Registration Dossier

Data platform availability banner - registered substances factsheets

Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.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.

Diss Factsheets

Toxicological information

Developmental toxicity / teratogenicity

Currently viewing:

Administrative data

Endpoint:
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
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:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
secondary literature
Qualifier:
according to guideline
Guideline:
other: Combined repeated and reproductive developmental toxicity screening test
Principles of method if other than guideline:
The above experiment was performed to assess and evaluate the toxicity of the test chemical on the reproductive and developmental toxicity parameters of the Sprague Dawley Rats.
GLP compliance:
not specified
Specific details on test material used for the study:
- Molecular formula (if other than submission substance): C7H14O2
- Molecular weight (if other than submission substance): 130.29 g/mol
- Substance type: Organic
- Physical state: Liquid
Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
No data available
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: No data available

DIET PREPARATION
- Rate of preparation of diet (frequency): No data available
- Mixing appropriate amounts with (Type of food): No data available
- Storage temperature of food: No data available

VEHICLE
- Justification for use and choice of vehicle (if other than water): No data available
- Concentration in vehicle: 0, 200, 1000 or 2000 mg/kg-bw/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 analytical verification of doses or concentrations:
No Data Available
Details on mating procedure:
- M/F ratio per cage: No Data Available
- Length of cohabitation: No data available
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility. No data available
- Further matings after two unsuccessful attempts: No data available
- Verification of same strain and source of both sexes: No data available
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy No data available
- Any other deviations from standard protocol: No data available
Duration of treatment / exposure:
For one week prior to a 7-day cohabitation period through gestation, parturition and a 4-day postpartum period.
Frequency of treatment:
No Data Available
Duration of test:
No Data Available
Remarks:
Doses / Concentrations:
0, 200, 1000 and 2000 mg/kg-bw/day
No. of animals per sex per dose:
No Data Available
Control animals:
yes, concurrent vehicle
Details on study design:
No Data Available
Maternal examinations:
Maternal animals were observed for Mortality, clinical signs, food consumption, body weights, mating and fertility,
Ovaries and uterine content:
Number of implantation and losses were investigated.
Fetal examinations:
Fetal examinations included implantations, length of gestation, proportion of dams delivering live pup or pup viability, Pup weights, malformations and gross lesions.
Statistics:
No Data Available
Indices:
No Data Available
Historical control data:
No Data Available
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
In the 1000 and 2000 mg/kg-bw/day dose groups, significant increases in the incidence of rales (p < 0.01) and excess salivation (p < 0.01) were reported during pre-mating and gestation. High-dose females also exhibited lethargy, unkempt coats and labored breathing.
Dermal irritation (if dermal study):
not specified
Mortality:
mortality observed, treatment-related
Description (incidence):
Mortality occurred in the high-dose group (3 of 10 rats) and mid-dose group (1 of 10 rats)
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Average maternal body weights were decreased on days 10 – 16 of gestation and body weight gains were significantly (p < 0.05) reduced.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
In the high-dose group, food consumption was reduced throughout the study.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Number of abortions:
not specified
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Changes in number of pregnant:
not specified
Other effects:
not specified
Dose descriptor:
NOAEL
Effect level:
200 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
body weight and weight gain
changes in pregnancy duration
dead fetuses
early or late resorptions
effects on pregnancy duration
food consumption and compound intake
mortality
number of abortions
pre and post implantation loss
total litter losses by resorption
Abnormalities:
not specified
Fetal body weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
Pup weights were reduced on day 4 post parturition in the high-dose group.
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): effects observed, non-treatment-related
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.DescriptionIncidenceAndSeverityFetalPupBodyWeightChanges): Pup weights were reduced on day 4 post parturition in the high-dose group.
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
not specified
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
not specified
External malformations:
no effects observed
Skeletal malformations:
not specified
Visceral malformations:
not specified
Other effects:
not specified
Dose descriptor:
NOAEL
Effect level:
2 000 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
external malformations
Abnormalities:
not specified
Developmental effects observed:
not specified
Conclusions:
Based on all the observation it was concluded that, NOAEL was considered to be 200 and 2000 mg/kg body weight/day for the maternal generation and the F1 generation respectively.
Executive summary:
In a reproductive/developmental toxicity study, female Sprague-Dawley rats (10/group) were administered with the test chemical via gavage (in corn oil) at doses of 0, 200, 1000 or 2000 mg/kg-bw/day for one week prior to a 7-day cohabitation period through gestation, parturition and a 4-day postpartum period. The parental animals were observed for Mortality, clinical signs, food consumption, body weights, mating and fertility, while Fetal examinations included implantations, length of gestation, proportion of dams delivering live pup or pup viability, Pup weights, malformations and gross lesions. After all the examinations it was observed that in maternal animals, mortality occured in high dose group. In clinical signs, in the 1000 and 2000 mg/kg-bw/day dose groups, significant increases in the incidence of rales (p < 0.01) and excess salivation (p < 0.01) were reported during pre-mating and gestation. High-dose females also exhibited lethargy, unkempt coats and labored breathing. Also, average maternal body weights were decreased on days 10 – 16 of gestation and body weight gains were significantly (p < 0.05) reduced. In the high-dose group, food consumption was reduced throughout the study. Although, no effects were observed in pre and post implantation loss, resorptions, viability of the pups and pregnancy duration in maternal animals. In pup parameters, no effects were observed in change in number of offsprings and litter size, and no external anomalies were observed at any dose levels. Thus, based on all the observation it was concluded that, NOAEL was considered to be 200 and 2000 mg/kg body weight/day for the maternal generation and the F1 generation respectively.
Reason / purpose for cross-reference:
read-across source
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
secondary literature
Justification for type of information:
Data is from a secondary source.
Qualifier:
according to guideline
Guideline:
other: Combined Repeated and Reproductive Developmental Toxicity Screening Test
Principles of method if other than guideline:
The above experiment was performed to evaluate and assess the reproductive toxicity of the test chemical in rats.
GLP compliance:
not specified
Specific details on test material used for the study:
- Molecular formula (if other than submission substance): C14-H28
- Molecular weight (if other than submission substance): 196.375 g/mol
- Substance type: Organic
- Physical state: No Data Available
- Impurities (identity and concentrations): No Data Available
Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
No data available
Route of administration:
oral: gavage
Vehicle:
not specified
Details on exposure:
Male rats were exposed for 28 days prior to mating, and through mating until euthanasia for a total of 43-47 consecutive days of dosing; while 12 females were dosed for 14 days prior to mating, during mating, gestation and lactation through euthanasia at lactation day 4 (42-51 consecutive days).
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No Data Available
Details on mating procedure:
No Data Available
Duration of treatment / exposure:
Males: 43-47 consecutive days
Females: 42-51 consecutive days
Frequency of treatment:
No Data Available
Duration of test:
No Data Available
Remarks:
Doses / Concentrations:
0, 100, 500 or 1000 mg/kg-bw/day
Basis:
no data
No. of animals per sex per dose:
24 animals were used per group.
Control animals:
yes, concurrent vehicle
Details on study design:
Further details on study design:
- Dose selection rationale: No Data Available
- Rationale for animal assignment (if not random): No Data Available
- Other: No Data Available
Maternal examinations:
The parental animals were observed for neurotoxic and pathological analyses.
Ovaries and uterine content:
No Data Available
Fetal examinations:
Pup viability, pup weights and malformations or gross lesions were observed.
Statistics:
No Data Available
Indices:
Copulation and fertility index, gestational index and pup viability indices
Historical control data:
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
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
It was observed that hepatocyte cytoplasmic vacuolation occurred in both sexes at >500 mg/kg/day (associated with an increase in liver weight), and pitted kidneys and accumulation of hyaline droplets in the proximal convoluted tubules of the kidneys of males at all dose levels. The kidney effects were interpreted to be a result of hydrocarbon nephropathy, which is specific to male rats.
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
The adverse effect observed was liver effect in non-pregnant satellite females histologically examined.
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Number of abortions:
no effects observed
Pre- and post-implantation loss:
not specified
Total litter losses by resorption:
not specified
Early or late resorptions:
not specified
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Changes in number of pregnant:
not specified
Other effects:
not specified
Details on maternal toxic effects:
No Data Available
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
changes in pregnancy duration
dead fetuses
gross pathology
histopathology: non-neoplastic
number of abortions
Abnormalities:
not specified
Fetal body weight changes:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
not specified
External malformations:
no effects observed
Skeletal malformations:
not specified
Visceral malformations:
not specified
Other effects:
not specified
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reduction in number of live offspring
changes in sex ratio
fetal/pup body weight changes
changes in litter size and weights
external malformations
Abnormalities:
not specified
Developmental effects observed:
not specified
Conclusions:
Based on all the above observations it was concluded that the NOEL for parental animals was found to be 100 mg/kg bw/day and the NOAEL for F1 generation was found to be 1000 mg/kg bw/day.
Executive summary:

A combined repeated and reproductive/developmental toxicity screening test was performed to assess and evaluate the reproductive toxicity of the test chemical in rats. In this test, the rats were dosed with the test chemical using three dose groups of 100, 500 and 1000 mg/kg bw/day. A concurrent control group and a satellite group was also used. A total of 14 animals were used per group in this study. Male rats were exposed for 28 days prior to mating, and through mating until euthanasia for a total  of  43-47 consecutive days of dosing; while 12 females were dosed for 14  days prior to mating, during mating, gestation and lactation through euthanasia at lactation day 4 (42-51 consecutive days). The parental animals were observed for pathological changes and neurotoxicity. After the examinations, it was observed that, hepatocyte cytoplasmic vacuolation occurred in both sexes at >500 mg/kg/day (associated with an increase in liver weight), and pitted kidneys and  accumulation of hyaline droplets  in  the  proximal  convoluted  tubules of the kidneys of males at all dose levels. The kidney effects were interpreted to be a result of hydrocarbon nephropathy, which is specific to male rats. Also, the determined NOEL was 100 mg/kg/day which was determined by the effect of liver through histopathological examination in non-pregnant satellite females. In reproductive parameters of the rats, there was no effects observed on copulation and fertility, precoital intervals, gestation length, time  to delivery or unusual nesting behavior. In pup parameters, mortality/viability of the pups, litter size and body weights, male to female pup ratio and external anomalies. After all examinations, no effects were observed in any of the pup parameters. Thus, based on all the above observations it was concluded that the NOEL for parental animals was found to be 100 mg/kg bw/day and the NOAEL for F1 generation was found to be 1000 mg/kg bw/day.

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:
secondary literature
Justification for type of information:
Data is from a secondary literature source.
Qualifier:
according to guideline
Guideline:
other: Reproduction and Developmental Toxicity Screening Test
Principles of method if other than guideline:
The above experiment was performed to evaluate and assess the reproductive and developmental toxicity potential of the test chemical in male and female rats.
GLP compliance:
not specified
Specific details on test material used for the study:
Details on test material:
-Molecular Formula: C6-H12
- Molecular weight (if other than submission substance): 84.1608 g/mol
- Substance type: Organic
- Physical state: No Data Available
- Impurities (identity and concentrations): No Data Available
Species:
rat
Strain:
not specified
Details on test animals or test system and environmental conditions:
No Data Available
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
Details on exposure
PREPARATION OF DOSING SOLUTIONS: No Data Available

DIET PREPARATION:
- Rate of preparation of diet (frequency): No Data Available
- Mixing appropriate amounts with (Type of food): No Data Available
- Storage temperature of food: No Data Available

VEHICLE:
- Justification for use and choice of vehicle (if other than water): The test chemical was best miscible in corn oil.
- Concentration in vehicle: 0, 100, 500 and 1000 mg/kg
- 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 analytical verification of doses or concentrations:
No Data Available
Details on mating procedure:
No Data Available
Duration of treatment / exposure:
Male rats were treated for 28 days prior to mating and for an additional 16 days (44 total days).
Females were dosed for 14 days prior to mating and during mating, gestation and lactation (41-55 days).
Frequency of treatment:
No Data Available
Duration of test:
No Data Available
Dose / conc.:
0 mg/kg bw/day
Remarks:
Control Group
Dose / conc.:
100 mg/kg bw/day
Remarks:
Low Dose Group
Dose / conc.:
500 mg/kg bw/day
Remarks:
Mid Dose Group
Dose / conc.:
1 000 mg/kg bw/day
Remarks:
High Dose Group
No. of animals per sex per dose:
No Data Available
Control animals:
yes, concurrent vehicle
Details on study design:
No Data Available
Maternal examinations:
Maternal animals were examined for precoital intervals, gestation length, pregnancy rats, copulation, fertility indices
Ovaries and uterine content:
No Data Available
Fetal examinations:
Number of litters, pup survival, pup viability, pup weight, and sex ratio.
Statistics:
No Data Available
Indices:
No Data Available
Historical control data:
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:
no effects observed
Gross pathological findings:
not specified
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Details on results:
No Data Availablr
Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Changes in number of pregnant:
no effects observed
Other effects:
not specified
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
changes in number of pregnant
changes in pregnancy duration
dead fetuses
early or late resorptions
effects on pregnancy duration
number of abortions
pre and post implantation loss
total litter losses by resorption
Abnormalities:
not specified
Fetal body weight changes:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
no effects observed
External malformations:
not specified
Skeletal malformations:
not specified
Visceral malformations:
not specified
Other effects:
not specified
Details on embryotoxic / teratogenic effects:
No Data Available
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reduction in number of live offspring
changes in sex ratio
fetal/pup body weight changes
changes in litter size and weights
changes in postnatal survival
Abnormalities:
not specified
Developmental effects observed:
not specified
Treatment related:
not specified
Relation to maternal toxicity:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified
Conclusions:
Based on all the above observations, it was concluded that, the NOAEL for both maternal and fetal parameters based on the test chemical was found to be 1000 mg/kg bw/day.
Executive summary:

An experiment was conducted to assess the reproductive and developmental toxicity potential of the test chemical in rats. In this experiment, the test chemical was mixed with the corn oil and administered orally to the animals in the dose groups of 0, 100, 500 and 1000 mg/kg bw/day. Male rats were treated for 28 days prior to mating and for an additional 16 days (44 total days). Females were dosed for 14 days prior to mating and during mating, gestation and lactation (41-55 days). During and after the dosing the animals were observed for any adverse effects of the test chemicals. After dosing, it was observed that there were no adverse effects observed in maternal animals at any given dose levels. However, in male rats, absolute epididymal weights for males were statistically lower in all treated groups compared to controls and the epididymal/brain relative weights were also lower in all treated groups compared to controls, although only the low dose group was statistically significant. The biological significance of the decreased epididymal weights was found to be uncertain because of no apparent histopathological effects in the epididymis and no evidence of impared fertility in the treated males and there was a lack of a dose response between treated groups. In maternal parameters, there were no effects on the following reproductive parameters: precoital intervals, gestation length, pregnancy rats, copulation and fertility indices. Also, in developmental parameters, it was observed that, there were no effects on the number of litters, pup survival, pup viability, pup weight, and sex ratio. Thus, based on all the above observations, it was concluded that, the NOAEL for both maternal and fetal parameters based on the test chemical was found to be 1000 mg/kg bw/day.

Data source

Reference
Reference Type:
publication
Title:
WoE for developmental toxicity study for CAS no 112-45-8
Author:
Sustainability Support Services (Europe) AB
Year:
2018
Bibliographic source:
WoE report, Sustainability Support Services (Europe) AB, 2018

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
other: Study 2: Combined Repeated and Reproductive Developmental Toxicity Screening Test
Qualifier:
according to guideline
Guideline:
other: Study 3: Combined Repeated and Reproductive Developmental Toxicity Screening Test
Qualifier:
according to guideline
Guideline:
other: Study 4: Reproductive and Developmental Toxicity Screening Test
Principles of method if other than guideline:
WoE report is based on three developmental toxicity studies on rats:
Study 2 and 3: Combined Repeated and Reproductive Developmental Toxicity Screening Test
Study 4: Reproductive and Development Toxicity Screning Test
All the above experiments were performed to assess and evaluate the reproducive and developmental toxicity of the test chemical in the test animals (rats).
GLP compliance:
not specified

Test material

Constituent 1
Chemical structure
Reference substance name:
Undec-10-enal
EC Number:
203-973-1
EC Name:
Undec-10-enal
Cas Number:
112-45-8
Molecular formula:
C11H20O
IUPAC Name:
undec-10-enal
Details on test material:
- Molecular formula (if other than submission substance): C11-H20-O
- Molecular weight (if other than submission substance): 168.278 g/mole
- Substance type: Organic
Specific details on test material used for the study:
- Molecular formula (if other than submission substance): C11-H20-O
- Molecular weight (if other than submission substance): 168.278 g/mole
- Substance type: Organic

Test animals

Species:
rat
Strain:
other: Study 2 and 3: Sprague Dawley; Study 3: Not Specified
Details on test animals or test system and environmental conditions:
Study 2, Study 3 and 4: No Data Available

Administration / exposure

Route of administration:
other: Study 2, 3 and 4: Oral
Vehicle:
other: Study 2 and 4: Corn Oil and Study 3: Not Specified
Details on exposure:
Study 2: PREPARATION OF DOSING SOLUTIONS: No data available

DIET PREPARATION
- Rate of preparation of diet (frequency): No data available
- Mixing appropriate amounts with (Type of food): No data available
- Storage temperature of food: No data available

VEHICLE
- Justification for use and choice of vehicle (if other than water): No data available
- Concentration in vehicle: 0, 200, 1000 or 2000 mg/kg-bw/day
- Amount of vehicle (if gavage): No data available
- Lot/batch no. (if required): No data available
- Purity: No data available

Study 3: Male rats were exposed for 28 days prior to mating, and through mating until euthanasia for a total of 43-47 consecutive days of dosing; while 12 females were dosed for 14 days prior to mating, during mating, gestation and lactation through euthanasia at lactation day 4 (42-51 consecutive days).

Study 4: Details on exposure
PREPARATION OF DOSING SOLUTIONS: No Data Available

DIET PREPARATION:
- Rate of preparation of diet (frequency): No Data Available
- Mixing appropriate amounts with (Type of food): No Data Available
- Storage temperature of food: No Data Available

VEHICLE:
- Justification for use and choice of vehicle (if other than water): The test chemical was best miscible in corn oil.
- Concentration in vehicle: 0, 100, 500 and 1000 mg/kg
- 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 analytical verification of doses or concentrations:
Study 2, 3 and 4: No Data Available
Details on mating procedure:
Study 2: - M/F ratio per cage: No Data Available
- Length of cohabitation: No data available
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility. No data available
- Further matings after two unsuccessful attempts: No data available
- Verification of same strain and source of both sexes: No data available
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy No data available
- Any other deviations from standard protocol: No data available

Study 3 and 4: No Data Available
Duration of treatment / exposure:
Study 2: For one week prior to a 7-day cohabitation period through gestation, parturition and a 4-day postpartum period.
Study 3: Males: 43-47 consecutive days
Females: 42-51 consecutive days
Study 4: Male rats were treated for 28 days prior to mating and for an additional 16 days (44 total days).
Females were dosed for 14 days prior to mating and during mating, gestation and lactation (41-55 days).
Frequency of treatment:
Study 2, 3 and 4: No Data Available
Duration of test:
Study 2, 3 and 4: No Data Available
Doses / concentrations
Remarks:
Study 2: 0, 200, 1000 and 2000 mg/kg bw/day
Study 3 and 4: 0, 100, 500 or 1000 mg/kg bw/day
No. of animals per sex per dose:
Study 2 and 4: No Data Available
Study 3: 24 animals were used per group.
Control animals:
other: Study 2,3 and 4: Yes, Concurrent Vehicle
Details on study design:
Study 2 and 4: No Data Available
Study 3: Further details on study design:
- Dose selection rationale: No Data Available
- Rationale for animal assignment (if not random): No Data Available
- Other: No Data Available

Examinations

Maternal examinations:
Study 2: Maternal animals were observed for Mortality, clinical signs, food consumption, body weights, mating and fertility,
Study 3: The parental animals were observed for neurotoxic and pathological analyses.
Study 4: Maternal animals were examined for precoital intervals, gestation length, pregnancy rats, copulation, fertility indices
Ovaries and uterine content:
Study 2: Number of implantation and losses were investigated.
Study 3 and 4: No Data Available
Fetal examinations:
Study 2: Fetal examinations included implantations, length of gestation, proportion of dams delivering live pup or pup viability, Pup weights, malformations and gross lesions.
Study 3: Pup viability, pup weights and malformations or gross lesions were observed.
Study 4: Number of litters, pup survival, pup viability, pup weight, and sex ratio.
Statistics:
Study 2, 3 and 4: No Data Available
Indices:
Study 3: Copulation and fertility index, gestational index and pup viability indices
Study 2 and 4: No Data Available
Historical control data:
No Data Available

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Study 2: In the 1000 and 2000 mg/kg-bw/day dose groups, significant increases in the incidence of rales (p < 0.01) and excess salivation (p < 0.01) were reported during pre-mating and gestation. High-dose females also exhibited lethargy, unkempt coats and labored breathing.

Study 3 and 4: No Data Available
Dermal irritation (if dermal study):
not specified
Description (incidence and severity):
Study 2, 3 and 4: No Data Available
Mortality:
mortality observed, treatment-related
Description (incidence):
Study 2: Mortality occurred in the high-dose group (3 of 10 rats) and mid-dose group (1 of 10 rats).
Study 3 and 4: No Data Available
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Study 2: Average maternal body weights were decreased on days 10 – 16 of gestation and body weight gains were significantly (p < 0.05) reduced.
Study 3 and 4: No Data Available
Food consumption and compound intake (if feeding study):
not specified
Description (incidence and severity):
Study 2: In the high-dose group, food consumption was reduced throughout the study.
Study 3 and 4: No Data Available
Food efficiency:
not specified
Description (incidence and severity):
Study 2, 3 and 4: No Data Available
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
Study 4: No effects were observed in any of the dose levels.
Study 2 and 3: No Data Available
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Study 3: It was observed that hepatocyte cytoplasmic vacuolation occurred in both sexes at >500 mg/kg/day (associated with an increase in liver weight), and pitted kidneys and accumulation of hyaline droplets in the proximal convoluted tubules of the kidneys of males at all dose levels. The kidney effects were interpreted to be a result of hydrocarbon nephropathy, which is specific to male rats.
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Study 3: The adverse effect observed was liver effect in non-pregnant satellite females histologically examined.
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Details on results:
No Data Available

Maternal developmental toxicity

Number of abortions:
no effects observed
Description (incidence and severity):
Study 2, 3 and 4: No effects were observed on abortion of fetus at any dose levels.
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
Study 2 and 4: No effects were observed at any dose levels on pre-- and post-implantation losses.
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
Study 2 and 4: No effects were observed on the litter losses at given dose levels.
Early or late resorptions:
no effects observed
Description (incidence and severity):
Study 2 and 4: No early or late resorptions were observed at any dose levels.
Dead fetuses:
not specified
Description (incidence and severity):
Study 2, 3 and 4: No fetuses were found dead at any dose levels.
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
Study 2, 3 and 4: No changes were observed in pregnancy duration of the female rats.
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.DescriptionIncidenceAndSeverityEffectsOnPregnancyDuration): Study 2, 3 and 4: No effects were observed on the pregnancy duration at any given dose levels.
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
Study 4: No changes were observed in the number of pregnant females at any dose levels.
Other effects:
not specified
Details on maternal toxic effects:
No Data Available

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
200 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
body weight and weight gain
changes in number of pregnant
changes in pregnancy duration
dead fetuses
early or late resorptions
effects on pregnancy duration
food consumption and compound intake
mortality
number of abortions
pre and post implantation loss
total litter losses by resorption

Maternal abnormalities

Abnormalities:
not specified

Results (fetuses)

Fetal body weight changes:
effects observed, treatment-related
Description (incidence and severity):
Study 2: Pup weights were reduced on day 4 post parturition in the high-dose group.
Study 3 and 4: No effects were observed
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): effects observed, treatment-related
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.DescriptionIncidenceAndSeverityFetalPupBodyWeightChanges): Study 2: Pup weights were reduced on day 4 post parturition in the high-dose group.
Study 3 and 4: No effects were observed
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
Study 2, 3 and 4: No effects were observed in reduction in number of live offsprings.
Changes in sex ratio:
no effects observed
Description (incidence and severity):
Study 3 and 4: No changes in sex ratio were observed at given dose levels.
Changes in litter size and weights:
no effects observed
Description (incidence and severity):
Study 2, 3 and 4: No changes were observed in liiter size and their weights at any dose levels.
Changes in postnatal survival:
no effects observed
Description (incidence and severity):
Study 4: No changes were observed in post natal survival at any dose levels.
External malformations:
no effects observed
Description (incidence and severity):
Study 3: No external malformations were obsrved at any dose levels.
Skeletal malformations:
not specified
Visceral malformations:
not specified
Other effects:
not specified
Details on embryotoxic / teratogenic effects:
No Data Available

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reduction in number of live offspring
changes in sex ratio
fetal/pup body weight changes
changes in litter size and weights
changes in postnatal survival
external malformations

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified
Treatment related:
not specified
Relation to maternal toxicity:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified

Applicant's summary and conclusion

Conclusions:
Study 2: Based on all the observation it was concluded that, NOAEL was considered to be 200 and 2000 mg/kg body weight/day for the maternal generation and the F1 generation respectively.

Study 3: Based on all the above observations it was concluded that the NOEL for parental animals was found to be 100 mg/kg bw/day and the NOAEL for F1 generation was found to be 1000 mg/kg bw/day.

Study 4: Based on all the above observations, it was concluded that, the NOAEL for both maternal and fetal parameters based on the test chemical was found to be 1000 mg/kg bw/day.
Executive summary:

Developmental Toxicity Study Summaries:

Study 2:

In a reproductive/developmental toxicity study, female Sprague-Dawley rats (10/group) were administered with the test chemical via gavage (in corn oil) at doses of 0, 200, 1000 or 2000 mg/kg-bw/day for one week prior to a 7-day cohabitation period through gestation, parturition and a 4-day postpartum period. The parental animals were observed for Mortality, clinical signs, food consumption, body weights, mating and fertility, while Fetal examinations included implantations, length of gestation, proportion of dams delivering live pup or pup viability, Pup weights, malformations and gross lesions. After all the examinations it was observed that in maternal animals, mortality occured in high dose group. In clinical signs, in the 1000 and 2000 mg/kg-bw/day dose groups, significant increases in the incidence of rales (p < 0.01) and excess salivation (p < 0.01) were reported during pre-mating and gestation. High-dose females also exhibited lethargy, unkempt coats and labored breathing. Also, average maternal body weights were decreased on days 10 – 16 of gestation and body weight gains were significantly (p < 0.05) reduced. In the high-dose group, food consumption was reduced throughout the study. Although, no effects were observed in pre and post implantation loss, resorptions, viability of the pups and pregnancy duration in maternal animals. In pup parameters, no effects were observed in change in number of offsprings and litter size, and no external anomalies were observed at any dose levels. Thus, based on all the observation it was concluded that, NOAEL was considered to be 200 and 2000 mg/kg body weight/day for the maternal generation and the F1 generation respectively.

Study 3:

A combined repeated and reproductive/developmental toxicity screening test was performed to assess and evaluate the reproductive toxicity of the test chemical in rats. In this test, the rats were dosed with the test chemical using three dose groups of 100, 500 and 1000 mg/kg bw/day. A concurrent control group and a satellite group was also used. A total of 14 animals were used per group in this study. Male rats were exposed for 28 days prior to mating, and through mating until euthanasia for a total  of  43-47 consecutive days of dosing; while 12 females were dosed for 14  days prior to mating, during mating, gestation and lactation through euthanasia at lactation day 4 (42-51 consecutive days). The parental animals were observed for pathological changes and neurotoxicity. After the examinations, it was observed that, hepatocyte cytoplasmic vacuolation occurred in both sexes at >500 mg/kg/day (associated with an increase in liver weight), and pitted kidneys and  accumulation of hyaline droplets  in  the  proximal  convoluted  tubules of the kidneys of males at all dose levels. The kidney effects were interpreted to be a result of hydrocarbon nephropathy, which is specific to male rats. Also, the determined NOEL was 100 mg/kg/day which was determined by the effect of liver through histopathological examination in non-pregnant satellite females. In reproductive parameters of the rats, there was no effects observed on copulation and fertility, precoital intervals, gestation length, time  to delivery or unusual nesting behavior. In pup parameters, mortality/viability of the pups, litter size and body weights, male to female pup ratio and external anomalies. After all examinations, no effects were observed in any of the pup parameters. Thus, based on all the above observations it was concluded that the NOEL for parental animals was found to be 100 mg/kg bw/day and the NOAEL for F1 generation was found to be 1000 mg/kg bw/day.

A combined repeated and reproductive/developmental toxicity screening test was performed to assess and evaluate the reproductive toxicity of the test chemical in rats. In this test, the rats were dosed with the test chemical using three dose groups of 100, 500 and 1000 mg/kg bw/day. A concurrent control group and a satellite group was also used. A total of 14 animals were used per group in this study. Male rats were exposed for 28 days prior to mating, and through mating until euthanasia for a total  of  43-47 consecutive days of dosing; while 12 females were dosed for 14  days prior to mating, during mating, gestation and lactation through euthanasia at lactation day 4 (42-51 consecutive days). The parental animals were observed for pathological changes and neurotoxicity. After the examinations, it was observed that, hepatocyte cytoplasmic vacuolation occurred in both sexes at >500 mg/kg/day (associated with an increase in liver weight), and pitted kidneys and  accumulation of hyaline droplets  in  the  proximal  convoluted  tubules of the kidneys of males at all dose levels. The kidney effects were interpreted to be a result of hydrocarbon nephropathy, which is specific to male rats. Also, the determined NOEL was 100 mg/kg/day which was determined by the effect of liver through histopathological examination in non-pregnant satellite females. In reproductive parameters of the rats, there was no effects observed on copulation and fertility, precoital intervals, gestation length, time  to delivery or unusual nesting behavior. In pup parameters, mortality/viability of the pups, litter size and body weights, male to female pup ratio and external anomalies. After all examinations, no effects were observed in any of the pup parameters. Thus, based on all the above observations it was concluded that the NOEL for parental animals was found to be 100 mg/kg bw/day and the NOAEL for F1 generation was found to be 1000 mg/kg bw/day.

Study 4:

An experiment was conducted to assess the reproductive and developmental toxicity potential of the test chemical in rats. In this experiment, the test chemical was mixed with the corn oil and administered orally to the animals in the dose groups of 0, 100, 500 and 1000 mg/kg bw/day. Male rats were treated for 28 days prior to mating and for an additional 16 days (44 total days). Females were dosed for 14 days prior to mating and during mating, gestation and lactation (41-55 days). During and after the dosing the animals were observed for any adverse effects of the test chemicals. After dosing, it was observed that there were no adverse effects observed in maternal animals at any given dose levels. However, in male rats, absolute epididymal weights for males were statistically lower in all treated groups compared to controls and the epididymal/brain relative weights were also lower in all treated groups compared to controls, although only the low dose group was statistically significant. The biological significance of the decreased epididymal weights was found to be uncertain because of no apparent histopathological effects in the epididymis and no evidence of impared fertility in the treated males and there was a lack of a dose response between treated groups. In maternal parameters, there were no effects on the following reproductive parameters: precoital intervals, gestation length, pregnancy rats, copulation and fertility indices. Also, in developmental parameters, it was observed that, there were no effects on the number of litters, pup survival, pup viability, pup weight, and sex ratio. Thus, based on all the above observations, it was concluded that, the NOAEL for both maternal and fetal parameters based on the test chemical was found to be 1000 mg/kg bw/day.