Registration Dossier

Administrative data

Description of key information

2-(2H-Benzotriazol-2-yl)-4-methylphenol the substance was reported to be sensitizing in a guinea pig maximization test (Hagemann 1992) performed under GLP and following the procedure of OECD testing guideline 406. The tested sample was a commercial product of more than 98% purity. Concentrations were 5% in arachis oil for intradermal induction and 20 or 30% in vaseline for epidermal challenge. With 20% challenge, 16 and 18 of 20 animals showed skin reactions after 24 and 48h, respectively. This is consistent with reports on single incidences of contact allergy (Kaniwa 1991, Arisu 1992, Bjoerkner 1997, DeGroot 1983 and Niklasson 1989) and with literature publications on further animal tests (Yamono 1993, Ikarashi 1994a and b). Two repeated insult patch tests with volunteers performed in the 1960s did not result in skin sensitization (Welch 1960 and Kligman 1964). Secondary information on the safety of use in cosmetics is available (Anonymous 2008).

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records
Reference
Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From Sep. 18, 1991 to Feb. 4, 1992
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
This study was performed in accordance with OECD guideline 406 (1981) and appears to follow the updated guideline 406 (1992) without deviation. Contains GLP certification statement. Dated and signed quality assurance inspection statements included.
Qualifier:
according to
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Version / remarks:
- 1981 followed, reliability scoring based on 1992 guideline
Deviations:
no
GLP compliance:
yes
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
When the study was performed, the LLNA did not yet exist. The Guinea Pig Maximization Test (GPMT) has been carried out as an animal test to predict human sensitization for over a decade and is recommended by international test guidelines such as OECD.
Specific details on test material used for the study:
- Name of test material (as cited in study report): TK 10047 (Tinuvin P)
- Physical state: solid
- Analytical purity: > 98.1%
- Lot/batch No.: EN 139879.82
- Expiration date of the lot/batch: September, 1993
- Storage condition of test material: Room temperature
Species:
guinea pig
Strain:
other: Pirbright White (Tif: DHP)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS- Source: CIBA-GEIGY Limited (Animal Production) 4332 Stein/Switzerland- Age at study initiation: Not reported- Weight at study initiation: 354 to 433 g- Housing: Housed individually in Macrolon cages (Type 3)- Diet (e.g. ad libitum): standard guinea pig pellets NAFAG No. 845, Gossau SG, ad libitum- Water (e.g. ad libitum): fresh water, ad libitum- Acclimation period: 6 daysENVIRONMENTAL CONDITIONS- Temperature (°C): 22 ± 3- Humidity (%): 30 to 70- Air changes (per hr): Not reported- Photoperiod (hrs dark / hrs light): 12/12
Route:
intradermal
Vehicle:
arachis oil
Concentration / amount:
5%
Day(s)/duration:
single injection
Adequacy of induction:
highest technically applicable concentration used
Route:
epicutaneous, occlusive
Vehicle:
other: vaseline
Concentration / amount:
30%
Day(s)/duration:
48h
Adequacy of induction:
highest technically applicable concentration used
No.:
#1
Route:
epicutaneous, occlusive
Vehicle:
other: vaseline
Concentration / amount:
20%
Adequacy of challenge:
highest non-irritant concentration
No. of animals per dose:
Test group: 10/sex
Control group: 5/sex
Details on study design:
RANGE FINDING TESTS:
The concentration for the intradermal injections was selected on account of the solubility of the test article in standard vehicles and its local and systemic tolerability. Since 5% in Oleum arachidis could be injected and was well tolerated, this concentration was used for the intradermal induction.The concentrations for the epidermal applications were selected on account of the primary irritation potential of the test article. The following concentrations have been examined on separate animals for the determination of the maximum subirritant concentration: 1, 5, 10, and 30% in vaseline (no other details provided).

MAIN STUDY
Control group: One side of flank induced with vehicle and challenged with vehicle; other side of flank induced with vehicle and challenged with test substance
Test group: One side of flank induced with test substance and challenged with vehicle; other side of flank induced with test substance and challenged with test substance.

INDUCTION EXPOSURE
- No. of exposures: 2
- Exposure period: single exposure (intradermal); 48 hours (epidermal)
- Test groups: First induction week, intradermal injection: Three pairs of intradermal injections (0.1 ml per injection) were made simultaneously into the shaved neck of the guinea pigs as follows:- adjuvant/saline mixture 1:1 (v/v)- test article 7 in Oleum arachidis (w/v)- test article in the adjuvant saline mixture (w/v)
Second induction week, epidermal application:In the second week of induction the substance was incorporated in vaseline (w/w) and applied on a filterpaper patch to the neck of the animals (patch 2x4 cm; approx. 0.4 g paste per patch; occluded administration for 48 hours).
- Control group: A control group of 10 animals (5 m/5 f) was treated with adjuvant and the vehicle during the induction period.
- Site: Intradermal injections into the neck region, followed by closed patch exposure over the injection sites
- Frequency of applications: Single dose exposures (intradermal injection in the first week and epidermal application in the second week)
- Duration: 0-8 days- Concentrations: 5% in vehicle (intradermal) and 30% in vaseline (epidermal)B. CHALLENGE EXPOSURE
- No. of exposures: 1- Day(s) of challenge: The animals were challenged at Week 5.
- Exposure period: 24 hours- Test groups: The animals were tested on the flank with the test material in vaseline (w/w) and the vehicle alone (patch 2x2 cm; approx. 0.2 g paste per patch; occluded administration).- Control group: During the challenge period the group was treated with the vehicle as well as with the test article to check the maximum subirritant concentration of the test article in adjuvant treated animals.
- Site: flank- Concentrations: 20% in vaseline (epidermal challenge)
- Evaluation (hr after challenge): 24 and 48 hrsChallenge reactions: Twenty four and forty eight hours after removing the dressings, the challenge reactions were graded according to the Draize scoring scale (Appraisal of the Safety of chemicals in Foods, Drugs and Cosmetics (1959), The US Association of Food and Drug Officials (AFDO). General: The sensitising potential was classified according to the grading of Magnusson and Kligman.Maximization grading:Sensitization rate (%) - Grade - Classification(0 – 8) - I - weak(9 – 28) - II - mild(29 – 64) - III - moderate(65 – 80) - IV - strong(81 – 100) - V - extreme
Challenge controls:
During the challenge period the group was treated with the vehicle as well as with the test article to check the maximum subirritant concentration of the test article in adjuvant treated animals.
Positive control substance(s):
yes
Remarks:
1-chloro-2,4-dinitrobenzol
Positive control results:
The sensitivity of the strain is checked every six months with a known sensitiser, such as 2,4-dinitrochlorobenzene, para-phenylene-diamine or potassium-dichromate). The number of positive animals per group after occlusive epidermal application (induced with sensitiser and challenged with sensitiser) was both 10/10 animals after 24 and 48 hours. The results of the latest positive control test were provided using 1-chloro-2,4-dinitrobenzol.
Reading:
1st reading
Hours after challenge:
24
Group:
test group
Dose level:
20%
No. with + reactions:
16
Total no. in group:
20
Remarks on result:
positive indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
48
Group:
test group
Dose level:
20%
No. with + reactions:
18
Total no. in group:
20
Remarks on result:
positive indication of skin sensitisation
Reading:
1st reading
Hours after challenge:
24
Group:
other: control (induced with vehicle, challenged with test article)
Dose level:
20%
No. with + reactions:
1
Total no. in group:
10
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: other: control (induced with vehicle, challenged with test article). Dose level: 20%. No with. + reactions: 1.0. Total no. in groups: 10.0.
Reading:
2nd reading
Hours after challenge:
48
Group:
other: control (induced with vehicle, challenged with test article)
Dose level:
20%
No. with + reactions:
2
Total no. in group:
10
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: other: control (induced with vehicle, challenged with test article). Dose level: 20%. No with. + reactions: 2.0. Total no. in groups: 10.0.
Reading:
1st reading
Hours after challenge:
24
Group:
positive control
Dose level:
0.1%
No. with + reactions:
10
Total no. in group:
10
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: positive control. Dose level: 0.1%. No with. + reactions: 10.0. Total no. in groups: 10.0.
Reading:
2nd reading
Hours after challenge:
48
Group:
positive control
Dose level:
0.1%
No. with + reactions:
10
Total no. in group:
10
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: positive control. Dose level: 0.1%. No with. + reactions: 10.0. Total no. in groups: 10.0.

Results from other groups tested:

Number of positive animals per group after occlusive epidermal application (induced with vehicle and challenged with vehicle) after 24 hours: 0/10

Number of positive animals per group after occlusive epidermal application (induced with vehicle and challenged with vehicle) after 48 hours: 0/10

Number of positive animals per group after occlusive epidermal application (induced with test article and challenged with vehicle) after 24 hours: 0/20

Number of positive animals per group after occlusive epidermal application (induced with test article and challenged with vehicle) after 48 hours: 0/20

Interpretation of results:
Category 1B (indication of skin sensitising potential) based on GHS criteria
Conclusions:
The substance is classified as a skin sensitiser in albino guinea pigs according to the grading of Magnusson and Kligman.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (sensitising)
Additional information:

The key study for skin sensitization (Hagemann 1992) was chosen because it was performed with a well-characterized test material at adequately high concentrations, according to the OECD testing guideline 406 and under GLP. In this study, 2-(2H-benzotriazol-2-yl)-4-methylphenol was reported to be sensitizing after intradermal induction with 5% in arachis oil and challenge at 20 or 30% in vaseline.

Sensitization in guinea pigs was also indicated in an English abstract of a Japanese publication (Yamano 1993). Published data for mice is available on results combining a local lymph node assay with intraperitoneal induction treatment and the mouse ear swelling test (Ikarashi 1994a and b). 2-(2H-Benzotriazol-2-yl)-4-methylphenol was found to be sensitizing in the MEST but not in the LLNA. However, for these investigations, neither positive control nor historical control data is reported and the applied concentrations of up to 2% and the number of animals used are very low. Therefore, this data is considered to be of limited use for hazard assessment.

Single incidences of contact allergy in consumers have been reported (Kaniwa 1991, Arisu 1992, Bjoerkner 1997, DeGroot 1983 and Niklasson 1989). In a repeated insult patch test with 25 male volunteers receiving five induction doses, no incidence of sensitization was observed (Kligman 1964). Also no contact dermatitis was observed in another HRIPT with 59 subjects that received 24-hour patch exposures to 0.2% of the test solution three times weekly - for three weeks, followed by a similar challenge exposure in the sixth week (Welsh 1960).

The substance was handled by the cosmetics industry under the name of Drometrizole and secondary information on sensitizing properties is published in the “Amended final report of the safety assessment of Drometrizole as used in cosmetics” (Anonymous 2008): It is stated that the substance was negative for sensitization in two Magnusson-Kligman maximization tests in guinea pigs. In addition, it is referred to a 3-year clinical therapeutic trial conducted to evaluate the effectiveness of two UV absorbing preparations containing up to 5% Drometrizole, in which two hypersensitivity reactions were observed during 445 applications. It is also referred to clinical tests of cosmetic products containing 0.03% to 1.0% Drometrizole which produced no irritation, sensitization, photosensitization, or phototoxicity in a total of 436 subjects.

Investigation of the structural formula using the QSAR tool DEREK identified the 4-methylphenol as a structural alert for sensitization (Ciba 2009).

Overall, the substance is considered to meet the criteria for classification as a skin sensitizer.



Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No. 1272/2008

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. As a result the substance is considered to be classified as a skin sensitizer of moderate potency (GHS Cat 1B) under Regulation (EC) No. 1272/2008, as amended for the thirteenth time in Regulation (EC) No. 2018/1480.