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EC number: 946-253-9 | CAS number: -
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- guideline study without detailed documentation
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Reference
- Endpoint:
- developmental toxicity
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Justification for type of information:
- see attached justification
- Reason / purpose for cross-reference:
- read-across source
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- no toxicologically relevant effects observed
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- One animal in the 70 mg/kg bw/day group showed an early delivery on GD 19 and was killed.
- Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Body weight gain was statistically significantly reduced on GD 9 and 12 in the 70 mg/kg bw/day dose group and on GD 9, 12 and 15 in the 200 mg/kg bw/day dose group. The effects were small and are not toxicologically relevant.
- Food consumption and compound intake (if feeding study):
- effects observed, non-treatment-related
- Description (incidence and severity):
- Food consumption in the 200 mg/kg bw/day dose group was decreased from days 6-12 post coitum. Food consumption of the 70 mg/kg bw/day dose group was decreased from GD6-9. The reductions were small and not toxicologically relevant.
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not specified
- Description (incidence and severity):
- acetylcholinesterase activity was determined in the plasma collected on gestation day 21. No conclusions could be drawn regarding the effect of d-carvone on the AChE activity.
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- No toxicologically relevant effects observed with macroscopic research.
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- No toxicologically relevant effects observed with macroscopic research.
- Neuropathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- no toxicologically relevant effects observed with microscopic research.
- Histopathological findings: neoplastic:
- no effects observed
- Description (incidence and severity):
- no toxicologically relevant effects observed with microscopic research.
- Other effects:
- not specified
- Description (incidence and severity):
- acetylcholinesterase activity was determined in the brain. No conclusions could be drawn regarding the effect of d-carvone on the AChE activity.
- Number of abortions:
- effects observed, non-treatment-related
- Description (incidence and severity):
- One animal in the 70 mg/kg bw/day dose group showed an early delivery on GD 19 and was killed.
- Pre- and post-implantation loss:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No toxicologically relevant effects observed regarding pre-implantation loss.
In the 200 mg/kg bw/day dose group a significant increase in post implantation loss and number of dead foetuses was observed. This was due to one litter consisting of ten dead foetuses. - Total litter losses by resorption:
- no effects observed
- Early or late resorptions:
- no effects observed
- Dead fetuses:
- effects observed, non-treatment-related
- Description (incidence and severity):
- In the 200 mg/kg bw/day dose group: one litter consisting of ten dead foetuses.
- 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
- Description (incidence and severity):
- Acetylcholinesterase activity was determined in the brain. No conclusions could be drawn regarding the effect of d-carvone on the AChE activity.
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 200 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- other: No treatment related adverse effects observed.
- Key result
- Abnormalities:
- no effects observed
- 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:
- effects observed, non-treatment-related
- Description (incidence and severity):
- In the 200 mg/kg bw/day dose group: one litter consisting of ten dead foetuses
- Changes in sex ratio:
- no effects observed
- Changes in litter size and weights:
- no effects observed
- Changes in postnatal survival:
- not examined
- External malformations:
- no effects observed
- Skeletal malformations:
- no effects observed
- Visceral malformations:
- no effects observed
- Other effects:
- not specified
- Description (incidence and severity):
- acetylcholinesterase activity was determined in the brain. No conclusions could be drawn regarding the effect of d-carvone on the AChE activity.
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 200 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No treatment related effects observed
- Key result
- Abnormalities:
- no effects observed
- Key result
- Developmental effects observed:
- no
- Conclusions:
- Under the conditions of the test the NOAEL was determined to be ≥ 200 mg/kg bw/day for maternal and developmental toxicity.
- Executive summary:
A OECD 414 study was performed with rats. The animals were dose with 0, 20, 70, and 200 mg/kg bw/day d-carvone during gestational day 6 to 20. The dams were examined for mortality, clinical sigs, pregnancy, abortions, corpus lutea, body weight gain, food consumption, and pathology (macro and microscopy). Litter response was determined by monitoring the live fetuses, fetal weight, pre-implantation loss, post implantation loss, and sex ratio. Fetal examination included no. of fetuses, no of abnormal fetuses, no. of dead fetuses, malformations, external observations and visceral deviation, and skeletal deviations. No treatment related adverse effects were observed in the dams and the fetuses. Under the conditions of the test the NOAEL was determined to be ≥ 200 mg/kg bw/day for maternal and developmental toxicity.
Summary table of the developmental toxicity study. Cited from: CLH report, 2012 (version 3) Submitted by: National Institute for Public Health and the Environment (RIVM).
|
Dose (mg/kg bw/day) |
0 |
20 |
70 |
200 |
Maternal effects |
Mortality* |
|
|
1 |
|
|
Clinical signs |
no toxicologically relevant effect |
|||
|
Pregnant animals |
no toxicologically relevant effect |
|||
|
Abortions* |
|
|
1 |
|
|
Corpus lutea |
no toxicologically relevant effect |
|||
|
Body weight gain** |
no toxicologically relevant effect |
|||
|
Food consumption*** |
|
|
|
|
|
Pathology |
|
|
|
|
|
-macroscopy |
no toxicologically relevant effect |
|||
|
-microscopy |
no toxicologically relevant effect |
|||
Litter response |
Live fetuses |
no toxicologically relevant effect |
|||
|
Fetal weight |
no toxicologically relevant effect |
|||
|
Pre implantation loss |
no toxicologically relevant effect |
|||
|
Post implantation loss**** |
no toxicologically relevant effect |
|||
|
Sex ratio |
no toxicologically relevant effect |
|||
Fetus examination |
No. of foetuses |
no toxicologically relevant effect |
|||
|
No. of abnormal foetuses |
no toxicologically relevant effect |
|||
|
No. of dead fetuses**** |
no toxicologically relevant effect |
|||
|
Malformations |
|
|
|
|
|
External observations and visceral deviations |
no toxicologically relevant effect |
|||
|
Skeletal deviations |
no toxicologically relevant effect |
|||
* One animal in the mid-dose group showed an early delivery on GD 19 and was killed.
** Body weight gain was statistically significantly reduced on GD 9 and 12 in the mid-dose group and on GD 9, 12 and 15 in the high-dose group. However, the effects were small and are not considered toxicologically relevant
*** Food consumption in the highest-dose group was decreased from days 6-12 post coitum. Food consumption of the mid-dose group was decreased from GD6-9. However, the reductions were small and not considered toxicologically relevant.
**** In the highest dose group a significant increase in post implantation loss and number of dead foetuses was observed. This was due to one litter consisting of ten dead foetuses. The study authors consider this a chance finding. The present reviewers endorse this view.
Data source
Reference
- Reference Type:
- review article or handbook
- Title:
- Unnamed
- Year:
- 2 012
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- GLP compliance:
- not specified
- Remarks:
- Data obtained from a review article and no details regarding GLP were available.
- Limit test:
- no
Test material
- Reference substance name:
- (S)-2-methyl-5-(1-methylvinyl)cyclohex-2-en-1-one
- EC Number:
- 218-827-2
- EC Name:
- (S)-2-methyl-5-(1-methylvinyl)cyclohex-2-en-1-one
- Cas Number:
- 2244-16-8
- Molecular formula:
- C10H14O
- IUPAC Name:
- (S)-2-methyl-5-(1-methylvinyl)cyclohex-2-en-1-one
- Test material form:
- liquid
Constituent 1
Test animals
- Species:
- rat
- Strain:
- not specified
Administration / exposure
- Route of administration:
- not specified
- Vehicle:
- not specified
- Duration of treatment / exposure:
- Gestational day 6 to 20
- Duration of test:
- until gestational day 21
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Dose / conc.:
- 20 mg/kg bw/day (nominal)
- Dose / conc.:
- 70 mg/kg bw/day (nominal)
- Dose / conc.:
- 200 mg/kg bw/day (nominal)
- Control animals:
- yes, concurrent vehicle
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
DETAILED CLINICAL OBSERVATIONS: Yes
BODY WEIGHT: Yes
FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
WATER CONSUMPTION AND COMPOUND INTAKE: No
POST-MORTEM EXAMINATIONS: Yes
OTHER: acetylcholinesterase activity in the brain was determined - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: No data
- Number of late resorptions: No data
- Fetal examinations:
- - External examinations: Yes
- Soft tissue examinations: Yes
- Skeletal examinations: Yes
- Head examinations: not specified
- Other: acetylcholinesterase activity in the brain was determined
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- no toxicologically relevant effects observed
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- One animal in the 70 mg/kg bw/day group showed an early delivery on GD 19 and was killed.
- Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Body weight gain was statistically significantly reduced on GD 9 and 12 in the 70 mg/kg bw/day dose group and on GD 9, 12 and 15 in the 200 mg/kg bw/day dose group. The effects were small and are not toxicologically relevant.
- Food consumption and compound intake (if feeding study):
- effects observed, non-treatment-related
- Description (incidence and severity):
- Food consumption in the 200 mg/kg bw/day dose group was decreased from days 6-12 post coitum. Food consumption of the 70 mg/kg bw/day dose group was decreased from GD6-9. The reductions were small and not toxicologically relevant.
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not specified
- Description (incidence and severity):
- acetylcholinesterase activity was determined in the plasma collected on gestation day 21. No conclusions could be drawn regarding the effect of d-carvone on the AChE activity.
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- No toxicologically relevant effects observed with macroscopic research.
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- No toxicologically relevant effects observed with macroscopic research.
- Neuropathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- no toxicologically relevant effects observed with microscopic research.
- Histopathological findings: neoplastic:
- no effects observed
- Description (incidence and severity):
- no toxicologically relevant effects observed with microscopic research.
- Other effects:
- not specified
- Description (incidence and severity):
- acetylcholinesterase activity was determined in the brain. No conclusions could be drawn regarding the effect of d-carvone on the AChE activity.
Maternal developmental toxicity
- Number of abortions:
- effects observed, non-treatment-related
- Description (incidence and severity):
- One animal in the 70 mg/kg bw/day dose group showed an early delivery on GD 19 and was killed.
- Pre- and post-implantation loss:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No toxicologically relevant effects observed regarding pre-implantation loss.
In the 200 mg/kg bw/day dose group a significant increase in post implantation loss and number of dead foetuses was observed. This was due to one litter consisting of ten dead foetuses. - Total litter losses by resorption:
- no effects observed
- Early or late resorptions:
- no effects observed
- Dead fetuses:
- effects observed, non-treatment-related
- Description (incidence and severity):
- In the 200 mg/kg bw/day dose group: one litter consisting of ten dead foetuses.
- 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
- Description (incidence and severity):
- Acetylcholinesterase activity was determined in the brain. No conclusions could be drawn regarding the effect of d-carvone on the AChE activity.
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 200 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- other: No treatment related adverse effects observed.
Maternal abnormalities
- Key result
- Abnormalities:
- no effects observed
Results (fetuses)
- 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:
- effects observed, non-treatment-related
- Description (incidence and severity):
- In the 200 mg/kg bw/day dose group: one litter consisting of ten dead foetuses
- Changes in sex ratio:
- no effects observed
- Changes in litter size and weights:
- no effects observed
- Changes in postnatal survival:
- not examined
- External malformations:
- no effects observed
- Skeletal malformations:
- no effects observed
- Visceral malformations:
- no effects observed
- Other effects:
- not specified
- Description (incidence and severity):
- acetylcholinesterase activity was determined in the brain. No conclusions could be drawn regarding the effect of d-carvone on the AChE activity.
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 200 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No treatment related effects observed
Fetal abnormalities
- Key result
- Abnormalities:
- no effects observed
Overall developmental toxicity
- Key result
- Developmental effects observed:
- no
Any other information on results incl. tables
Summary table of the developmental toxicity study. Cited from: CLH report, 2012 (version 3) Submitted by: National Institute for Public Health and the Environment (RIVM).
|
Dose (mg/kg bw/day) |
0 |
20 |
70 |
200 |
Maternal effects |
Mortality* |
|
|
1 |
|
|
Clinical signs |
no toxicologically relevant effect |
|||
|
Pregnant animals |
no toxicologically relevant effect |
|||
|
Abortions* |
|
|
1 |
|
|
Corpus lutea |
no toxicologically relevant effect |
|||
|
Body weight gain** |
no toxicologically relevant effect |
|||
|
Food consumption*** |
|
|
|
|
|
Pathology |
|
|
|
|
|
-macroscopy |
no toxicologically relevant effect |
|||
|
-microscopy |
no toxicologically relevant effect |
|||
Litter response |
Live fetuses |
no toxicologically relevant effect |
|||
|
Fetal weight |
no toxicologically relevant effect |
|||
|
Pre implantation loss |
no toxicologically relevant effect |
|||
|
Post implantation loss**** |
no toxicologically relevant effect |
|||
|
Sex ratio |
no toxicologically relevant effect |
|||
Fetus examination |
No. of foetuses |
no toxicologically relevant effect |
|||
|
No. of abnormal foetuses |
no toxicologically relevant effect |
|||
|
No. of dead fetuses**** |
no toxicologically relevant effect |
|||
|
Malformations |
|
|
|
|
|
External observations and visceral deviations |
no toxicologically relevant effect |
|||
|
Skeletal deviations |
no toxicologically relevant effect |
|||
* One animal in the mid-dose group showed an early delivery on GD 19 and was killed.
** Body weight gain was statistically significantly reduced on GD 9 and 12 in the mid-dose group and on GD 9, 12 and 15 in the high-dose group. However, the effects were small and are not considered toxicologically relevant
*** Food consumption in the highest-dose group was decreased from days 6-12 post coitum. Food consumption of the mid-dose group was decreased from GD6-9. However, the reductions were small and not considered toxicologically relevant.
**** In the highest dose group a significant increase in post implantation loss and number of dead foetuses was observed. This was due to one litter consisting of ten dead foetuses. The study authors consider this a chance finding. The present reviewers endorse this view.
Applicant's summary and conclusion
- Conclusions:
- Under the conditions of the test the NOAEL was determined to be ≥ 200 mg/kg bw/day for maternal and developmental toxicity.
- Executive summary:
A OECD 414 study was performed with rats. The animals were dose with 0, 20, 70, and 200 mg/kg bw/day d-carvone during gestational day 6 to 20. The dams were examined for mortality, clinical sigs, pregnancy, abortions, corpus lutea, body weight gain, food consumption, and pathology (macro and microscopy). Litter response was determined by monitoring the live fetuses, fetal weight, pre-implantation loss, post implantation loss, and sex ratio. Fetal examination included no. of fetuses, no of abnormal fetuses, no. of dead fetuses, malformations, external observations and visceral deviation, and skeletal deviations. No treatment related adverse effects were observed in the dams and the fetuses. Under the conditions of the test the NOAEL was determined to be ≥ 200 mg/kg bw/day for maternal and developmental toxicity.
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.
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