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EC number: 237-926-1 | CAS number: 14073-97-3
- 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
Endpoint summary
Administrative data
Description of key information
Read-across compound DL-menthol is not toxic in rats when applied daily by oral (feed) at a dose of 375 mg/kg bw/day for 103 weeks (data derived to L-menthan-3-one NOEL = 370 mg/kg bw/day).
Key value for chemical safety assessment
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- chronic toxicity: oral
- Remarks:
- combined repeated dose and carcinogenicity
- Type of information:
- migrated information: read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Not GLP compliant study, no guideline specifically mentionned. However, the study is documented enough to be scientifically assessed and found reliable.
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
- GLP compliance:
- not specified
- Limit test:
- no
- Species:
- rat
- Strain:
- Fischer 344
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Frederick Cancer Research Center, Frederick, Maryland
- Age at study initiation: 9 weeks
- Weight at study initiation: Not specified
- Diet (e.g. ad libitum): Wayne Lab Chow Meal and water available ad libitum
- Housing: Polycarbonate cages covered with stainless steel cage lids and non-woven fiber filter bonnets (Filtek, Appleton, Wis.).
Rats were housed 5 per cage until week 48, and then the males were divided into groups of 2 or 3 per cage.
- Diet : ad libitum
- Water : ad libitum
- Acclimation period: 4 weeks
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24 °C
- Humidity (%): 45-55%
- Air changes (per hr): 12 changes per hour
- Photoperiod : 12 hours dark/ 12 hours light - Route of administration:
- oral: feed
- Vehicle:
- corn oil
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
DIET PREPARATION
- Rate of preparation of diet (frequency): prepared each week and used within 1 week of preparation.
- Storage temperature of food: The containers were stored at room temperature. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Duplicate 10g dosed feed sample were extracted with 20ml of carbon disulfide, and aliquots of the extract analyzed by gas chromatography (thermal conductivity detector).
(see attached illustration for values) - Duration of treatment / exposure:
- The compound was administered in the diet seven days a week for 103 weeks at the indicated level.
During the 2 weeks of observation, the animals were supplied with standard diet. - Frequency of treatment:
- Feed hoppers were sanitized once a week at 81°C.
- Remarks:
- Doses / Concentrations:
0.375 %
Basis:
nominal in diet - Remarks:
- Doses / Concentrations:
0.75%
Basis:
nominal in diet - No. of animals per sex per dose:
- 50 animals per dose (sex ratio not mentionned)
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: Based on the results of 13-week study (see cross reference studies).
- Rationale for animal assignment (if not random): Animals were segregated by body weight so that a homogeneous distribution of mean weight ranges was obtained between groups. - Observations and examinations performed and frequency:
- All animals were observed twice a day for signs of toxicity.
Clinical signs and the presence of palpable masses were recorded every week.
Mean body weights and food consumption were recorded every 2 weeks for the first 12 weeks and every month thereafter. - Sacrifice and pathology:
- Animals that were moribund and those that survived to the termination of the study were killed by exsanguination under sodium pentobarbital anesthesia (Diabutal, Diamond Laboratories, Inc., Des Moines, Iowa).
The pathologic evaluation consisted of gross and microscopic examination of major tissues, major organs, and all gross lesions from killed animals and from animals found dead. The tissues were preserved in 10% buffered formalin, embedded in paraffin, sectioned, and stained with hematoxylin and eosin. The following tissues were examined microscopically: brain (frontal cortex and basal ganglia, parietal cortex and thalamus, and cerebellum and pons), pituitary, spinal cord (if neurologic signs were present), eyes (if grossly abnormal), esophagus, trachea, salivary gland, mandibular lymph node, thyroid, parathyroid, heart, thymus, lungs and mainstem bronchi, liver, gallbladder (mice), pancreas, spleen, kidney, adrenal, stomach, small intestine, colon, urinary bladder, prostate or uterus, testes or ovaries, sternebrae, femur, or vertebrae including marrow, mammary gland, tissue masses, and any macroscopic lesions.
A few tissues from some animals were not examined, particularly from those animals that died early. Also, some animals may have been missing, cannibalized, or judged to be in such an advanced state of autolysis as to preclude histopathologic evaluation. Thus, the number of animals from which particular organs or tissues were examined microscopically varies, and does not necessarily represent the number of animals that were placed on study in each group. - Statistics:
- Pertinent data on this experiment have been recorded in an automatic data processing system, the Carcinogenesis Bioassay Data System (Linhart et al., 1974).
Probabilities of survival were estimated by the product-limit procedure of Kaplan and Meier (1958)
Statistical analyses for a possible dose-related effect on survival used the method of Cox (1972) for testing 2 groups for equality and Tarone's (1975) extensions of Cox's methods for testing dose related trend.
The one-tailed Fisher exact test (Cox, 1970) wa used to compare the tumor incidence of a control group with that of a group of dosed animals at each dose level.
The Cochran-Armitage test for linear trend in proportions, with continuity correction (Armitage, 1971) was also used. - Clinical signs:
- no effects observed
- Description (incidence and severity):
- not significant in either sex
- Mortality:
- no mortality observed
- Description (incidence):
- not significant in either sex
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- mean body weight gains in dosed groups were slightly lower than in the control groups
- Food consumption and compound intake (if feeding study):
- not specified
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- nephritis of questionable origin (see below "Details on results")
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- A. Body Weights and Clinical Signs (Rats)
Mean body weights of the dosed male and female rats were slightly lower than those of the corresponding controls throughout the bioassay. No other clinical signs related to administration of the dl—menthol were noted. Clinical signs commonly observed among rats of this strain were noted at comparable rates in the control and dosed groups, particularly during the second year of the bioassay, and increased in incidence as the animals aged. These signs included eye changes (redness, paleness, cloudiness, lacrimination, a red discharge or bloody crust, and an enlarged or protruding eye), a hunched and/or thin appearance, urine stains on the abdominal fur, and occasionally, nasal discharge, sores on the body or the extremities, soft feces, and enlarged testes.
The incidence of palpable nodules and tissue masses in the dosed males was generally comparable to that in the control males, but was lower in the dosed females than in the control females.
B. Survival (Rats)
The Kaplan and Meier curves estimates the probabilities of survival for male and female rats administered dl—menthol in the diet at the doses of this bioassay, together with those of the matched controls. The results of the Tarone test for dose—related trend in mortality and the results of the Cox test comparing the survival of the control group with each dosed group are not significant in either sex.
In male rats, 34/50 (68%) of the high—dose group, 33/50 (66%) of the low—dose group, and 31/50 (62%) of the controls were alive at week 105. In females, 38/50 (76%) of the high—dose group, 35/50 (70%) of the low—dose group, and 36/50 (72%) of the controls were alive at week 105. Sufficient numbers of rats of each sex were at risk for the development of late—appearing tumors.
C. Pathology (Rats)
Each of the tumor types observed has been encountered previously as a spontaneous lesion, and occurred with no appreciable differences in frequency between control and dosed rats with a few exceptions. In female rats, chromophobe adenomas of the pituitary gland and fibroadenomas of the mammary gland were observed with greater frequency in female control rats. Chromophobe adenomas occurred in 28/48 controls, 25/47 low—dose, and 19/43 high—dose female rats. Mammary gland fibroadenomas were diagnosed in 20/50 female controls, 10/49 low—dose, and 7/49 high—dose rats. Mammary adenocarcinomas were seen in 1/50 controls, 3/49 low—dose, and 0/49 high—dose rats.
Chronic inflammation of the kidney was observed with greater frequency in the dosed males than in the control males (29/49 controls, 41/50 low—dose, 41/50 high—dose); however, this finding is of questionable importance, since such lesions are often found in aged male Fischer 344 rats.
All other inflammatory, degenerative, and hyperplastic lesions that occurred were similar in incidence and kind to those naturally occurring lesions found in aged Fischer 344 rats. - Dose descriptor:
- NOAEL
- Effect level:
- > 7 500 ppm
- Based on:
- act. ingr.
- Sex:
- male/female
- Basis for effect level:
- other: overall effects
- Remarks on result:
- not determinable
- Remarks:
- no NOAEL identified
- Dose descriptor:
- NOAEL
- Effect level:
- > 375 mg/kg bw/day (nominal)
- Based on:
- act. ingr.
- Sex:
- male/female
- Basis for effect level:
- other: No effects were observed; 7500 ppm in diet applied to rats were converted to 375 mg/kg/day calculated for rats with a mean body weight of 400 g and 20 g/day of food consumption
- Remarks on result:
- not determinable
- Remarks:
- no NOAEL identified
- Dose descriptor:
- NOAEL
- Effect level:
- > 370 mg/kg bw/day (nominal)
- Based on:
- other: L-menthan-3-one
- Sex:
- male/female
- Remarks on result:
- not determinable
- Remarks:
- no NOAEL identified
- Critical effects observed:
- not specified
- Conclusions:
- Based on the histopathologic examination, DL-menthol was neither toxic nor carcinogenic to Fischer 344 rats under the conditions of this bioassay.
- Executive summary:
Mean body weights of the dosed rats and mice were slightly lower than those of corresponding controls. No other clinical signs related to administration of DL-menthol were noted in any dosed groups of rats and mice. Survival at the end of the bioassay was at least 62% in all dosed and control groups of animals of each species, and sufficient numbers of animals were at risk for the development of late-appearing tumours.
In male rats, no tumours occurred at incidences which were considered to be associated with the administration of DL-menthol.
In female rats, no tumours occurred at higher incidences in dosed groups than in control groups. Fibro adenomas of the mammary gland occurred at lower incidences in the low-dose (10/49) and high-dose (7/49) groups than in the control group (20/50), and alveolar/bronchiolar adenomas or carcinomas of the lung occurred only in the controls (3/50).The acute oral LD50 of menthol in Osborne-Mendel rats has been reported as 3,180 mg/kg body weight (Jenner et al., 1964) and as 2,900 mg/kg body weight (Herken, 1961).When administered in the diet to male and female rats for 5.5 weeks, D- or DL-menthol at 100 or 200 mg/kg body weight caused no adverse effects on gain in weight (Herken, 1961). No long-term studies have been reported previous to the present bioassay.
It is concluded that under the conditions of this bioassay, DL-menthol was not carcinogenic for either Fischer 344 rats or B6C3F1 mice.
Reference
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 370 mg/kg bw/day
- Study duration:
- chronic
- Species:
- rat
- Quality of whole database:
- Four reliable studies: chronic in rat and mouse and subchronic in rat and mouse are available for LD-menthol as read-across compound. One unreliable subacute study in rat is available for menthone (racemic).
Repeated dose toxicity: inhalation - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: inhalation - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
- Repeated dose toxicity, oral:
There is no data on L-menthan-3-one.
According to reliable chronic (103-week) repeated dose toxicity studies in rat and mouse, the NOAEL for the read-across compound DL-menthol was not identified, since at the highest intake dose no adverse effect was observed, i.e at 375 mg/kg bw/day (370 mg/kg bw/day for L-menthan-3-one) in rat and at 667 mg/kg bw/day (658 mg/kg bw/day for L-menthan-3-one) in mouse. In two reliable 90-day studies, basing on few examination parameters (clinical signs and mortality, body weight and weight gain, haematology and histopathology), the NOAEL of the read-across compound LD-menthol was identified: 750 mg/kd bw/day in rat and 1250 mg/kg bw/day in mouse. The available results show that toxicity of the compound does not lead to a RE-STOT classification according to CLP.
- Repeated dose toxicity, dermal: no studies available
- Repeated dose toxicity, inhalation: no studies available
Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Read-across from reliable 103-week DL-menthol study. This study in rats provides better profile on results of examinations comparing to 90-day DL-menthol study in rat.
Justification for classification or non-classification
- Repeated dose toxicity, oral:
Based on the above stated assessment of the specific target organ toxicity potential after repeated oral exposure of read-across compound DL-menthol, L-menthan-3-one does not need to be classified according to Council Directive 2001/59/EC (28th ATP of Directive 67/548/EEC) or according to CLP (Regulation (EC) No 1272/2008 of the European Parliament and of the Council) as implementation of UN-GHS in the EU.
- Repeated dose toxicity, dermal:
As no data on of the specific target organ toxicity potential after repeated dermal exposure of L-menthan-3-one is available a classification is not possible according to Council Directive 2001/59/EC (28th ATP of Directive 67/548/EEC) and according to CLP (Regulation (EC) No 1272/2008 of the European Parliament and of the Council) as implementation of UN-GHS in the EU.
- Repeated dose toxicity, inhalation:
As no reliable data on of the specific target organ toxicity potential after repeated inhalation exposure of L-menthan-3-one is available a classification is not possible according to Council Directive 2001/59/EC (28th ATP of Directive 67/548/EEC) and according to CLP (Regulation (EC) No 1272/2008 of the European Parliament and of the Council) as implementation of UN-GHS in the EU.
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