Menthol

Acute Toxicity: inhalation

Administrative data

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

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2012

Report date:

2012

Materials and methods

Test guideline

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

Test material

Test material information

Constituent 1

Reference substance name:

Menthol

EC Number:

201-939-0

EC Name:

Menthol

Cas Number:

89-78-1

Molecular formula:

C10H20O

IUPAC Name:

2-isopropyl-5-methylcyclohexanol

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

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Administration / exposure

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

Results and discussion

Effect levels

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

Any other information on results incl. tables

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.

Applicant's summary and conclusion

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.