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Description of key information

The studies on acute oral toxicity were not performed according to guideline methods. However, the number of treated animals and the used protocols are scientifically acceptable to evaluate this endpoint sufficiently.
A valid study on acute inhalation toxicity according OECD TG 403 was conducted.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: sufficient documented for evaluation
Principles of method if other than guideline:
Groups of 10 young adult Osborne-Medel rats were given menthol by intubation. Animals were observed for 2 weeks during which time the development of toxic signs were followed and time of death noted. The acute oral LD50 was determined.
GLP compliance:
no
Test type:
standard acute method
Specific details on test material used for the study:
OTHER SPECIFICS: Menthol (p-menthan-3-ol)
Species:
rat
Strain:
Osborne-Mendel
Sex:
male/female
Route of administration:
oral: gavage
Vehicle:
corn oil
Doses:
no data
No. of animals per sex per dose:
5 males + 5 females/group
Control animals:
not specified
Key result
Dose descriptor:
LD50
Effect level:
3 180 mg/kg bw

toxic signs: ataxia, scrawny appearance

death time: 4 hr - 3 days

Interpretation of results:
GHS criteria not met
Conclusions:
The acute oral LD50 was 3180 mg/kg bw (rat, male/female)
Executive summary:

Groups of 10 young adult Osborne-Medel rats were given menthol by intubation. Animals were observed for 2 weeks during which time the development of toxic signs were followed and time of death noted.

The acute oral LD50 was 3180 mg/kg bw (rat, male/female)

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
3 180 mg/kg bw
Quality of whole database:
Sufficient documented for evaluation.

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Principles of method if other than guideline:
Two groups of 5 male and female rats each were nose-only at actual aerosol concentration of 4225 and 5038 mg/m³. The aerosol was generated neat without any vehicle (aerosolization of the molten crystalline, solid substance above the melting point). The animals were observed for mortality, weight and clinical signs through day 14. A gross necropsy was performed.
GLP compliance:
yes
Test type:
standard acute method
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: CHHYDN0130
- Purity: D-Menthol 50.6%
L-Menthol 49.4%
Nonvolatile residue: 0.01%
Water: 0.01%

FORM AS APPLIED IN THE TEST
White crystalline solid

OTHER SPECIFICS:
Characterization of chamber atmosphere - Mean values
Group 1 Group 2 Group 3
Target Conc. (mg/m³) 0 4500 5000
Gravimetric Conc. (mg/m³) -- 4225 5037.5

Cascade Impactor:
MMAD (μm) -- 3.16 3.07
GSD 1.63 1.97
Mass <3 μm (%) 46.0 50.1
Species:
rat
Strain:
Wistar
Sex:
male/female
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
air
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
0, 4225, or 5038 mg/m³
No. of animals per sex per dose:
5 male and 5 female animals per dose
Control animals:
yes
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
ca. 5 289 mg/m³ air
Based on:
act. ingr.
Exp. duration:
4 h
Remarks on result:
other: LC50 inhalation aerosol

Summary of acute inhalation toxicity - 4 hour exposure - Mean values

NGroup /sex       Target Concentration (mg/m³)       Toxicological Result       Onset and Duration of Signs       Onset of Mortality

1 / m                                   0                                          0 / 0 / 5                             --                                           --

2 / m                                    4500                                    0 / 5 / 5                             0d– 10d                                  --

3 / m                                    5000                                    2 / 1 / 3                             0d – 14d                             3h

1 / f                                    0                                           0 / 0 / 5                               --                                         --

2 / f                                    4500                                    0 / 5 / 5                             0d – 8d                             --

3 / f                                    5000                                    1 / 2 / 3                             0d – 8d                                  2h

N = group assignment, m = males, f = females, animals found dead 2-3h after onset of exposure (0h-

3h), * = p < 0.05, ** = p < 0.01.

Values given in the 'Toxicological results' column are: 1st = number of dead animals, 2nd = number of

animals with signs after cessation of exposure, 3rd = number of animals exposed.

Necropsy

The qualitative description given below focuses on key-findings only.

Animals succumbing during the observation period: The most salient findings are characterized by colorless discharge from nose and a viscous, white content in the nostrils; less collapsed lung; stomach: bloated; small intestine: reddened mucosa and red mucous content; parenchymatous organs: pallor.

Animals sacrificed at the end of the observation period: The macroscopic findings in surviving rats were essentially indistinguishable from the control.

Interpretation of results:
GHS criteria not met
Executive summary:

A study on the acute inhalation toxicity of DL-Menthol on rats has been conducted in accordance with OECD TG#403 (2009). Two groups of rats were exposed nose-only at actual aerosol concentration of 4225 and 5038 mg/m³. The aerosol was generated neat without any vehicle (aerosolization of the molten crystalline, solid substance above the melting point).

The results can be summarized as follows:

LC50 (inhalation aerosol, 4 h) Approximate LC50-males&females: 5289 mg/m³.

NO(A)EL Males&females: <4225 mg/m³

The following clinical signs were observed: bradypnea, labored breathing pattern, dyspnea, motility reduced, atony, tremor, high-legged gait, staggering gait, movements uncoordinated, piloerection, haircoat ungroomed, nasal discharge (serous), nose and/or muzzle: red encrustations, nostrils: red encrustations, stridor, breathing sounds, apathy, narcosis, prostration, miosis, hypothermia, decreased reflexes, and transient decrease in body weights. The lead pathodiagnostic effects were suggestive of a narcotic condition associated with increased airway secretions/mucous membrane irritation. Consistent with this mode of action, mortality occurred at 5038 mg/m³ during the course of the exposure period. CNS-related effects were rapidly reversible. Bradypnea and labored breathing patterns were observed up to postexposure day 10.

The respirability of the aerosol was adequate to achieve the objective of study, i.e. the average mass median aerodynamic diameter (MMAD) was 3.1 μm, the average geometric standard deviation (GSD) was 1.8.

The aerosolized test substance proved to have a low acute inhalation toxicity in rats and a classification is not justified.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
Value:
5 289 mg/m³ air
Quality of whole database:
GLP guideline study.

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available
Quality of whole database:
Data from a secondary source showed a LD50 > 5000 mg/kg bw for acute dermal toxicity.

Additional information

Studies on rats and mice showed acute oral toxicity with LD50 values higher than 2000 mg/kg bw with one exception where a value of 940 mg/kg bw was found in an insufficient documented mutagenic evaluation study.

In the acute inhalation toxicity study on rats a LC50 (aerosol, 4h) = 5289 mg/m³ was determined.

Data from a secondary source showed a LD50 > 5000 mg/kg bw for acute dermal toxicity.

Justification for classification or non-classification

In the reliable acute oral toxicity study demonstrated a low systemic toxicity with a LD50 higher than 2000 mg/kg bw.

In the acute inhalation study a LC50 > 5000 mg/m³ was (rat, aerosol, 4 h) was determined.

According to CLP classification criteria (Regulation (EC) No 1272/2008) a classification is therefore not justified.