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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
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- August 1981 - November 1981
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study with acceptable restrictions
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Reference
- Endpoint:
- sub-chronic toxicity: oral
- 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:
- effects observed, treatment-related
- Description (incidence and severity):
- Clinical signs observed in the 750 and 1500 mg/kg bw dose group: hypoactivity, coat unkempt, piloerection, dehydration, excessive salivation, wet yellow stained anogenital region, impaired righting reflex, decreased grasping reflex, decreased limb tone, hypothermia, ataxia and prostration.
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- 1500 mg/kg bw: all animals died during the first week.
750 mg/kg bw: 9/10 males and 10/10 females died before study termination. - Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Final mean body weights of the males rats in the 187 and 375 mg/kg bw dose groups were lower than the body weights of the control group 7 and 11%, respectively. Female body weights were not significantly different compared to the control group.
- 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
- 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):
- - The relative liver weights of the males and females of the 93, 187, and 375 mg/kg bw dose groups were increased. These increases in weight were statistically significantly compared with controls (t-test, P< 0.05). The weight increase was dose-related and there was no dose without effect.
- The relative kidney weights of the males and females of the 375 mg/kg bw dose group were increased. Furthermore, the relative kidney weights of the males in the 187 dose group were increased. A slight, but not significant increase in kidney weight was observed in the kidneys of the females at 187 mg/kg bw/day and in both sexes at 93 mg/kg bw/day.
- The relative weight of the right testis and lung/bronchi of the males in the 187 and 375 mg/kg bw dose groups were increased.
- The relative brain weight of females of the 375 mg/kg bw dose group was decreased. - Gross pathological findings:
- not specified
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Histopathology was performed on vehicle controls, rats receiving 375 mg/kg bw test substance and all animals dying or killed before study termination.
- Kidney: 1500 mg/kg bw dose group: kidney degeneration was reported for 27 males. 750 mg/kg bw dose group: kidney degeneration was reported for 7 males. 375 mg/kg bw dose group: one male had renal dilatation and three has tubular protein casts in the kidney but otherwise no degenerative changes.
- Liver: 375 mg/kg bw dose group: in 3 males cytoplasmic vacuolation in the liver was observed. 1500 mg/kg bw dose group: similar changes in liver were observed. 750 mg/kg bw dose group: no changes in the liver were observed.
- Reproductive organs:
375 mg/kg bw dose group: There was depressed sperm motility and a mild decrease in sperm concentration, in the assessments made at the end of the study but not on any other occasion.
750 mg/kg bw dose group: Testicular degeneration was seen in this group. This was characterised by moderate to marked loss of germinal epithelium in the seminiferous tubules and an absence of the sperm in the epididymal ducts. Syncytial giant cells of the spermatids were present in the seminiferous tubules of some rats.
No effects were seen on testes or sperm parameters or any aspect of reproductive function at lower doses.
- Thymic cortex: In the male and female rats of the 750 mg/kg bw dose group, atrophy of the thymic cortex was observed.
- Stomach: 750 mg/kg bw dose group: Gastric mucosal ulceration involving both glandular and non-glandular regions was recorded at necropsy and confirmed by microscopic examination in 3 males and in 2 females. - Histopathological findings: neoplastic:
- not specified
- Other effects:
- not specified
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- < 93 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- organ weights and organ / body weight ratios
- Key result
- Critical effects observed:
- not specified
- Lowest effective dose / conc.:
- 93 mg/kg bw/day (nominal)
- System:
- hepatobiliary
- Organ:
- liver
- Key result
- Critical effects observed:
- not specified
- Lowest effective dose / conc.:
- 93 mg/kg bw/day (nominal)
- System:
- urinary
- Organ:
- kidney
- Conclusions:
- Under the conditions of the test the NOAEL was determined to be <93 mg/kg bw/day based on the decreased male body weights and increased liver and kidney weights in males as well as females.
- Executive summary:
A 13 week repeated dose study was performed to determine the cumulative toxicity of d-carvone. F344/N rats were exposed to 0 (corn oil), 93, 187, 375, 750, and 1500 mg/kg bw. 10 animals per sex were dosed with 187 and 750 mg/kg bw d-carvone. For the remaining dose groups 30 animals per sex were used. Animals were dosed via oral gavage, 5 doses/week for 13 weeks. In the 1500 mg/kg bw dose group, all animals died during the first week. In the 750 mg/kg bw dose group, 9/10 males and 10/10 females died before study termination. Final mean body weights of the males rats in the 187 and 375 mg/kg bw dose groups were lower than the body weights of the control group 7 and 11%, respectively. Female body weights were not significantly different compared to the control group. Effects on liver, kidney, testis, lung/bronchi and brain weight were observed. The relative liver weights of the males and females of the 93, 187, and 375 mg/kg bw dose groups were increased. These increases in weight were statistically significantly compared with controls (t-test, P< 0.05). The weight increase was dose-related and there was no dose without effect. The relative kidney weights of the males and females of the 375 mg/kg bw dose group were increased. Furthermore, the relative kidney weights of the males in the 187 dose group were increased. Under the conditions of the test the NOAEL was determined to be <93 mg/kg bw/day based on the decreased male body weights and increased liver and kidney weights in males as well as females.
Cited from EFSA Journal 2014;12(7):3806:
Liver data
Dose (mg/kg)
|
Liver/Bodyweight ratio (%) Mean (SD) |
Liver/Bodyweight ratio (%) Median (Min, Max) |
Dose group / control Means Difference (95% CI)
|
p-value *
|
Control - Males |
3.50 (0.200) |
3.42 ( 3.32, 3.89) |
|
|
93 mg/kg - Males |
3.99 (0.200) |
3.98 ( 3.73, 4.31) |
0.49 (0.251, 0.723) |
<0.001 |
187 mg/kg - Males |
4.13 (0.200) |
4.10 ( 3.80, 4.54) |
0.63 (0.393, 0.865) |
<0.001 |
375 mg/kg - Males |
4.86 (0.180) |
4.83 ( 4.65, 5.19) |
1.36 (1.119, 1.590) |
<0.001 |
Control - Females |
2.96 (0.170) |
2.99 ( 2.68, 3.24) |
|
|
93 mg/kg - Females |
3.39 (0.240) |
3.30 ( 3.17, 3.97) |
0.43 (0.126, 0.726) |
0.003 |
187 mg/kg - Females |
3.47 (0.140) |
3.43 ( 3.29, 3.75) |
0.51 (0.210, 0.809) |
<0.001 |
375 mg/kg - Females |
4.19 (0.370) |
4.07 ( 3.76, 4.89) |
1.23 (0.927, 1.527) |
<0.001 |
* Tukey’s multiple comparisons of means (compared to the control group)
Kidney data
Dose (mg/kg)
|
Kidney/Bodyweight ratio (%) Mean (SD) |
Kidney/Bodyweight ratio (%) Median (Min, Max) |
Dose group / control Means Difference (95% CI)
|
p-value *
|
Control - Males |
0.31 (0.020) |
0.30 ( 0.28, 0.34) |
|
|
93 mg/kg - Males |
0.32 (0.020) |
0.32 ( 0.28, 0.34) |
0.01 (-0.008, 0.033) |
0.384 |
187 mg/kg - Males |
0.34 (0.010) |
0.33 ( 0.32, 0.36) |
0.03 (0.009, 0.051) |
0.002 |
375 mg/kg - Males |
0.38 (0.010) |
0.38 ( 0.36, 0.41) |
0.07 (0.054, 0.096) |
<0.001 |
Control - Females |
0.32 (0.020) |
0.32 ( 0.29, 0.35) |
|
|
93 mg/kg - Females |
0.34 (0.020) |
0.33 ( 0.31, 0.38) |
0.02 (-0.011, 0.044) |
0.38 |
187 mg/kg - Females |
0.34 (0.020) |
0.34 ( 0.32, 0.37) |
0.02 (-0.006, 0.048) |
0.179 |
375 mg/kg - Females |
0.36 (0.030) |
0.37 ( 0.33, 0.43) |
0.04 (0.017, 0.071) |
<0.001 |
|
|
|
|
|
* Tukey’s multiple comparisons of means (compared to the control group)
Data source
Referenceopen allclose all
- Reference Type:
- review article or handbook
- Title:
- Initial risk assessment provided by the rapporteur Member State Sweden for the existing active substance SPEARMINT OIL of the fourth stage of the review programme referred to in Article 8(2) of Council Directive 91/414/EEC.
- Author:
- KEMI (kemikalieinspektionen, Swedisch Chemicals Agency)
- Year:
- 2 008
- Bibliographic source:
- DAR, Volume 3, Annex B, Part 2, B.6
- Reference Type:
- review article or handbook
- Title:
- Unnamed
- Year:
- 2 014
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- GLP compliance:
- not specified
- 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
- Details on test material:
- - Analytical purity: approximately 96%
Constituent 1
- Specific details on test material used for the study:
- d-CARVONE
CAS NO.2244-16-8
Test animals
- Species:
- rat
- Strain:
- Fischer 344
- Details on species / strain selection:
- F 344/N rats
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Age at study initiation: 4 - 5 weeks
- Diet: ad libitum
- Water: ad libitum
- Housing: 5 animals per cage
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
- Preparation: Appropriate weight of d-carvone was dissolved in corn oil to a specified volume in a graduated cylinder. Mixture was stored under nitrogen.
- Maximum Storage Time: 1 week
- Storage Conditions: Room temperature
VEHICLE
- Justification for use and choice of vehicle (if other than water): Because the feed blends of d-carvone were found to be unstable under the feed blending and simulated dosing conditions and because d-carvone is insoluble in water, corn oil gavage was selected as the route of administration for these studies. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Stability studies performed by high-performance liquid chromatography (Varian 5000) indicated that d-carvone was stable as a bulk chemical when stored in the dark in glass containers with Teflon-lined caps at temperatures up to 25° C for 2 weeks. Samples kept at 60° C had about 3% decomposition.
The stability of d-carvone in corn oil at 0.5% (5mg/g) stored at room temperature or at 5° C for 21 days was determined. The corn oil solutions were extracted with methanol and analyzed by high-performance liquid chromatography with a Brownlee RP-18 column and ultraviolet detection at 229 nm. The d-carvone corn oil solutions were found to be stable for at least 21 days when stored in the dark at room temperature or at 5"C. The corn oil solutions were also stable under simulated dosing conditions for at least 3 hours.
The appropriate amount of d-carvone was mixed (w/v) with corn oil to give the desired concentrations. Periodic analyses of formulated d-carvone corn oil dose mixtures were conducted at the study laboratory and the analytical chemistry laboratory. Dose mixtures were analyzed before the start of, and once during, the 13-week studies. During the 13-week studies, concentrations of d-carvone in corn oil were determined by gas chromatography with a 10% Carbowax column and flame ionization detection. During the 13-week studies, all dose mixtures were found to be within 10% of the target concentrations by the study laboratory. The referee laboratory analyzed one dose mixture. - Duration of treatment / exposure:
- 13 weeks
- Frequency of treatment:
- 5 doses/ week for 13 weeks.
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 other: mg/kg bw
- Dose / conc.:
- 93 other: mg/kg bw
- Dose / conc.:
- 187 other: mg/kg bw
- Dose / conc.:
- 375 other: mg/kg bw
- Dose / conc.:
- 750 other: mg/kg bw
- Dose / conc.:
- 1 500 other: mg/kg bw
- No. of animals per sex per dose:
- 10 animals per sex per dose for the 187 and 750 mg/kg dose groups. 30 animals per sex per dose for the 0, 93, 375, and 1500 mg/kg dose groups.
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: based on toxicity observed in the 16 day (12 doses) study with 0,150, 328, 723, 1590, and 3,500 mg/kg test substance.
- Positive control:
- no postive control included.
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: All animals were observed two times per day.
DETAILED CLINICAL OBSERVATIONS: Not specified
BODY WEIGHT: Yes
- Time schedule for examinations: Body weights were recorded at the beginning of the study, once per week, and at the end of the study.
HAEMATOLOGY: No
CLINICAL CHEMISTRY: No
URINALYSIS: No - Sacrifice and pathology:
- HISTOPATHOLOGY: Necropsy was performed on all animals. Full macroscopic examination and weights of brain, lungs, heart, thymus, liver, right testis and right kidney recorded.
- Other examinations:
- Semen was collected from the animals in the 0, 93, and 375 mg/kg bw dose groups during week 2, 4, 6, and 8. Sperm concentration, motility and morphology were monitored. The same examination was conducted on all survivors at scheduled necropsy.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Clinical signs observed in the 750 and 1500 mg/kg bw dose group: hypoactivity, coat unkempt, piloerection, dehydration, excessive salivation, wet yellow stained anogenital region, impaired righting reflex, decreased grasping reflex, decreased limb tone, hypothermia, ataxia and prostration.
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- 1500 mg/kg bw: all animals died during the first week.
750 mg/kg bw: 9/10 males and 10/10 females died before study termination. - Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Final mean body weights of the males rats in the 187 and 375 mg/kg bw dose groups were lower than the body weights of the control group 7 and 11%, respectively. Female body weights were not significantly different compared to the control group.
- 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
- 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):
- - The relative liver weights of the males and females of the 93, 187, and 375 mg/kg bw dose groups were increased. These increases in weight were statistically significantly compared with controls (t-test, P< 0.05). The weight increase was dose-related and there was no dose without effect.
- The relative kidney weights of the males and females of the 375 mg/kg bw dose group were increased. Furthermore, the relative kidney weights of the males in the 187 dose group were increased. A slight, but not significant increase in kidney weight was observed in the kidneys of the females at 187 mg/kg bw/day and in both sexes at 93 mg/kg bw/day.
- The relative weight of the right testis and lung/bronchi of the males in the 187 and 375 mg/kg bw dose groups were increased.
- The relative brain weight of females of the 375 mg/kg bw dose group was decreased. - Gross pathological findings:
- not specified
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Histopathology was performed on vehicle controls, rats receiving 375 mg/kg bw test substance and all animals dying or killed before study termination.
- Kidney: 1500 mg/kg bw dose group: kidney degeneration was reported for 27 males. 750 mg/kg bw dose group: kidney degeneration was reported for 7 males. 375 mg/kg bw dose group: one male had renal dilatation and three has tubular protein casts in the kidney but otherwise no degenerative changes.
- Liver: 375 mg/kg bw dose group: in 3 males cytoplasmic vacuolation in the liver was observed. 1500 mg/kg bw dose group: similar changes in liver were observed. 750 mg/kg bw dose group: no changes in the liver were observed.
- Reproductive organs:
375 mg/kg bw dose group: There was depressed sperm motility and a mild decrease in sperm concentration, in the assessments made at the end of the study but not on any other occasion.
750 mg/kg bw dose group: Testicular degeneration was seen in this group. This was characterised by moderate to marked loss of germinal epithelium in the seminiferous tubules and an absence of the sperm in the epididymal ducts. Syncytial giant cells of the spermatids were present in the seminiferous tubules of some rats.
No effects were seen on testes or sperm parameters or any aspect of reproductive function at lower doses.
- Thymic cortex: In the male and female rats of the 750 mg/kg bw dose group, atrophy of the thymic cortex was observed.
- Stomach: 750 mg/kg bw dose group: Gastric mucosal ulceration involving both glandular and non-glandular regions was recorded at necropsy and confirmed by microscopic examination in 3 males and in 2 females. - Histopathological findings: neoplastic:
- not specified
- Other effects:
- not specified
Effect levels
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- < 93 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- organ weights and organ / body weight ratios
Target system / organ toxicity
open allclose all
- Key result
- Critical effects observed:
- not specified
- Lowest effective dose / conc.:
- 93 mg/kg bw/day (nominal)
- System:
- hepatobiliary
- Organ:
- liver
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- not specified
- Key result
- Critical effects observed:
- not specified
- Lowest effective dose / conc.:
- 93 mg/kg bw/day (nominal)
- System:
- urinary
- Organ:
- kidney
- Treatment related:
- yes
- Dose response relationship:
- not specified
- Relevant for humans:
- not specified
Any other information on results incl. tables
Cited from EFSA Journal 2014;12(7):3806:
Liver data
Dose (mg/kg)
|
Liver/Bodyweight ratio (%) Mean (SD) |
Liver/Bodyweight ratio (%) Median (Min, Max) |
Dose group / control Means Difference (95% CI)
|
p-value *
|
Control - Males |
3.50 (0.200) |
3.42 ( 3.32, 3.89) |
|
|
93 mg/kg - Males |
3.99 (0.200) |
3.98 ( 3.73, 4.31) |
0.49 (0.251, 0.723) |
<0.001 |
187 mg/kg - Males |
4.13 (0.200) |
4.10 ( 3.80, 4.54) |
0.63 (0.393, 0.865) |
<0.001 |
375 mg/kg - Males |
4.86 (0.180) |
4.83 ( 4.65, 5.19) |
1.36 (1.119, 1.590) |
<0.001 |
Control - Females |
2.96 (0.170) |
2.99 ( 2.68, 3.24) |
|
|
93 mg/kg - Females |
3.39 (0.240) |
3.30 ( 3.17, 3.97) |
0.43 (0.126, 0.726) |
0.003 |
187 mg/kg - Females |
3.47 (0.140) |
3.43 ( 3.29, 3.75) |
0.51 (0.210, 0.809) |
<0.001 |
375 mg/kg - Females |
4.19 (0.370) |
4.07 ( 3.76, 4.89) |
1.23 (0.927, 1.527) |
<0.001 |
* Tukey’s multiple comparisons of means (compared to the control group)
Kidney data
Dose (mg/kg)
|
Kidney/Bodyweight ratio (%) Mean (SD) |
Kidney/Bodyweight ratio (%) Median (Min, Max) |
Dose group / control Means Difference (95% CI)
|
p-value *
|
Control - Males |
0.31 (0.020) |
0.30 ( 0.28, 0.34) |
|
|
93 mg/kg - Males |
0.32 (0.020) |
0.32 ( 0.28, 0.34) |
0.01 (-0.008, 0.033) |
0.384 |
187 mg/kg - Males |
0.34 (0.010) |
0.33 ( 0.32, 0.36) |
0.03 (0.009, 0.051) |
0.002 |
375 mg/kg - Males |
0.38 (0.010) |
0.38 ( 0.36, 0.41) |
0.07 (0.054, 0.096) |
<0.001 |
Control - Females |
0.32 (0.020) |
0.32 ( 0.29, 0.35) |
|
|
93 mg/kg - Females |
0.34 (0.020) |
0.33 ( 0.31, 0.38) |
0.02 (-0.011, 0.044) |
0.38 |
187 mg/kg - Females |
0.34 (0.020) |
0.34 ( 0.32, 0.37) |
0.02 (-0.006, 0.048) |
0.179 |
375 mg/kg - Females |
0.36 (0.030) |
0.37 ( 0.33, 0.43) |
0.04 (0.017, 0.071) |
<0.001 |
|
|
|
|
|
* Tukey’s multiple comparisons of means (compared to the control group)
Applicant's summary and conclusion
- Conclusions:
- Under the conditions of the test the NOAEL was determined to be <93 mg/kg bw/day based on the decreased male body weights and increased liver and kidney weights in males as well as females.
- Executive summary:
A 13 week repeated dose study was performed to determine the cumulative toxicity of d-carvone. F344/N rats were exposed to 0 (corn oil), 93, 187, 375, 750, and 1500 mg/kg bw. 10 animals per sex were dosed with 187 and 750 mg/kg bw d-carvone. For the remaining dose groups 30 animals per sex were used. Animals were dosed via oral gavage, 5 doses/week for 13 weeks. In the 1500 mg/kg bw dose group, all animals died during the first week. In the 750 mg/kg bw dose group, 9/10 males and 10/10 females died before study termination. Final mean body weights of the males rats in the 187 and 375 mg/kg bw dose groups were lower than the body weights of the control group 7 and 11%, respectively. Female body weights were not significantly different compared to the control group. Effects on liver, kidney, testis, lung/bronchi and brain weight were observed. The relative liver weights of the males and females of the 93, 187, and 375 mg/kg bw dose groups were increased. These increases in weight were statistically significantly compared with controls (t-test, P< 0.05). The weight increase was dose-related and there was no dose without effect. The relative kidney weights of the males and females of the 375 mg/kg bw dose group were increased. Furthermore, the relative kidney weights of the males in the 187 dose group were increased. Under the conditions of the test the NOAEL was determined to be <93 mg/kg bw/day based on the decreased male body weights and increased liver and kidney weights in males as well as females.
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