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EC number: 946-253-9 | CAS number: -
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
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- Endpoint summary
- Stability
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- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
Administrative data
Key value for chemical safety assessment
Effects on fertility
Description of key information
OECD 416, GLP compliant: the NOAEL for fertility was determined to be ≥ 90 mg/kg bw/day.
Link to relevant study records
- Endpoint:
- two-generation reproductive 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
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- Wistar
- Details on species / strain selection:
- Wistar Crl : (WI) BR
- Sex:
- male/female
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- not specified
- Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- Dosing of the F0 generation with 0, 3,10, and 30 mg/kg bw/day started 10 weeks prior to mating.
Dosing of the F1 generation with 0, 10, 30 and 90 mg/kg/day mg/kg bw/day started when the animals were 3-5 weeks old. Pups were not treated during the weaning period. 10 weeks prior to mating animals were dosed. - Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Remarks:
- F0, F1
- Dose / conc.:
- 3 mg/kg bw/day (nominal)
- Remarks:
- F0
- Dose / conc.:
- 10 mg/kg bw/day (nominal)
- Remarks:
- F0, F1
- Dose / conc.:
- 30 mg/kg bw/day (nominal)
- Remarks:
- F0, F1
- Dose / conc.:
- 90 mg/kg bw/day (nominal)
- Remarks:
- F1
- No. of animals per sex per dose:
- F1: 25
- Control animals:
- yes, concurrent vehicle
- Positive control:
- no positive control performed
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least once daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: at least once daily
BODY WEIGHT: Yes
- Time schedule for examinations: weekly
FOOD CONSUMPTION
- Time schedule for examinations: weekly
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No - Oestrous cyclicity (parental animals):
- Oestrus cycle was examined in P and F1.
The ovaries and uterus were examined prior to fixation and the number of corpora lutea and implantation sites recorded. - Sperm parameters (parental animals):
- Parameters examined in P and F1 male parental generations.
Sperm motility, sperm morphology, enumeration of homogenisation-resistant spermatids, and cauda epididymal sperm reserves. - Litter observations:
- STANDARDISATION OF LITTERS.
On day 4 after birth all litters of more than 8 pups were culled to approximately 4 males and 4 females.
PARAMETERS EXAMINED
The following parameters were examined in F1, F2 pups:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities.
Weights of live pups were recorded at day 1, 4, 7, 14 and 21.
ASSESSMENT OF DEVELOPMENTAL NEUROTOXICITY: not performed
ASSESSMENT OF DEVELOPMENTAL IMMUNOTOXICITY: Not performed - Postmortem examinations (parental animals):
- SACRIFICE
F0 Females from both generations were killed at day 21 post partum. F0 males were killed as soon as possible after successful mating while F1 males were only killed after successful delivery of the dams.
GROSS NECROPSY
All parental animals were subject to a necropsy and some tissues weighed adrenals, brain, epididymides, kidneys, liver, ovaries, pituitary, prostate, seminal vesicles, spleen, testes, thyroid, uterus with oviducts and cervix.
All pups not selected for mating were taken for necropsy at day 21 post partum or shortly thereafter; organ weights were recorded for brain, spleen and thymus.
HISTOPATHOLOGY / ORGAN WEIGHTS
adrenals, brain, coagulating glands, epididymides, identification marks, kidneys, liver, ovaries, pituitary, prostate, seminal vesicles, spleen, testes, thyroid, uterus with oviducts and cervix, vagina were preserved for histological examination. - Postmortem examinations (offspring):
- GROSS NECROPSY
- yes only macroscopic pathology was performed on the F1 and F2 pups.
- Reproductive indices:
- Parameters: Mating, fertility index, conception rate, gestation index, duration of gestation, percentage live offspring by sex, percentage of post-natal loss, percentage of breeding loss, percentage live at weaning by sex, viability index, weaning index.
- Offspring viability indices:
- Litters were examined for number of live and dead pups.
- Clinical signs:
- no effects observed
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- F0: 2 males and 1 female (0 mg/kg bw/day), 1 female (3 mg/kg bw/day), 1 female (10 mg/kg bw/day), 1 females (30 mg/kg bw/day).
Animals were found dead or killed in extremis due to bad health or delivery difficulties. The deaths are not considered to be treatment-related. - Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Females of the 30 mg/kg bw/day group showed small but significant decreases in body weight gain during lactation on days 4, 7 and 14, and body weight loss on day 4 during lactation.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Females of the 30 mg/kg bw/day group showed a significant decrease in food consumption from day 1-4 during lactation.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not specified
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Histopathology of the male kidneys showed changes typical of 2u -globulin nephropathy at all doses. No other histopathological changes were reported and no similar changes were observed in females.
- Histopathological findings: neoplastic:
- no effects observed
- Other effects:
- not examined
- Reproductive function: oestrous cycle:
- no effects observed
- Reproductive function: sperm measures:
- no effects observed
- Reproductive performance:
- no effects observed
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 30 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no treatment related adverse effects on fertility were observed
- Dose descriptor:
- NOAEL
- Effect level:
- 10 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- organ weights and organ / body weight ratios
- Remarks on result:
- other:
- Remarks:
- Male toxicity
- Dose descriptor:
- NOAEL
- Effect level:
- >= 30 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: No substance related adverse effects observed
- Remarks on result:
- other:
- Remarks:
- Female toxicity
- Key result
- Critical effects observed:
- no
- Lowest effective dose / conc.:
- 30 mg/kg bw/day (nominal)
- System:
- urinary
- Organ:
- kidney
- Treatment related:
- yes
- Dose response relationship:
- no
- Relevant for humans:
- not specified
- Clinical signs:
- no effects observed
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- 0 mg/kg bw/day: 1 female
10 mg/kg bw/day: 1 female
30 mg/kg bw/day: 2 females
90 mg/kg bw/day: 1 female
Animals were found dead or killed in extremis due to bad health or delivery difficulties. The deaths are not considered to be treatment-related. - Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Females of the 90 mg/kg bw/day group had in increased body weight and body weight gain.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- 30 mg/kg bw/day: Increased relative liver weight and absolute and relative increased kidney weights in the male rats.
90 mg/kg bw/day:Increased relative liver weight and absolute and relative increased kidney weights in the male rats.
Effects were dose related. - Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Histopathology of the male kidneys showed changes typical of 2u -globulin nephropathy at all doses. No differences were seen in females and no other histopathological changes were reported.
- Histopathological findings: neoplastic:
- no effects observed
- Other effects:
- not examined
- Reproductive function: oestrous cycle:
- no effects observed
- Reproductive function: sperm measures:
- no effects observed
- Reproductive performance:
- no effects observed
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 90 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No substance related effects on fertility
- Dose descriptor:
- NOAEL
- Effect level:
- 10 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- organ weights and organ / body weight ratios
- Remarks on result:
- other:
- Remarks:
- male toxicity
- Dose descriptor:
- NOAEL
- Effect level:
- >= 90 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: No treatment related effects observed.
- Remarks on result:
- other:
- Remarks:
- female toxicity
- Key result
- Critical effects observed:
- no
- Lowest effective dose / conc.:
- 30 mg/kg bw/day (nominal)
- System:
- urinary
- Organ:
- kidney
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- not specified
- Key result
- Critical effects observed:
- no
- Lowest effective dose / conc.:
- 30 mg/kg bw/day (nominal)
- System:
- hepatobiliary
- Organ:
- liver
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- not specified
- Clinical signs:
- no effects observed
- Dermal irritation (if dermal study):
- not examined
- Mortality / viability:
- not specified
- Description (incidence and severity):
- Survival index: no toxicological relevant effects found.
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Sexual maturation:
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- not examined
- Other effects:
- not examined
- Behaviour (functional findings):
- no effects observed
- Developmental immunotoxicity:
- not examined
- Key result
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- >= 30 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No adverse effects observed on the pups.
- Key result
- Critical effects observed:
- no
- Clinical signs:
- no effects observed
- Dermal irritation (if dermal study):
- not examined
- Mortality / viability:
- not specified
- Description (incidence and severity):
- Survival index: no toxicological relevant effects found.
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Sexual maturation:
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- not examined
- Other effects:
- not examined
- Behaviour (functional findings):
- no effects observed
- Developmental immunotoxicity:
- not examined
- Key result
- Dose descriptor:
- NOAEL
- Generation:
- F2
- Effect level:
- >= 90 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no adverse effects on fertility were observed
- Key result
- Reproductive effects observed:
- no
- Conclusions:
- Under the conditions of the test no adverse effects on fertility were observed. Therefore the NOAEL for fertility ≥ 90 mg/kg bw/day
- Executive summary:
An OECD 416 study was performed in compliance with GLP. In this 2 generation study, 25 Wistar rats were exposed by oral gavage to 0, 3, 10, and 30 mg/kg bw d-carvone (F0). Dosing of the F0 generation started 10 weeks prior to mating. Dosing of the F1 generation with 0, 10, 30 and 90 mg/kg/day mg/kg bw/day started after weaning when the animals were 3-5 weeks old. Parental animals were subject to necropsy and tissues were weighted (adrenals, brain, epididymides, kidneys, liver, ovaries, pituitary, prostate, seminal vesicles, spleen, testes, thyroid, uterus with oviducts and cervix). Histological examination was performed on adrenals, brain, coagulating glands, epididymides, identification marks, kidneys, liver, ovaries, pituitary, prostate, seminal vesicles, spleen, testes, thyroid, uterus with oviducts and cervix, and vagina. The oestrus cycle was examined in the females and sperm parameters were examined in the males. Mortality, weight and sex were recorded for the pups. Furthermore, physical or behavioural abnormalities were recorded. Macroscopic examinations after necropsy was performed on the pups. The following reproductive indices were determined: mating, fertility index, conception rate, gestation index, duration of gestation, percentage live offspring by sex, percentage of post-natal loss, percentage of breeding loss, percentage live at weaning by sex, viability index, weaning index. Under the conditions of the test no adverse effects on fertility were observed. Therefore, the NOAEL for fertility ≥ 90 mg/kg bw/day.
Reference
Summary table of the 2 generation 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 |
|
3 |
|
10 |
|
30 |
|
90 |
|
|
Sex |
m |
f |
m |
f |
m |
f |
m |
f |
m |
f |
F0 animals |
Mortality (A) |
2 |
1 |
|
1 |
|
1 |
|
1 |
|
|
|
Clinical signs |
no toxicologically relevant effect |
|
|
|||||||
|
Body weight (gain)(B) |
|
|
|
|
|
|
|
ds |
|
|
|
Food consumption (C) |
|
|
|
|
|
|
|
ds |
|
|
|
Mating, fertility, gestation |
no toxicologically relevant effect |
|
|
|||||||
|
Oestrus cycle |
no toxicologically relevant effect |
|
|
|||||||
|
Sperm parameters |
no toxicologically relevant effect |
|
|
|||||||
|
Organ weights -kidney -thyroid |
|
|
|
|
Is (a) |
|
Is (r ) |
|
|
|
|
Pathology |
no toxicologically relevant effect |
|
|
|||||||
|
macroscopy |
no toxicologically relevant effect |
|
|
|||||||
|
Microscopy (D) |
no toxicologically relevant effect |
|
|
|||||||
F1 pups |
Litter size |
no toxicologically relevant effect |
|
|
|||||||
|
Survival index |
no toxicologically relevant effect |
|
|
|||||||
|
Sex ratio |
no toxicologically relevant effect |
|
|
|||||||
|
Body weight |
no toxicologically relevant effect |
|
|
|||||||
|
Organ weight |
no toxicologically relevant effect |
|
|
|||||||
|
Pathology |
|
|
|
|||||||
|
macroscopy |
no toxicologically relevant effect |
|
|
|||||||
|
Microscopy(weanlings) |
Not performed |
|
|
|||||||
F1 animals |
Mortality (A) |
|
1 |
|
|
|
1 |
|
2 |
|
1 |
|
Clinical signs |
|
|
|
no toxicologically relevant effect |
||||||
|
Body weight E |
|
|
|
no toxicologically relevant effect |
||||||
|
Food consumption |
|
|
|
no toxicologically relevant effect |
||||||
|
Mating, fertility, gestation |
|
|
|
no toxicologically relevant effect |
||||||
|
Oestrus cycle |
|
|
|
no toxicologically relevant effect |
||||||
|
Sperm parameters |
|
|
|
no toxicologically relevant effect |
||||||
dr dr |
Organs weights -kidney -liver |
|
|
|
|
|
|
Is (r ) Is(ar) |
|
Is (r ) Is(ar) |
|
|
Pathology |
|
|
|
|
||||||
|
-macroscopy |
|
|
|
no toxicologically relevant effect |
||||||
|
-microscopy |
|
|
|
no toxicologically relevant effect |
||||||
F2 pups |
Litter size |
|
|
|
no toxicologically relevant effect |
||||||
|
Survival index |
|
|
|
no toxicologically relevant effect |
||||||
|
Sex ratio |
|
|
|
no toxicologically relevant effect |
||||||
|
Body weight |
|
|
|
no toxicologically relevant effect |
||||||
|
pathology |
|
|
|
|
||||||
|
-macroscopy |
|
|
|
no toxicologically relevant effect |
||||||
|
-microscopy |
|
|
|
Not performed |
dr = dose related; i = increased; d = decreased; is = increased significantly; ds = decreased significantly, a= absolute, r=relative
A. Animals were found dead or killed in extremis due to bad health or delivery difficulties. The deaths are not considered to be treatment-related.
B. Females of the 30 mg/kg bw/day group showed small but significant decreases in body weight gain during lactation on days 4, 7 and 14, and body weight loss on day 4 during lactation.
C. Females of the 30 mg/kg bw/day group showed a significant decrease in food consumption from day 1-4 during lactation.
D. Males of all treated groups showed histopathological changes in the kidney consistent with accumulation of α2u-globulin.
E. Females of the 90 mg/kg bw/day group had in increased body weight and body weight gain. The study authors considers this finding not toxicologically relevant. The present reviewers endorse this view
Effect on fertility: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 90 mg/kg bw/day
- Species:
- rat
- Quality of whole database:
- An OECD 416, GLP compliant study was performed.
Effect on fertility: via inhalation route
- Endpoint conclusion:
- no study available
Effect on fertility: via dermal route
- Endpoint conclusion:
- no study available
Additional information
An OECD 416 study was performed in compliance with GLP. In this 2 generation study, 25 Wistar rats were exposed by oral gavage to 0, 3, 10, and 30 mg/kg bw d-carvone (F0). Dosing of the F0 generation started 10 weeks prior to mating. Dosing of the F1 generation with 0, 10, 30 and 90 mg/kg/day mg/kg bw/day started after weaning when the animals were 3-5 weeks old. Parental animals were subject to necropsy and tissues were weighted (adrenals, brain, epididymides, kidneys, liver, ovaries, pituitary, prostate, seminal vesicles, spleen, testes, thyroid, uterus with oviducts and cervix). Histological examination was performed on adrenals, brain, coagulating glands, epididymides, identification marks, kidneys, liver, ovaries, pituitary, prostate, seminal vesicles, spleen, testes, thyroid, uterus with oviducts and cervix, and vagina. The oestrus cycle was examined in the females and sperm parameters were examined in the males. Mortality, weight and sex were recorded for the pups. Furthermore, physical or behavioural abnormalities were recorded. Macroscopic examinations after necropsy was performed on the pups. The following reproductive indices were determined: mating, fertility index, conception rate, gestation index, duration of gestation, percentage live offspring by sex, percentage of post-natal loss, percentage of breeding loss, percentage live at weaning by sex, viability index, weaning index. Under the conditions of the test no adverse effects on fertility were observed. Therefore, the NOAEL for fertility ≥ 90 mg/kg bw/day.
Effects on developmental toxicity
Description of key information
OECD 414: NOAEL was determined to be ≥ 200 mg/kg bw/day for maternal and developmental toxicity.
Link to relevant study records
- 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
- Reason / purpose for cross-reference:
- reference to same study
- 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
- Species:
- rat
- Strain:
- not specified
- Route of administration:
- not specified
- Vehicle:
- not specified
- Duration of treatment / exposure:
- Gestational day 6 to 20
- Duration of test:
- until gestational day 21
- 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
- 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 - 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.
Reference
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.
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 200 mg/kg bw/day
- Species:
- rat
- Quality of whole database:
- An OECD 414 study is available.
Effect on developmental toxicity: via inhalation route
- Endpoint conclusion:
- no study available
Effect on developmental toxicity: via dermal route
- Endpoint conclusion:
- no study available
Additional information
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.
Justification for classification or non-classification
The substance is not classified for reproductive or developmental toxicity, according to Regulation 1272/2008/EC (CLP).
Additional information
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