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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
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- 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
Toxicity to reproduction
Administrative data
- 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
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Reference
- Endpoint:
- two-generation reproductive 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
- 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
- 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
- Key result
- Critical effects observed:
- no
- Lowest effective dose / conc.:
- 30 mg/kg bw/day (nominal)
- System:
- hepatobiliary
- Organ:
- liver
- 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.
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
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 416 (Two-Generation Reproduction Toxicity Study)
- GLP compliance:
- yes
- 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:
- Wistar
- Details on species / strain selection:
- Wistar Crl : (WI) BR
- Sex:
- male/female
Administration / exposure
- 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.
Doses / concentrationsopen allclose all
- 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
Examinations
- 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.
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- 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 / performance (P0)
- Reproductive function: oestrous cycle:
- no effects observed
- Reproductive function: sperm measures:
- no effects observed
- Reproductive performance:
- no effects observed
Effect levels (P0)
open allclose all
- 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
Target system / organ toxicity (P0)
- 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
Results: P1 (second parental generation)
General toxicity (P1)
- 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 / performance (P1)
- Reproductive function: oestrous cycle:
- no effects observed
- Reproductive function: sperm measures:
- no effects observed
- Reproductive performance:
- no effects observed
Effect levels (P1)
open allclose all
- 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
Target system / organ toxicity (P1)
open allclose all
- 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
Results: F1 generation
General toxicity (F1)
- 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
Developmental neurotoxicity (F1)
- Behaviour (functional findings):
- no effects observed
Developmental immunotoxicity (F1)
- Developmental immunotoxicity:
- not examined
Effect levels (F1)
- 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.
Target system / organ toxicity (F1)
- Key result
- Critical effects observed:
- no
Results: F2 generation
General toxicity (F2)
- 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
Developmental neurotoxicity (F2)
- Behaviour (functional findings):
- no effects observed
Developmental immunotoxicity (F2)
- Developmental immunotoxicity:
- not examined
Effect levels (F2)
- 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
Overall reproductive toxicity
- Key result
- Reproductive effects observed:
- no
Any other information on results incl. tables
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
Applicant's summary and conclusion
- 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.
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