Registration Dossier

Administrative data

Description of key information

No data is availabe with (±)-neomenthol. Reliabel data are available from L-menthol and (+)-menthol.

L-menthol and thus (±)-neomenthol are:
Skin irritant.
Eye irritant.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation: in vivo
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
Reason / purpose:
read-across source
Related information:
Composition 1
Test material information:
Composition 1
Irritation parameter:
erythema score
Remarks:
L-menthol at 100%
Basis:
mean
Time point:
24/48/72 h
Score:
3
Max. score:
4
Reversibility:
not fully reversible within: 14 days
Remarks on result:
other: underlying skin intact despite white to white-brown scales
Irritation parameter:
erythema score
Remarks:
L-menthol at 50%
Basis:
mean
Time point:
24/48/72 h
Score:
1.6
Max. score:
4
Reversibility:
not fully reversible within: 14 days for 2 animals
Remarks on result:
other: scattered scale formation on intact skin on 2 of the animals
Irritation parameter:
erythema score
Remarks:
L-menthol at 25%
Basis:
mean
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
erythema score
Remarks:
L-menthol at 5%
Basis:
mean
Time point:
24/48/72 h
Score:
0.3
Max. score:
4
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
erythema score
Remarks:
L-menthol at 1%
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
fully reversible within: half an hour
Irritation parameter:
erythema score
Remarks:
vehicle (L-menthol study) control
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
fully reversible within: half an hour
Irritation parameter:
edema score
Remarks:
L-menthol at 100%
Basis:
mean
Time point:
24/48/72 h
Score:
2.9
Max. score:
4
Reversibility:
not fully reversible within: 14 days
Remarks on result:
other: underlying skin intact despite white to white-brown scales
Irritation parameter:
edema score
Remarks:
L-menthol at 50%
Basis:
mean
Time point:
24/48/72 h
Score:
2.2
Max. score:
4
Reversibility:
fully reversible within: 14 days for 2 animals
Remarks on result:
other: scattered scale formation on intact skin on 2 of the animals
Irritation parameter:
edema score
Remarks:
L-menthol at 25%
Basis:
mean
Time point:
24/48/72 h
Score:
0.2
Max. score:
4
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
edema score
Remarks:
L-menthol at 5%
Basis:
mean
Time point:
24/48/72 h
Score:
0.1
Max. score:
4
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
edema score
Remarks:
L-menthol at 1%
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
fully reversible within: half an hour
Irritation parameter:
erythema score
Remarks:
(+)-menthol at 100%
Basis:
mean
Time point:
24/48/72 h
Score:
2.5
Max. score:
4
Reversibility:
fully reversible within: 14 days
Remarks on result:
other: underlying skin intact despite white to white-brown scales
Irritation parameter:
erythema score
Remarks:
(+)-menthol at 50%
Basis:
mean
Time point:
24/48/72 h
Score:
1.9
Max. score:
4
Reversibility:
not fully reversible within: 14 days for 3 animals
Remarks on result:
other: scattered scale formation on intact skin on 3 of the animals
Irritation parameter:
erythema score
Remarks:
(+)-menthol at 25%
Basis:
mean
Time point:
24/48/72 h
Score:
0.7
Max. score:
4
Reversibility:
fully reversible within: 7 days
Remarks on result:
other: thin layer of white scales on one rabbit (No. 4290) and scattered white scales on another one (No. 4288)
Irritation parameter:
erythema score
Remarks:
(+)-menthol at 5%
Basis:
mean
Time point:
24/48/72 h
Score:
0.2
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
erythema score
Remarks:
(+)-menthol at 1%
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Irritation parameter:
erythema score
Remarks:
(+)-menthol study: vehicle control
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Irritation parameter:
edema score
Remarks:
(+)-menthol at 100%
Basis:
mean
Time point:
24/48/72 h
Score:
2.4
Max. score:
4
Reversibility:
not fully reversible within: 14 days
Remarks on result:
other: underlying skin intact despite white to white-brown scales
Irritation parameter:
edema score
Remarks:
(+)-menthol at 50%
Basis:
mean
Time point:
24/48/72 h
Score:
1.3
Max. score:
4
Reversibility:
not fully reversible within: 14 days for 3 animals
Remarks on result:
other: scattered scale formation on intact skin on 3 of the animals
Irritation parameter:
edema score
Remarks:
(+)-menthol at 25%
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Irritation parameter:
edema score
Remarks:
(+)-menthol at 5%
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Irritation parameter:
edema score
Remarks:
(+)-menthol at 1%
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable

Under the experimental conditions described in the authorized report with L-menthol, the mean scores for erythema in the four rabbits were as follows :

test substance concentration

100%

50%

25%

5%

1%

Vehicle

Erythema

3.0

1.6

1.0

0.3

0.0

0.0

Oedema

2.9

2.2

0.2

0.1

0.0

0.0

Under the experimental conditions described in the authorized report with (+)-mentol, the mean scores for erythema in the four rabbits were as follows :

 test substance concentration  100%  50%  25%  5%  1%  Vehicle
 Erythema 2.5   1.9  0.7  0.2  0.0  0.0
 Oedema 2.4   1.3  0.0  0.0  0.0  0.0
Interpretation of results:
other: Skin Irrit. 2
Remarks:
according to Regulation (EC) No 1272/2008
Conclusions:
The test article (100%) and equal and above a 50% concentration shall be classified as skin irritant, whereas in concentrations of 25%, 5% and 1% shall not be classified as skin irritant.
Executive summary:

Two studies are available from structural analogues L-menthol (CAS 2216 -51 -5) and (+)-menthol (CAS 15356 -60 -2). It is concluded that (±)-neomenthol is skin irritating (Cat. 2) at concentration above or equal to 50%. At concentrations of 50% and below it is not irritant as found from studies with the structural analogue at different concentrations. 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 skin irritation potential.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation, other
Remarks:
in vivo and in vitro
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
Reason / purpose:
read-across source
Related information:
Composition 1
Reason / purpose:
read-across source
Related information:
Composition 1
Test material information:
Composition 1
Irritation parameter:
in vitro irritation score
Run / experiment:
240 min
Value:
6.86
Vehicle controls valid:
yes
Negative controls valid:
yes
Positive controls valid:
yes
Remarks on result:
other: key study 2015
Other effects / acceptance of results:
With the negative control (0.9% (w/v) NaCl solution in deionised water) neither an increase of opacity nor permeability of the corneae could be observed.
The positive control (10% (w/v) benzalkonium chloride in saline) showed clear opacity of the corneae corresponding to a classification as serious eye damaging.
Relative to the negative control, the test item caused any slight increase of the corneal opacity but not of the permeability. The calculated mean IVIS was 6.86. In the calculation, only two treated bovine eyes of three were included because the values of one eye were considered as outliers. Based on the experimental results the test substance is not classified as corrosive (Eye Cat. 1) but no prediction for the damage hazard can be made.
Irritation parameter:
cornea opacity score
Remarks:
at concentration 64.3%
Basis:
mean
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 7 days
Remarks on result:
other: key study 1989b
Irritation parameter:
iris score
Remarks:
at concentration 64.3%
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
2
Reversibility:
other: not applicable
Remarks on result:
other: key study 1989b
Irritation parameter:
conjunctivae score
Remarks:
at concentration 64.3%
Basis:
mean
Time point:
24/48/72 h
Score:
2
Max. score:
3
Reversibility:
fully reversible within: 7 days
Remarks on result:
other: key study 1989b
Irritation parameter:
chemosis score
Remarks:
at concentration 64.3%
Basis:
mean
Time point:
24/48/72 h
Score:
0.6
Max. score:
3
Reversibility:
fully reversible within: 7 days
Remarks on result:
other: key study 1989b
Irritation parameter:
cornea opacity score
Remarks:
50%
Basis:
mean
Time point:
24/48/72 h
Score:
1.2
Max. score:
4
Reversibility:
fully reversible within: 7 days
Remarks on result:
other: key study 1989c
Irritation parameter:
iris score
Remarks:
50%
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
2
Reversibility:
other: not applicable
Remarks on result:
other: key study 1989c
Irritation parameter:
conjunctivae score
Remarks:
50%
Basis:
mean
Time point:
24/48/72 h
Score:
2.1
Max. score:
3
Reversibility:
fully reversible within: 7 days
Remarks on result:
other: key study 1989c
Irritation parameter:
chemosis score
Remarks:
50%
Basis:
mean
Time point:
24/48/72 h
Score:
0.3
Max. score:
3
Reversibility:
fully reversible within: 48 hours
Remarks on result:
other: key study 1989c
Irritant / corrosive response data:
Key study 1989b: results with test substance (L-menthol) at concentration of 28.6%: mean of all animals at 24/48/72h: corneal opacity: 0.8; iris: 0.0; conjunctivae: 1.2; chemosis: 0.3 = not irritant

Supporting study 1989a: results with test substance (L-menthol) at concentration of 30%: mean of all animals at 24/48/72h: corneal opacity: 0.2; iris: 0.0; conjunctivae: 0.6; chemosis: 0.1 = not irritant

Supporting study 1989d: results with test substance ((+)-menthol) at concentration of 30%: mean of all animals at 24/48/72h: corneal opacity: 0.4; iris: 0.0; conjunctivae: 1.3; chemosis: 0.1 = not irritant

Table 1: Results after 240 min incubation time

Test group

Opacity value = Difference (t240-t0) of Opacity

Permeability at 490 nm (OD490)

IVIS

Mean IVIS

 

Mean

 

Mean

 

 

Negative control

0

0.00

0.063

0.063

0.95

0.95

0

0.065

0.98

0

0.061

0.92

Positive control

96.00*

0.045*

96.68

101.85

90.00*

0.041*

90.62

118.00*

0.017*

118.26

Test substance

7.00*

0.873*

20.10

 

7.00*

0.046*

7.69

6.86

5.00*

0.068*

6.02

*corrected values

grey shaded groups were not included in calculation because the values are outliers

Interpretation of results:
other: Eye Irrit. 2
Remarks:
according to Regulation (EC) No 1272/2008
Conclusions:
The corneal damage potential of L-menthol was assessed in the BCOP assay using three fresh bovine corneae. The calculated mean IVIS was 6.86 (only two treated bovine eyes were included, the third was considered as outlier). According to OECD 437 the test item's hazard for eye damaging cannot be predicted but the test item is not classified as Eye Dam. 1.
Furthermore, in an in vivo study with L-menthol and (+)-menthol eye irritating potential was observed leading to a Category 2 classification above 25% test substance concentrations.
Executive summary:

One in vitro and four in vivo eye irritation studies are available from structural analogue L-menthol (CAS 2216-51-5) and (+)-menthol (CAS 15356 -60 -2). It is concluded that (±)-neomenthol is not corrosive to the eyes as found from the in vitro study but irritating to eyes (Cat. 2) at concentration above 25%. At concentrations at 25% and below it has not to be classified as eye irritant as found from studies with the structural analogue at different concentrations. 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 eye irritation potential.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Additional information

There is no reliable skin and/or eye irritation 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 irritating potential of L-menthol and (+)-menthol:

Skin irritation

The cutaneous irritation potential of L-menthol (1989) and (+)-menthol (1989a) at 5 different concentrations in diethylphthalate (DEP) (i.e. 1, 5, 25, 50 and 100%) was assessed following guideline OECD 404. All the tests were performed in the same institute and followed the same protocol.

L-menthol and thus (±)-neomenthol in concentrations higher than 25% shall be classified as skin irritant.

Eye irritation

The eye irritation potential of L-menthol was determined in a BCOP assay using fresh bovine corneae and by acute eye irritation studies in the rabbit.

The BCOP assay was performed according to OECD guideline 437 and in compliance with GLP. The calculated mean IVIS for the test substance L-menthol was 6.86 (only two treated bovine eyes were included, the values of the third cornea were considered as outliers). The negative control (saline) showed no irritating effects (mean IVIS = 0.95), whereas the positive control (10% (w/v) benzalkonium chloride in saline) resulted in serious eye damage (mean IVIS of 101.85). According to OECD guideline 437 the test item's hazard for eye damaging cannot be predicted but the test item is not classified as Eye Dam. 1.

In addition, L-menthol was tested for eye irritation according to the OECD guideline 405 (1989a, b). The vehicle diethylphthalate (DEP) alone revealed no irritating properties. Slightly irritating effects to the eye have been found using L-menthol concentrations of 29 to 64%. At concentration of 64% mean cornea opacity score of 1.0, mean iris score of 1.0, mean conjunctivae redness of 2.0 and mean conjunctivae chemosis of 0.6 were observed. All effects were fully reversible after 7 days. Furthermore, (+)-menthol was tested for eye irritation according to the OECD guideline 405 at concentrations of 50 and 30% (1989c,d). At concentrations of 50% in DEP

mean cornea opacity score of 1.2, mean iris score of 0.0, mean conjunctivae redness of 2.1 and mean conjunctivae chemosis of 0.5 were observed. All effects were fully reversible after 7 days. However, the vehicle control in the opposite eye showed also irritating effects (mean cornea opacity score of 0.5, mean iris score of 0.0, conjunctivae score ofe 1.2 and chemosis score of 0.08). The observed results with the test substance were evaluated as a worst case. The study performed with 30% (+)-menthol showed slight irritating effects but below the limits which would lead to a classification.

Thus L-menthol and (+)-menthol including (±)-neomenthol should be classified as eye irritant category 2 under Regulation (EC) No 1272/2008 (CLP).

Justification for classification or non-classification

Skin irritation:

(±)-neomenthol meets the criteria for classification and labelling as skin irritant, as defined in Regulation (EC) No. 1272/2008.

A concentration limit for skin irritation Category 2 respectively Xi, R38 according to DSD is set to "> 25% by weight".

 

Eye irritation:

(±)-neomenthol meets the criteria for classification and labelling as eye irritant, as defined in Regulation (EC) No. 1272/2008.

A concentration limit for eye irritation Category 2 is set to "> 25% by weight".

 

Respiratory irritation:

Menthol was tested several times in 13 weeks inhalation studies (OECD 413) in rats in the context of cigarette smoke. No irritating potential exceeding the irritation of tobacco smoke was reported.