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EC number: 242-958-4 | CAS number: 19321-38-1
Endpoint summary
Administrative data
Key value for chemical safety assessment
Genetic toxicity in vitro
Description of key information
Menthol
WoE, bacterial reverse mutation assay, Salmonella typhimunum strains TA97, TA98, TA100, TA1535, and TA1537, +/- S9, negative (Zeiger, 1988)
WoE, bacterial reverse mutation assay,Salmonella typhimunumstrains TA97a, TA98, TA100 and TA102, +/- S9, negative (Gomes-Carneiro, 1998)
Sodium hydroxide
WoE, bacterial reverse mutation assay, Salmonella typhimunum strains TA98, TA100, TA1535, TA1537 and TA1538, +/- S9, negative (DeFlora, 1984)
Link to relevant study records
- Endpoint:
- in vitro gene mutation study in bacteria
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- weight of evidence
- Justification for type of information:
- REPORTING FORMAT FOR THE ANALOGUE APPROACH
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The registered substance rapidly degrades to sodium hydroxide and menthol via hydrolysis. It hydrolyses within minutes (2 min 24 s) (please refer to RSS of hydrolysis study linked under 'Cross-reference). Therefore, the properties of the registered substance in aqueous media, as found in genetic toxicity in vitro test systems are determined by its hydrolysis products. This approach is in accordance with Scenario 1 of the RAAF (ECHA 2017).
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Please refer to test material.
3. ANALOGUE APPROACH JUSTIFICATION
As the test substance rapidly degrades to sodium hydroxide and menthol via hydrolysis, the hydrolysis products menthol and sodium hydroxide determine the toxicity of the target substance in aqueous media of in vitro test systems. Thus, to fulfil the data requirements of Regulation EC No 1907/2006 Annex VII, it is fully justified to adress this endpoint with data on the degradation products menthol and sodium hydroxide. - Reason / purpose for cross-reference:
- read-across source
- Reason / purpose for cross-reference:
- read-across: supporting information
- Species / strain:
- S. typhimurium TA 100
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not examined
- True negative controls validity:
- not examined
- Positive controls validity:
- valid
- Species / strain:
- S. typhimurium TA 98
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not examined
- True negative controls validity:
- not examined
- Positive controls validity:
- valid
- Species / strain:
- S. typhimurium TA 97
- Remarks:
- TA97a
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not examined
- True negative controls validity:
- not examined
- Positive controls validity:
- valid
- Species / strain:
- S. typhimurium TA 102
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not examined
- True negative controls validity:
- not examined
- Positive controls validity:
- valid
- Additional information on results:
- RANGE-FINDING/SCREENING STUDIES (if applicable):
Toxicity to S. typhimurium was investigated in a preliminary test carried out with TA100 strain without and with addition of S9 mixture. In all subsequent assays, the upper limit of the dose interval tested was
either the highest non-toxic dose or the lowest toxic dose determined in this preliminary assay. Toxicity was apparent either as a reduction in the number of revertants, and or as an alteration of the auxotrophic background growth i.e., background lawn. Pkease refer to the results in table 1.
Ames test:
- Mean number of revertant colonies per plate and standard deviation : please refer to Table 2 - Conclusions:
- In a bacterial reverse mutation assay d-menthol was negative in S. typhimurium strains TA 97a, TA98, TA100 and TA102 with and without metabolic activation.
- Executive summary:
In this study similar to OECD Test Guideline 471 d-menthol was tested in S. typhimurium strains TA 97a, TA98, TA100 and TA102 with and without rat liver S9 fraction. As a result, d-menthol was negative in all test strains with and without metabolic activation. As menthol is a degradation product of the target substance, this study is relevant for the target substance.
- Endpoint:
- in vitro gene mutation study in bacteria
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- weight of evidence
- Justification for type of information:
- REPORTING FORMAT FOR THE ANALOGUE APPROACH
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The registered substance rapidly degrades to sodium hydroxide and menthol via hydrolysis. It hydrolyses within minutes (2 min 24 s) (please refer to RSS of hydrolysis study linked under 'Cross-reference). Therefore, the properties of the registered substance in aqueous media, as found in genetic toxicity in vitro test systems are determined by its hydrolysis products. This approach is in accordance with Scenario 1 of the RAAF (ECHA 2017).
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Please refer to test material.
3. ANALOGUE APPROACH JUSTIFICATION
As the test substance rapidly degrades to sodium hydroxide and menthol via hydrolysis, the hydrolysis products menthol and sodium hydroxide determine the toxicity of the target substance in aqueous media of in vitro test systems. Thus, to fulfil the data requirements of Regulation EC No 1907/2006 Annex VII, it is fully justified to adress this endpoint with data on the degradation products menthol and sodium hydroxide. - Reason / purpose for cross-reference:
- read-across: supporting information
- Reason / purpose for cross-reference:
- read-across source
- Species / strain:
- S. typhimurium TA 1535
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- not specified
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not examined
- True negative controls validity:
- not examined
- Positive controls validity:
- valid
- Species / strain:
- S. typhimurium TA 1537
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- not specified
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not examined
- True negative controls validity:
- not examined
- Positive controls validity:
- valid
- Species / strain:
- S. typhimurium TA 98
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- not specified
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not examined
- True negative controls validity:
- not examined
- Positive controls validity:
- valid
- Species / strain:
- S. typhimurium TA 100
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- not specified
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not examined
- True negative controls validity:
- not examined
- Positive controls validity:
- valid
- Species / strain:
- S. typhimurium TA 97
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- not specified
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not examined
- True negative controls validity:
- not examined
- Positive controls validity:
- valid
- Additional information on results:
- RANGE-FINDING/SCREENING STUDIES (if applicable):
All chemicals were tested initially in a toxicity assay to determine the appropriate dose range for the mutagenicity assay. Toxic concentrations were those that produced a decrease in the number of his+ colonies, or a clearing in the density of the background lawn, or both. Each chemical was tested initially at half-log dose intervals up to a dose that elicited toxicity, or to a dose immediately below one which was toxic in the preliminary toxicity test. Subsequent trials occasionally used narrower dose increments and may not have included doses in the toxic range. Chemicals that were not toxic were tested, with few exceptions, to a maximum dose of 10 mg/plate. - Conclusions:
- d-Menthol was not mutagenic to the bacterial strains Salmonella typhimurium TA98, TA100, TA1535, and TA97 and/or TA1537 in a bacterial reverse mutation assay with and without metabolic activation.
- Executive summary:
In this study d-menthol was tested in a bacterial reverse mutation assay with and without metabolic activation. The test procedure is comparabale to OECD Test Guideline 471 (pre-incubation method). In this study the test item d-menthol was not mutagenic to the bacterial strains Salmonella typhimurium TA98, TA100, TA1535, TA97 and TA1537 with and without metabolic activation. As menthol is a degradation product of the target substance, this study is relevant for the target substance.
- Endpoint:
- in vitro gene mutation study in bacteria
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- weight of evidence
- Justification for type of information:
- REPORTING FORMAT FOR THE ANALOGUE APPROACH
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The registered substance rapidly degrades to sodium hydroxide and menthol via hydrolysis. It hydrolyses within minutes (2 min 24 s) (please refer to RSS of hydrolysis study linked under 'Cross-reference). Therefore, the properties of the registered substance in aqueous media, as found in genetic toxicity in vitro test systems are determined by its hydrolysis products. This approach is in accordance with Scenario 1 of the RAAF (ECHA 2017).
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Please refer to test material.
3. ANALOGUE APPROACH JUSTIFICATION
As the test substance rapidly degrades to sodium hydroxide and menthol via hydrolysis, the hydrolysis products menthol and sodium hydroxide determine the toxicity of the target substance in aqueous media of in vitro test systems. Thus, to fulfil the data requirements of Regulation EC No 1907/2006 Annex VII, it is fully justified to adress this endpoint with data on the degradation products menthol and sodium hydroxide. - Reason / purpose for cross-reference:
- read-across source
- Reason / purpose for cross-reference:
- read-across: supporting information
- Species / strain:
- S. typhimurium TA 1535
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- not specified
- Vehicle controls validity:
- not specified
- Untreated negative controls validity:
- not specified
- True negative controls validity:
- not specified
- Positive controls validity:
- not specified
- Species / strain:
- S. typhimurium TA 1537
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- not specified
- Vehicle controls validity:
- not specified
- Untreated negative controls validity:
- not specified
- True negative controls validity:
- not specified
- Positive controls validity:
- not specified
- Species / strain:
- S. typhimurium TA 100
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- not specified
- Vehicle controls validity:
- not specified
- Untreated negative controls validity:
- not specified
- True negative controls validity:
- not specified
- Positive controls validity:
- not specified
- Species / strain:
- S. typhimurium TA 98
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- not specified
- Vehicle controls validity:
- not specified
- Untreated negative controls validity:
- not specified
- True negative controls validity:
- not specified
- Positive controls validity:
- not specified
- Species / strain:
- S. typhimurium TA 1538
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- not specified
- Vehicle controls validity:
- not specified
- Untreated negative controls validity:
- not specified
- True negative controls validity:
- not specified
- Positive controls validity:
- not specified
- Additional information on results:
- sensitivity (genotoxic/carcinogens): 73.5 % (36/49)
specificity (nongenotoxic/noncarcinogens): 51.8 % (14/27)
accuracy (correct results/chemicals tested): 65.8 % (50/76) - Conclusions:
- In a bacterial reverse mutation assay sodium hydroxide was negative in S. typhimurium strains TA98, TA100, TA1535, TA1537 and TA1538 with and without metabolic activation. As sodium hydroxide is a degradation product of the target substance, this study is relevant for the target substance.
- Executive summary:
In this study similar to OECD Test Guideline 471 sodium hydroxide was tested in S. typhimurium strains TA98, TA100, TA1535, TA1537 and TA1538 with and without rat liver S9 fraction. As a result, sodium hydroxide was negative in all test strains with and without metabolic activation. As sodium hydroxide is a degradation product of the target substance, this study is relevant for the target substance.
Referenceopen allclose all
Table 1: Toxicity of (-)-menthol to S. typhimurium TA100 strain
Dose (µg/plate) |
(-)-Menthol |
|
|
- S9 |
+ S9 |
3000 |
|
|
2750 |
|
|
2500 |
|
|
2000 |
|
|
1500 |
|
|
1250 |
|
|
1000 |
|
|
900 |
|
101 * /0/0+ |
800 |
93 ±39* |
167* /0/0+ |
700 |
134±29* |
77±6* |
600 |
159±14 |
120±10* |
500 |
165±12 |
166±17 |
400 |
|
|
300 |
|
|
200 |
|
|
0 |
174±15a |
184±26b |
PC |
924±41a |
591±69b |
(*) Toxicity apparent as an alteration of the background lawn. (a,b) Toxicity assays carried out concomitantly shared the same solvent-andpositive controls. (-) Dose not tested. (/ + ) Mutant counts of individual plates. Data are shown as mutant counts (mean±SD) of three plates. |
||
Table 2: Mutagenicity testing of (-)-menthol (5-methyl-2-(1-methyl-ethyl)cyclohexanol) in the Salmonella/microsome assay [TA100, TA98, TA97a and TA102 tester strains]
NUMBER OF REVERTANTS (Mean ±S.D.) |
|||||||||
(-) - MENTHOL |
DOSE (µg/plate) |
TA100 |
TA98 |
TA97a |
TA102 |
||||
|
|
-S9 |
+S9 |
-S9 |
+S9 |
-S9 |
+S9 |
-S9 |
+S9 |
|
800 |
- |
- |
- |
43/0/0+ |
- |
93±4* |
- |
- |
|
700 |
- |
168 ± 15 |
- |
48±6 |
86±54* |
154±8 |
- |
- |
|
600 |
161 ± 7 |
170 ± 10 |
41±4 |
50±10 |
132 ± 11 |
181 ± 8 |
- |
- |
|
500 |
161±10 |
179 ± 11 |
46±1 |
64±3 |
137±6 |
186±11 |
- |
552±114* |
|
400 |
183 ± 3 |
182 ± 18 |
40 ± 8 |
57 ± 12 |
148±11 |
198 ±13 |
312±135 |
826±21 |
|
300 |
199 ± 17 |
182±13 |
39 ± 8 |
57 ± 9 |
155 ± 6 |
209±14 |
409±152 |
754±33 |
|
200 |
205 ± 11 |
183 ± 7 |
35±4 |
55 + 10 |
169±13 |
209 ± 16 |
643±62 |
897±18 |
|
100 |
211 ± 12 |
- |
42 ± 2 |
- |
149±2 |
- |
665±34 |
873±66 |
|
50 |
- |
- |
- |
- |
- |
- |
686±35 |
738±19 |
|
25 |
- |
- |
- |
- |
- |
- |
574±50 |
- |
|
10 |
- |
- |
- |
- |
- |
- |
648±32 |
- |
|
5 |
- |
- |
- |
- |
- |
- |
708±34 |
- |
|
0 |
219 ± 21 |
196 ± 18 |
47±3 |
63 ± 1 |
160±22 |
172±6 |
719±25 |
832±67 |
|
PC |
860 ± 1 |
1003 ± 66 |
159±16 |
343 ± 57 |
998±52 |
844±18 |
5967±1198 |
1589±157 |
Dose 0 — Negative Control: 100 µL ethanol PA; PC — Positive Control: TA100/-S9, SA (0.5 µg/plate); TA100/+S9, 2AA (1 µg/plate); TA98/-S9, NPD (1 µg/plate); TA98/+S9, 2AA (0.5 µg/plate); TA97a/-S9, 4-NQNO (1 µg/plate); TA97a/+S9, 2AF (10 µg/plate); TA102/+S9, MC (0.5 µg/plate); TA102/+S9, B-[a]-P (50 µg/plate)
(-) Dose not tested.
(*) Toxicity apparent as an alteration of the background lawn.
(/+) mutant counts of individual plates.
Values are the means ± SD of three plates of one (out of two) representative experiment.
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed (negative)
Genetic toxicity in vivo
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
Menthol
Bacterial reverse mutation assay (Zeiger, 1988)
In this study d-menthol was tested in a bacterial reverse mutation assay with and without metabolic activation. The test procedure is comparabale to OECD Test Guideline 471 (pre-incubation method). In this study the test item d-menthol was not mutagenic to the bacterial strains S. typhimurium strains TA98, TA100, TA1535, TA97 and TA1537 with and without metabolic activation. As menthol is a degradation product of the target substance, this study is relevant for the target substance.
Bacterial reverse mutation assay (Gomes-Carneiro, 1998)
In this study similar to OECD Test Guideline 471 d-menthol was tested in S. typhimurium strains TA 97a, TA98, TA100 and TA102 with and without rat liver S9 fraction. As a result, d-menthol was negative in all test strains with and without metabolic activation. As menthol is a degradation product of the target substance, this study is relevant for the target substance.
Sodium hydroxide
Bacterial reverse mutation assay (DeFlora, 1984)
In this study similar to OECD Test Guideline 471 sodium hydroxide was tested inS. typhimurium strains TA98, TA100, TA1535, TA1537 and TA1538 with and without rat liver S9 fraction. As a result, sodium hydroxide was negative in all test strains with and without metabolic activation. As sodium hydroxide is a degradation product of the target substance, this study is relevant for the target substance.
Justification for classification or non-classification
Based on the presented results for genetic toxicity, the registered substance is not subject to classification according to Regulation (EC) No 1272/2008.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
