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Toxicological information

Endpoint summary

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Administrative data

Description of key information

The endpoint 'Skin sensitisation' is waived based on the classification as Skin Corr. 1B (H314). As supporting information several studies are available. The key results of these studies are as follows:

Guinea pig, Open Epicutaneous Test (OET), Draize Test (DT), Maximisation Test (MT), Freund's Complete Adjuvant Test (FCAT): negative (Klecak 1977, Ishihara 1986)

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Principles of method if other than guideline:
In a Freund's complete adjuvant test (Fdoses of 0.05 ml of the undiluted compound mixed with the same volume of FCA (Freund's complete adjuvant) were injected intradermally into the neck on days 0, 2, 4, 7, and 9 (total dose 250 mg). All the animals were tested epicutaneously on days 21 and 35.
GLP compliance:
no
Type of study:
Freund's complete adjuvant test
Justification for non-LLNA method:
The study was published in the year 1977. At this time-point no valid guideline for an LLNA was available.
Species:
guinea pig
Strain:
Himalayan
Sex:
male/female
Route:
intradermal
Vehicle:
other: 0.05 ml undiluted compound mixed with the same volume of FCA
Concentration / amount:
induction: 0.05 ml on day 0,2,4,7,and 9 (total dose 250 mg)
challenge: subirritant concentration
Route:
epicutaneous, occlusive
Vehicle:
other: 0.05 ml undiluted compound mixed with the same volume of FCA
Concentration / amount:
induction: 0.05 ml on day 0,2,4,7,and 9 (total dose 250 mg)
challenge: subirritant concentration
No. of animals per dose:
6
Details on study design:
Doses of 0.05 ml of the undiluted compound mixed with the same volume of FCA (Freund's complete adjuvant) were injected intradermally into the neck on days 0, 2, 4, 7, and 9 (total dose 250 mg). The control animals were similarly treated with 5 x 0.05 ml of FCA alone. All the animals were tested epicutaneously on days 21 and 35 at a subirritant concentration in petrolatum .
Group:
test chemical
Remarks on result:
other: Thymol was not sensitizing at 10%. Higher concentrations were not used because of systemic toxicity.
Group:
positive control
Remarks on result:
other: see 'Remarks'
Remarks:
Benzyl alcohol, Benzyl cinnamate, carvacrol, cinnamic aldehyde, citral, citronellal, cuminic aldehyde, geraniol, iso-eugenol, limonene, methyl cinnamate, methyl heptane carbonate, phenylacetaldehyde, phenyl-ethyl salicylate, 3-phenyl-propionaldehyde, 10-undecanal, benzaldehyde, cinnamic alcohol, vanilin.
Group:
negative control
Remarks on result:
other: see 'Remarks'
Remarks:
Solvents, like water, ethanol and acetone, even when applied repeatedly, yielded no macroscopically detectable alteration on the treated skin. When other bases were applied, like Vaseline, diethyl phthalate or polyethylene glycol, additional controls for the vehicles were set in.

Thymol was negative in the Freund's complete adjuvant test (individual scores not mentioned).

Interpretation of results:
GHS criteria not met
Executive summary:

In a Freund's complete adjuvant test doses of 0.05 ml of the undiluted compound mixed with the same volume of  FCA (Freund's complete adjuvant) were injected intradermally into the  neck on days 0, 2, 4, 7, and 9 (total dose 250 mg). The control animals  were similarly treated with 5 x 0.05 ml of FCA alone. All the animals  were tested epicutaneously on days 21 and 35 at a subirritant concentration in petrolatum. Thymol was netative in this test.

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: no guideline study,
Principles of method if other than guideline:
The minimum skin irritation concentration of the test substance was determined in an open epicutaneous test;
induction: 6-8 guinea pigs/dose group, undiluted or 30, 10, 3, 1, 0.3, 0.1, 0.03, 0 % solution, 21 d;
challenge: d 21 and d 35
GLP compliance:
no
Type of study:
open epicutaneous test
Justification for non-LLNA method:
The study was published in the year 1977. At this time-point no valid guideline for an LLNA was available.
Species:
guinea pig
Strain:
Himalayan
Sex:
male/female
Route:
epicutaneous, open
Vehicle:
other: acetone, ethanol, diethyl phthalate, etc.
Concentration / amount:
undiluted, 30, 10, 3, 1, 0.3, 0.1, or 0.03%
Route:
epicutaneous, open
Vehicle:
other: acetone, ethanol, diethyl phthalate, etc.
Concentration / amount:
undiluted, 30, 10, 3, 1, 0.3, 0.1, or 0.03%
No. of animals per dose:
6
Group:
test chemical
Remarks on result:
other: Thymol was not sensitizing at 10%. Higher concentrations were not used because of systemic toxicity.
Group:
negative control
Remarks on result:
other: see 'Remark'
Remarks:
Solvents, like water, ethanol and acetone, even when applied repeatedly, yielded no macroscopically detectable alteration on the treated skin. When other bases were applied, like Vaseline, diethyl phthalate or polyethylene glycol, additional controls for the vehicles were set in.
Group:
positive control
Remarks on result:
other: A total of 32 compounds described in the literature as allergenic for man were tested by the OET. Of the compounds tested, all those with well-established allergenicity for man were detected by the OET.

Thymol was tested undiluted as well as dissolved in acetone, ethanol,diethylphthalate, etc., at concentrations of 30, 10, 3, 1, 0.3, 0.1, and 0.03 per cent in order to establish a dose-response curve making itpossible to determine the minimal irritating and the maximal tolerated concentrations on an 'all or none' basis. Induction period: On day 0, 0.1 ml of each undiluted compound and of itsprogressively diluted solutions was applied to an area of measuring 8 cm² on the clipped flank skin of 6 to 8 guinea pigs per concentration group, using 4 to 6 groups for each compound. The applications were repeated daily for 21 days, always using the same skin site. The application site was left uncovered and the reactions were read 24 h after each application. Challenge procedure: to determine wheather or not allergic contact dermatitis was induced, all groups of guinea pigs previously treated for 21 days as described above as well as 6 to 8 untreated controls for each compound, were tested on days 21 and 35 on the contralateral flank with  the same compound. Thymol was was negatve in the OET (individual scores not mentioned).

Interpretation of results:
GHS criteria not met
Executive summary:

Thymol was tested undiluted as well as dissolved in acetone, ethanol, diethylphthalate, etc., at concentrations of 30, 10, 3, 1, 0.3, 0.1, and 0.03 per cent in order to establish a dose-response curve making it possible to determine the minimal irritating and the maximal tolerated concentrations on an 'all or none' basis. Induction period: On day 0, 0.1 ml of undiluted thymol and of its progressively diluted solutions was applied to an area of measuring 8 cm² on the clipped flank skin of 6 to 8 guinea pigs per concentration group, using 4 to 6 groups for each compound. The applications were repeated daily for 21 days, always using the same skin site. The application site  was left uncovered and the reactions were read 24 h after each application. The maximum nonirritant and the minimal irritating concentrations were determined. Challenge procedure: to determine wheather or not allergic contact dermatitis was induced, all groups of guinea pigs previously treated for  21 days as described above as well as 6 to 8 untreated controls for each  compound, were tested on days 21 and 35 on the contralateral flank with the same compound at the minimal irritating concentration and at some lower nonirritant concentrations.Thymol was negative in this test

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: according to: Magnusson B, Kligman AM (1969), The identification of contact allergens by animal assay. The guinea pig maximization-test, J. Invest. Dermatol., 52, p. 269-276
Principles of method if other than guideline:
according to: Kligman, J. Invest. Dermatol. 52, 268-276 (1969)
GLP compliance:
no
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
The study was published in the year 1977. At this time-point no valid guideline for an LLNA was available.
Species:
guinea pig
Strain:
Himalayan
Sex:
male/female
Route:
intradermal and epicutaneous
Vehicle:
petrolatum
Concentration / amount:
induction: 0.1 ml of a 5 % solution (intradermally) and in addition , 250 mg of a 25% solution in petrolatum (epicutan)
Route:
epicutaneous, occlusive
Vehicle:
petrolatum
Concentration / amount:
challenge: subirritant concentration (epicutan)
No. of animals per dose:
6
Group:
test chemical
Remarks on result:
other: Thymol was not sensitizing at 10%. Higher concentrations were not used because of systemic toxicity.
Group:
positive control
Remarks on result:
other: see 'Remarks'
Remarks:
Benzyl cinnamate, carvacrol, cinnamic aldehyde, citral, citronellal, cuminic aldehyde, geraniol, heliotropin, iso-eugenol, limonene, methyl cinnamate, methyl heptane carbonate, phenylacetaldehyde, phenyl-ethyl salicylate, benzaldehyde, cinnamic alcohol, vanilin
Group:
negative control
Remarks on result:
other: see 'Remarks'
Remarks:
Solvents, like water, ethanol and acetone, even when applied repeatedly, yielded no macroscopically detectable alteration on the treated skin. When other bases were applied, like Vaseline, diethyl phthalate or polyethylene glycol, additional controls for the vehicles were set in.

thymol was negative in the maximisation test (individual scores not mentioned).

Interpretation of results:
GHS criteria not met
Executive summary:

A maximisation test according Magnusson and Kligman was conducted. On day 0 the animals were injected intradermally with 0.1 ml of a 5 per cent solution of the compound tested, with 0.1 ml of a 5 per cent emulsion of the same compound in Freund's Complete Adjuvant (FCA) and  with 0.1 ml of FCA alone, each injection being given twice. In addition,  250 mg of the compound dissolved in petrolatum at a concentration of 25 per cent, which always causes mild to moderate skin irritation under occlusion, was applied on day 8 to a clipped skin area of the neck and  was kept under occlusive bandage for 2 days (total dose 20 mg intradermally plus 250 mg epicutaneously). On day 21 an occlusive patch test with the compound at a subirritant concentration in petrolatum was applied to the flank for 24 hours. The reactions were read 24 and 48 h after removing the patch.Thymol was negative in the test.

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: only summary - original paper in Japanese
Principles of method if other than guideline:
thymol was tested in the GPMT
GLP compliance:
no
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
The study was published in the year 1977. At this time-point no valid guideline for an LLNA was available.
Species:
guinea pig
Strain:
not specified
Sex:
not specified
Route:
intradermal
Vehicle:
not specified
Concentration / amount:
induction: 10 %
Route:
other: epicutaneous
Vehicle:
not specified
Concentration / amount:
10%
No. of animals per dose:
no data
Group:
test chemical
Remarks on result:
other: induction: 10 %; challenge: 10 %; rate: II; score: 0.1%
Group:
negative control
Remarks on result:
other: no data
Group:
positive control
Remarks on result:
other: no data
Sensitization to thymol:
guinea pig maximization test
induction: 10 %
challenge: 10 %
rate: II
score: 0.1%
Interpretation of results:
study cannot be used for classification
Executive summary:

Thymol was tested in the GPMT. In this test thymol was negative

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: Method according to Draize JH (1959), Appraisal of the safety of chemicals in foods, drugs and cosmetics. Dermal toxicity, The assoc. of food and drug officials of the United States. Texas State Dept. of Health, Austin, p.46-59
Principles of method if other than guideline:
A dose of 0.05 ml of a 0.1 per cent solution of the compound tested in isotonic saline was injected intradermally on day 0 and further doses of 0.1 ml each were injected on 9 alternate days (total dose = 0.95 mg). The treated animals and untreated controls were challenged intradermally with 0.05 ml of a 0.1 per cent solution on days 35 and 49. The evaluation criterion was the mean diameter of the papular reactions.
according to Draize, Appraisal of the safety of chemicals in foods, drugs and cosmetics; dermal toxicity; The Assoc. of Food Drug Officials of the U.S., Texas State Dep. of Health, Austin, 1959, pp 46-59
GLP compliance:
no
Type of study:
Draize test
Justification for non-LLNA method:
The study was published in the year 1977. At this time-point no valid guideline for an LLNA was available.
Species:
guinea pig
Strain:
Himalayan
Sex:
male/female
Route:
intradermal
Vehicle:
other: isotonic saline
Concentration / amount:
induction: 0.1%
Route:
intradermal
Vehicle:
other: isotonic saline
Concentration / amount:
challenge: 0.1%
No. of animals per dose:
6
Group:
test chemical
Remarks on result:
other: Thymol was not sensitizing at 10%. Higher concentrations were not used because of systemic toxicity.
Group:
positive control
Remarks on result:
other: Benzyl cinnamate, cinnamic aldehyde, cuminic aldehyde, iso-eugenol, methyl cinnamate, phenylacetaldehyde, benzaldehyde
Group:
negative control
Remarks on result:
other: see 'Remarks'
Remarks:
Solvents, like water, ethanol and acetone, even when applied repeatedly, yielded no macroscopically detectable alteration on the treated skin. When other bases were applied, like Vaseline, diethyl phthalate or polyethylene glycol, additional controls for the vehicles were set in.

thymol was negative in the Draize test (DT) (individual scores not mentioned)

Interpretation of results:
GHS criteria not met
Executive summary:

A dose of 0.05 ml of a 0.1 per cent solution of the compound tested in isotonic saline was injected intradermally on day 0 and further doses of  0.1 ml each were injected on 9 alternate days (total dose = 0.95 mg). The  treated animals and untreated controls were challenged intradermally with 0.05 ml of a 0.1 per cent solution on days 35 and 49. The evaluation criterion was the mean diameter of the papular reactions. Thymol was negative in this test

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

The endpoint 'Skin sensitisation' is waived based on the classification as Skin Corr. 1B (H314). As supporting information several studies are available. In these studies thymol was negative in the Open Epicutaneous Test (OET), the Draize Test (DT), the Maximisation Test (MT) and the Freund's Complete Adjuvant Test (FCAT) (Klecak 1977, Ishihara 1986). Also, from several patch tests in humans conducted in dermatological institutions (please refer to section 7.10.3), it can be concluded that the sensitising potential of thymol is very low.


Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

Based on the outcome of the skin sensitisation tests in animals and humans showing low sensitising potential of thymol, it is concluded that the substance does not need to be classified according to Regulation (EC) No 1272/2008 with regard to sensitisation.