Registration Dossier

Administrative data

Description of key information

No data are availabe for (±)-neomenthol, therefore reliable data from the menthol category group were used.

Oral, rat (WoE): LD50: 2046 mg/kg bw

Dermal, rat: LD50 >5000 mg/kg bw (RL4 not sufficient for classification)

Inhalation, rat: LC50 (aerosol, 4 h): 5289 mg/m³

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
Please refer to IUCLID section 13 for a detailed justification of the category approach.
Reason / purpose:
read-across source
Related information:
Composition 1
Reason / purpose:
read-across source
Related information:
Composition 1
Reason / purpose:
read-across source
Related information:
Composition 1
Reason / purpose:
read-across source
Related information:
Composition 1
Reason / purpose:
read-across source
Related information:
Composition 1
Reason / purpose:
read-across source
Related information:
Composition 1
Reason / purpose:
read-across source
Related information:
Composition 1
Reason / purpose:
read-across source
Related information:
Composition 1
Test material information:
Composition 1
Sex:
female
Dose descriptor:
LD50
Remarks:
rat
Effect level:
2 602 mg/kg bw
Based on:
test mat.
95% CL:
> 2 328 - < 2 861
Remarks on result:
other: study from 1974a
Key result
Sex:
female
Dose descriptor:
LD50
Remarks:
rat
Effect level:
2 046 mg/kg bw
Based on:
test mat.
95% CL:
> 1 777 - < 2 303
Remarks on result:
other: study from 1974b
Sex:
female
Dose descriptor:
LD50
Remarks:
rat
Effect level:
2 615 mg/kg bw
Based on:
test mat.
95% CL:
> 2 156 - < 2 998
Remarks on result:
other: study from 1974c
Sex:
female
Dose descriptor:
LD50
Remarks:
rat
Effect level:
2 426 mg/kg bw
Based on:
test mat.
95% CL:
> 2 144 - < 2 662
Remarks on result:
other: study from 1974d
Sex:
not specified
Dose descriptor:
LD50
Remarks:
rat
Effect level:
3 180 mg/kg bw
Based on:
test mat.
Remarks on result:
other: study from 1964
Sex:
male
Dose descriptor:
LD50
Remarks:
mouse
Effect level:
1 470 mg/kg bw
Based on:
test mat.
Remarks on result:
other: study from 1980a
Sex:
male
Dose descriptor:
LD50
Remarks:
mouse
Effect level:
ca. 9 mL/kg bw
Based on:
test mat.
Remarks on result:
other: study from 1980b
Sex:
not specified
Dose descriptor:
LD50
Remarks:
mouse
Effect level:
3 400 mg/kg bw
Based on:
test mat.
Remarks on result:
other: study from 1932
Mortality:
1974a: deaths: 2000 mg/kg bw: 1/10; 2500 mg/kg bw: 4/10; 3000 mg/kg bw: 7/10; 3500 mg/kg bw: 10/10
1974b: deaths: 1000 mg/kg bw: 0/10; 1500 mg/kg bw: 1/10; 2000 mg/kg bw: 5/10; 2500 mg/kg bw: 7/10; 3000 mg/kg bw: 10/10
1974c: deaths: 1000 mg/kg bw: 0/10; 2000 mg/kg bw: 3/10; 2500 mg/kg bw: 4/10; 3000 mg/kg bw: 6/10; 3500 mg/kg bw: 7/10; 4000 mg/kg bw: 10/10
1974d: deaths: 1000 mg/kg bw: 0/10; 2000 mg/kg bw: 2/10; 2400 mg/kg bw: 4/10; 2700 mg/kg bw: 7/10; 3000 mg/kg bw: 9/10
1980a: deaths: 681 mg/kg bw: 0/2; 1000 mg/kg bw: 0/2; 1470 mg/kg bw: 1/2; 2150 mg/kg bw: 2/2
1980b: deaths: 4.64 mL/kg bw: 0/2; 6.81 mL/kg bw: 0/2; 8.25 mL/kg bw: 1/2; 10 mL/kg bw: 1/2; 12.1 mL/kg bw: 2/2
Clinical signs:
1974a/c/d: 1-3 days after application animals were in a narcosis-like state.
1974b: 1-2 day after application animals were in a narcosis-like state.
1964: toxic signs: ataxia, scrawny appearance
1980a: signs of intoxication included sedation, ataxia, dyspnoe , laying in a prone position, and muscular hypotony
1980b: Signs of intoxication included sedation, ataxia, dyspnoe, and laying in a prone position.
Gross pathology:
1980b: Necropsy in one animal revealed that the liver was pale.
Interpretation of results:
other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No 1272/2008
Conclusions:
In several acute oral toxicty study in rats (standard species), the LD50 of menthols was determined at least 2046 mg/kg bw.
Executive summary:

Several studies are available from three category group members (menthol, (+)-menthol and L-menthol). The LD50 for (±)-neomenthol was estimated to be 2046 mg/kg bw from these studies. As explained in the justification for type of information, the differences in molecular structure between the target and the source are unlikely to lead to differences in the oral LD50.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
2 046 mg/kg bw
Quality of whole database:
The available information comprises adequate, reliable studies from reference substances with similar structure and intrinsic properties. Read-across is justified based on structural similarities of menthols in PC/ECO/TOX properties (refer to category justification for further details).
Taken together, the information from these independent sources is consistent and provides sufficient weight of evidence for hazard assessment leading to an endpoint conclusion in accordance with Annex XI, 1.2, of Regulation (EC) No 1907/2006. Therefore, the available information as a whole is sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
Please refer to IUCLID section 13 for a detailed justification of the category approach.
Reason / purpose:
read-across source
Related information:
Composition 1
Limit test:
no
Test material information:
Composition 1
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
Mortality:
2/3 male rats and 1/3 female rats died in the highest dose group. None died in the 4225 mg/m³ dose group.
Clinical signs:
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;
CNS-related effects were rapidly reversible. Bradypnea and labored breathing patterns were observed up to postexposure day 10.
Body weight:
transient decrease in body weights
Gross pathology:
Animals succumbing during the observation period: 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.

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:
other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No 1272/2008
Conclusions:
(±)-neomenthol was estimated to be of low acute toxicity when applied as aerosol to rats. The LC50 (rat, aerosol, 4h) found was 5289 mg/m³ and therefore above the threshold for classification being 5 mg/L according to CLP (Regulation (EC) No 1272/2008).
Executive summary:

One study is available from one category group member (menthol, CAS 89-78-1). The LC50 for (±)-neomenthol was estimated to be 5289 mg/m³ from this study. As explained in the justification for type of information, the differences in molecular structure between the target and the source are unlikely to lead to differences in the inhalative LC50.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
5 289 mg/m³
Quality of whole database:
The available information comprises an adequate and reliable study from a reference substance with similar structure and intrinsic properties. Read-across is justified based on structural similarities of menthols in PC/ECO/TOX properties (refer to category justification for further details). The selected study is thus sufficient to fulfil the standard information requirements set out in Annex VIII, 8.5, in accordance with Annex XI, 1.5, of Regulation (EC) No. 1907/2006.

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Data waiving:
other justification
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
5 000 mg/kg bw
Quality of whole database:
The available information comprises one study (reliability 4) from a reference substance with similar in structure and intrinsic properties. Read-across is justified based on structural similarities of menthols in PC/ECO/TOX properties (refer to category justification for further details). The selected indicates that menthols are of low toxicity regarding acute dermal toxicity.

Additional information

There is no reliable acute dose toxicity study on (±)-neomenthol available.

Justification for Read-across:

Based on the identical profiles of the different menthols and supported by the Read-Across Justification for menthols (IUCLID chapter 13) all studies on stereoisomers of (±)-neomenthol are used for read across. These isomers are L-menthol (CAS 2216-51-5), (+)-menthol (CAS 15356-60-2), D/L-menthol (CAS 1490 -04 -6) and menthol (CAS 89-78-1).Moreover, a comparative physico-chemical profile of these isomers reinforces this similarity. As structural isomers, the members of the menthol category share the same molecular weight. Of particular importance to environmental effects and human effects are the values for partition coefficient (log Pow between 3.12 and 3.45 at 25°C), vapour pressure (from 3.6 to 21 Pa at 25°C) and water solubility (moderately soluble from 231 to 456 mg/L at 25°C). The read across is consistent based on these physico-chemical parameters.

Details on the Acute toxicity studies with menthols:

ORAL:

Several studies are availabe which are used as weight of evidence approach since the are all older studies prior to guideline and GLP.

A LD50 value of 3400 mg/kg for L-menthol was determined in mice (1932). An oral LD50 value in rat was found to be 2615 mg/kg bw for L-menthol (1974c), 2602 mg/kg bw, 2426 mg/kg bw and 3180 mg/kg bw for menthol (1974a, b and 1964, respectively), and 2046 mg/kg bw for (+)-menthol (1974b).

Two studies, one with menthol (1980a and b) administered to NMRI mice by gavage resulted in a LD50 value of 1.47 g/kg bw and 9 mL/kg bw, respectively. The studies are not regarded to be relevant for classification because only 2 animals per dose were used and in case of the of 9 mL/kg bw dose no information was found to translate the result into a mg/kg bw value.

Therefore, LD50 of 2046 mg/kg bw was the lowest LD50 value found in these studies. It can be assumed that (±)-neomenthol has a low acute oral toxic potential.

 

INHALATIVE:

The acute inhalative toxicity testing was determined in an OECD 403 study using rats, administering menthol as aerosol. The LC50 in this study (4 hours exposure) was determined to be 5289 mg/m³ and therefore also (±)-neomenthol is considered to have a low acute inhalative toxic potential.

 

DERMAL:

The acute dermal LD50 of L-menthol in rabbits was determined to be greater than 5000 mg/kg bw from secondary literature.

It can be assumed that L-menthol and thus (±)-neomenthol has a low acute dermal toxic potential but this study is not sufficient to use for classification as the documentation is insufficient for assessment.

 

Justification for classification or non-classification

Studies performed by oral and inhalation exposure indicate LD50 values beyond the limits for classification and hence (±)-neomenthol does not meet the criteria for classification and labelling for these endpoints, as set out in Regulation (EC) No. 1272/2008. For dermal exposure the available study is not sufficient for assessment.

Specific target organ toxicity: According to CLP classification criteria, the substance does not meet the criteria for classification and labelling for this endpoint (STOT single exposure) as set out in Regulation (EC) No. 1272/2008 as no indications were observed in acute animal studies.