):
- No significant effect were observed percentage of live male fetuses of treated female rats as compared to control.
- Changes in pregnancy duration:
- no effects observed
- Changes in number of pregnant:
- not specified
- Other effects:
- not specified
- Details on maternal toxic effects:
- 2. Maternal toxic effects:no effects
Details on maternal toxic effects:
Mortality: No effect was observed on survival of treated female rats as compared to control.
Clinical sing: Chromorhinorrhea, excess salivation, sparse hair coat, localized alopecia, urine-stained abdominal fur, soft or liquid feces, or decreased activities were observed in a few animals from each group of rats.
None of these clinical signs were attributed to treatment because the number of affected rats was not dosage related and did not significantly differ between control and treated groups.
Body weight and body weight gain: No effects were observed on body weight and body weight gain of treated female rat during dosing and post dosage period (GDs 18 to 21).
Food consumption: Absolute feed consumption was 101.0%, 102.1%, and 102.6% of the control value for 3, 10, and 30 mg/kg/day dose group.
No effect was observed on food consumption of treated female rats as compared to control.
Reproductive performence: No significant effect were observed on corpora lutea, implantations, litter sizes, live fetuses, resorptions, percentage of dead or resorbed conceptuses and percentage of live male fetuses of treated female rats as compared to control.
Gross pathology: No alterations were observed on litters with fetuses and % fetuses/litter in treated female rats as compared to control.
3. Maternal toxic effects:no effects. Remark: No dose related effects observed
Details on maternal toxic effects:
Clinical sign: No overt signs of maternal toxicity were observed as compared to control.
Body weight gain: No dose-related reduction of pregnancy weight gain were observed in treated rats.
Reproductive performance-When treated with 1000 mg/kg/day of BI the ratio of resorptions per implantations, and the percentage of resorptions per implantations per litter were substantially increased, while the ratio of live fetuses per implantations per litter was drastically decreased.
Organ weights-Decreased gravid uterus weight were observed in dams exposed to 1000 mg/kg/day.
Effect levels (maternal animals)
open allclose all
- Dose descriptor:
- NOAEL
- Remarks:
- 2
- Effect level:
- >= 30 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- clinical signs
- food efficiency
- gross pathology
- maternal abnormalities
- mortality
- Remarks on result:
- other: No toxic effects were observed
- Dose descriptor:
- NOAEL
- Remarks:
- 3
- Effect level:
- 750 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: maternal toxicity: No effects on Maternal weight gain, reproductive performance and organ weight
Maternal abnormalities
- Abnormalities:
- not specified
- Localisation:
- not specified
Results (fetuses)
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- 2. No effect was observed on fetus weight in treated groups as compared to control.
- Reduction in number of live offspring:
- no effects observed
- Description (incidence and severity):
- 2. No effect was observed on number of live fetuses in treated groups as compared to control.
3. When treated with 1000 mg/kg/day of BI the ratio of live fetuses per implantations per litter was drastically decreased. - Changes in sex ratio:
- not specified
- Changes in litter size and weights:
- not specified
- Changes in postnatal survival:
- not specified
- External malformations:
- not specified
- Description (incidence and severity):
- 2. No data
3. No externally-visible anomaly and skull defects were observed in fetuses of treated rats as compared to control. - Skeletal malformations:
- effects observed, treatment-related
- Description (incidence and severity):
- Limited to infrequent incidences of skeletal variations as delayed ossification at various bone ossification centers (non–dose dependent) and the presence of cervical ribs at the 7th cervical vertebra in four foetuses of 30 mg/kg/day and in control.
- Visceral malformations:
- not specified
- Other effects:
- not specified
- Details on embryotoxic / teratogenic effects:
- 2. Embryotoxic / teratogenic effects:no effects
Details on embryotoxic / teratogenic effects:
Mortality: No effect was observed on number of live fetuses in treated groups as compared to control.
Fetus weight: No effect was observed on fetus weight in treated groups as compared to control.
Gross pathology: No gross external fetal alterations were observed in treated rats as compared to control.
Soft tissue malformations:
Limited to infrequent incidences of skeletal variations as delayed ossification at various bone ossification centers (non–dose dependent) and the presence of cervical ribs at the 7th cervical vertebra in four foetuses of 30 mg/kg/day and in control.
Folded retinas in seven foetuses and aberrant umbilical artery in two fetuses at 10 mg/kg/day
Slight dilation of the renal pelvis in one fetus at 3 mg/kg/day was observed.
All fetal gross external, soft tissue, or skeletal alterations (malformations or variations) were considered unrelated to test material
because (1) neither the fetal nor litter incidences were dosage dependent; (2) the incidences did not significantly differ from the control group values; and/or (3) the incidences were within the ranges observed historically at the Testing Facility.
3. Embryotoxic / teratogenic effects:no effects
Details on embryotoxic / teratogenic effects:
Gross pathology:
No externally-visible anomaly and skull defects were observed in fetuses of treated rats as compared to control
Effect levels (fetuses)
open allclose all
- Dose descriptor:
- NOAEL
- Remarks:
- 2
- Effect level:
- >= 30 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- reduction in number of live offspring
- fetal/pup body weight changes
- changes in litter size and weights
- skeletal malformations
- Remarks on result:
- other: All fetal gross external, soft tissue, or skeletal alterations (malformations or variations) were considered unrelated to test material
- Dose descriptor:
- NOAEL
- Remarks:
- 3
- Effect level:
- 1 000 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- not specified
- Basis for effect level:
- other: embryotoxicity: No effect on Fetal body weight, gross pathology and histopathology
Fetal abnormalities
- Key result
- Abnormalities:
- no effects observed
- Localisation:
- other: not specified
Overall developmental toxicity
- Developmental effects observed:
- not specified
- Treatment related:
- not specified
Applicant's summary and conclusion
- Conclusions:
- The no observed adverse effect level (NOAEL) was considered to be 30 mg/kg/day for F0 and F1 generation when rats were treated with test chemical by gavage route of exposure.
- Executive summary:
Data available for various test chemicals was reviewed to determine the developmental toxic nature of the test chemical. The studies are as mentioned below:
Developmental study was initiated to study the toxicity of test material . In this study, Crl:CD® (SD) IGS BR VAF®/Plus male and female rats were mated for 5 days and the presence of spermatozoa and/or a copulatory plug in situ was designated as gestational day 0 (GD 0). The test material in a corn oil vehicle was administered orally via gavage to four groups of presumed pregnant rats on GDs 7 to 17 at dosages of 0, 3, 10, or 30 mg/kg/day. No effects were observed on survival, body weight and body weight gain and food consumption of treated female rats as compared to control. Chromorhinorrhea, excess salivation, sparse hair coat, localized alopecia, urine-stained abdominal fur, soft or liquid feces, or decreased activities were observed in a few animals from each group of rats. None of these clinical signs were attributed to treatment because the number of affected rats was not dosage related and did not significantly differ between control and treated groups. Similarly, No significant effect were observed on corpora lutea, implantations, litter sizes, live fetuses, resorptions, percentage of dead or resorbed conceptuses and percentage of live male fetuses and no alterations were observed on litters with fetuses and % fetuses/litter in treated female rats as compared to control. In addition, no effects were observed on number of live fetuses, fetus weight and on gross external fetal alterations in treated rats as compared to control. Limited to infrequent incidences of skeletal variations as delayed ossification at various bone ossification centers (non–dose dependent) and the presence of cervical ribs at the 7thcervical vertebra in four foetuses were observed in 30 mg/kg/day and in control. Folded retinas in seven foetuses and aberrant umbilical artery in two fetuses at 10 mg/kg/day and Slight dilation of the renal pelvis in one fetus at 3 mg/kg/day was observed. All fetal gross external, soft tissue, or skeletal alterations (malformations or variations) were considered unrelated to treatment because (1) neither the fetal nor litter incidences were dosage dependent; (2) the incidences did not significantly differ from the control group values; and/or (3) the incidences were within the ranges observed historically at the Testing Facility. Therefore, the no observed adverse effect level (NOAEL) was considered to be 30 mg/kg/day for F0 and F1 generation when Crl: CD® (SD) IGS BR VAF®/Plus female rats were treated with test material orally by gavage for 11 days.
In another teratogenicity study, Wistar female rats were treated with test material in the concentration of 250,500, 750 and 1000 mg/kg body weight orally by gavage in corn oil at day 11 of pregnancy.No overt signs of maternal toxicity and effect on body weight gain were observed in treated rats as compared to control. Substantially increased in ratio of resorptions per implantations, and the percentage of resorptions per implantations per litter, while the ratio of live fetuses per implantations per litter was drastically decreased at 1000 mg/kg bw in treated rats as compared to control. Similarly, Decreased in gravid uterus weight were observed in dams treated with 1000 mg/kg/day. In addition, no significant effect on externally visible anomaly and skull defects were observed in fetuses of treated rats as compared to control. Therefore, the no observed adverse effect level (NOAEL) was considered to be 750 mg/kg bw for P generation and 1000 mg/kg bw for F1 generation when Wistar female rats were treated with test material once orally by gavage in corn oil at day 11 of pregnancy.
Based on the details of the study, the no observed adverse effect level (NOAEL) was considered to be 30 mg/kg/day for F0 and F1 generation when rats were treated with test chemical by gavage route of exposure.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
