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Description of key information

The skin sensitisation potential of TBBS was evaluated in guinea pigs and in studies with human volunteers. No skin sensitization was noted in guinea pigs after treatment with TBBS (Monsanto Co 1982). However, an allergic response (13/54) was noted in a Repeated Insult Patch test with human volunteers (Monsanto Co. 1983). No cases of skin sensitisation related with professional activities derived from contact with Sulfenamides and Thiazoles were reported from several companies. The applied RMMs (Risk Management Measures) and OCs (Operational conditions) in these factories  correspond  with the moderate hazard band, which applies for substances having a moderate hazard profile i.e. moderate sensitisers, categorized as Skin Sens. 1 B (H 317). On a weight-of-evidence consideration, classification with Skin Sens.1B (H317: May cause an allergic skin reaction) is justified.

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:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Principles of method if other than guideline:
Repeated Insult Patch test (modified Shelanski (4 x 4 method))
GLP compliance:
not specified
Type of study:
patch test
Justification for non-LLNA method:
The study was reported 1983. At this time an OECD guideline for a LLNA was not available.
Species:
human
Sex:
male/female
Route:
epicutaneous, semiocclusive
Vehicle:
petrolatum
Concentration / amount:
200 mg of the test material tested as a 60 % preparation in petrolatum
Route:
epicutaneous, semiocclusive
Vehicle:
petrolatum
Concentration / amount:
200 mg of the test material tested as a 60 % preparation in petrolatum
No. of animals per dose:
54 volunteers
Details on study design:
The potential for TBBS to cause primary skin irritation and/or sensitization was assessed in 54 volunteer human subjects. This chemical was tested as a 60 % preparation in petrolatum.
Positive control substance(s):
no
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
test group
Dose level:
200 mg
No. with + reactions:
15
Total no. in group:
54
Clinical observations:
mild to intense inflammatory changes
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 200 mg. No with. + reactions: 15.0. Total no. in groups: 54.0. Clinical observations: mild to intense inflammatory changes.
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
test group
Dose level:
200 mg
No. with + reactions:
13
Total no. in group:
54
Clinical observations:
mild to intense inflammatory changes
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 200 mg. No with. + reactions: 13.0. Total no. in groups: 54.0. Clinical observations: mild to intense inflammatory changes.
Key result
Group:
negative control
Remarks on result:
other: Human patch test - no negative control group was included
Key result
Group:
positive control
Remarks on result:
other: Human patch test - no positive control group was included

Forty-five subjects completed the study. During the induction period, eleven subjects demonstrated intense irritation consisting of erythema and induration. These responses were considered indicative of an allergic reaction. Due to the severity of reaction during the induction period, these eleven subjects were not tested during the portion of the induction phase which followed their response. Following the single 24 hour challenge application, six subjects demonstrated slight to moderate erythema. Twenty-four hours after removal of the test material, mild to intense inflammatory changes were observed in 15 individuals. At 48 hours after removal, responses were still noted in 13 subjects. These responses were considered characteristic for allergic contact dermatitis.

In conclusion, the test substance, tested as a 60 % preparation in petrolatum, produced sensitization in 13/54 subjects who completed the study. No evidence of primary irritation was observed.This chemical was considered to be a strong skin sensitizer.

Interpretation of results:
Category 1A (indication of significant skin sensitising potential) based on GHS criteria
Conclusions:
The test substance, tested as a 60 % preparation in petrolatum, produced sensitization in 13/54 subjects who completed the study. No evidence of primary irritation was observed.This chemical was considered to be a strong skin sensitizer.
Executive summary:

Forty-five subjects completed the study. During the induction period, eleven subjects demonstrated intense irritation consisting of erythema and induration. These responses were considered indicative of an allergic reaction. Due to the severity of reaction during the induction period, these eleven subjects were not tested during the portion of the induction phase which followed their response. Following the single 24 hour challenge application, six subjects demonstrated slight to moderate erythema. Twenty-four hours after removal of the test material, mild to intense inflammatory changes were observed in 15 individuals. At 48 hours after removal, responses were still noted in 13 subjects. These responses were considered characteristic for allergic contact dermatitis.

In conclusion, the test substance, tested as a 60 % preparation in petrolatum, produced sensitization in 13/54 subjects who completed the study. No evidence of primary irritation was observed.This chemical was considered to be a strong skin sensitizer.

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Principles of method if other than guideline:
The test material (lot NA 08 -100) was applied at a concentration of 25 % in ethanol to the shaved skin of 10 male and ten female guinea pigs. Test material was administered for one six-hour insult period in each of three consecutive weeks. Each site was examined for irritation at 24 and 48 hours after treatment. Fourteen days after the last induction exposure, the animals were treated with a challenge application applied 6 hours to a new site. Twenty-four hours after the challenge, all animals were treated with depilatory at the test site for 30 minutes. At approximately 2 hours after washing, the response of the test site was graded. The grading was repeated 48 hours after the challenge. A severity index was calculated based on the scores reported following the challenge application.
GLP compliance:
yes
Type of study:
Buehler test
Justification for non-LLNA method:
The test was conducted 1982.
Species:
guinea pig
Strain:
Hartley
Sex:
male/female
Route:
epicutaneous, semiocclusive
Vehicle:
other: ethanol
Concentration / amount:
induction: 25 %, challenge: 25%
Route:
epicutaneous, semiocclusive
Vehicle:
other: ethanol
Concentration / amount:
induction: 25 %, challenge: 25%
No. of animals per dose:
10 per dose and sex per group, positive control: 10 animals, negative control: four animals
Positive control substance(s):
yes
Remarks:
dinitrochlorobenzene
Reading:
1st reading
Hours after challenge:
24
Group:
test group
Dose level:
25%
No. with + reactions:
0
Total no. in group:
19
Clinical observations:
no effects
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 25% . No with. + reactions: 0.0. Total no. in groups: 19.0. Clinical observations: no effects.
Reading:
2nd reading
Hours after challenge:
48
Group:
test group
Dose level:
25%
No. with + reactions:
0
Total no. in group:
19
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 25%. No with. + reactions: 0.0. Total no. in groups: 19.0.

In the pilot study, one of the four treated animals showed severe irritation with the application of 50 % test material; slight irritation was noted in one animal at the 10% and 1% concentrations. On the basis of these results a concentration of 25% was used for induction and challenge application.

For the induction period, no irritation was noted for any of the animals treated with 25% test material or for the solvent controls. The positive control did show responses during this period. For test material-induced or solvent-induced animals, no positive response were seen during 24 or 48 hour periods following the challenge application of the test material. Positive responses were noted in all positive control animals.

Conclusion: The test substance, when applied at a concentration of 25% in ethanol, did not cause delayed hypersensitivity in guinea pigs.

note: one male died during week #2 induction face

Interpretation of results:
GHS criteria not met
Conclusions:
The test substance, when applied at a concentration of 25% in ethanol, did not cause delayed hypersensitivity in guinea pigs.
Executive summary:

The test material (lot NA 08 -100) was applied at a concentration of 25 % in ethanol to the shaved skin of 10 male and ten female guinea pigs. Test material was administered for one six-hour insult period in each of three consecutive weeks. Each site was examined for irritation at 24 and 48 hours after treatment. Fourteen days after the last induction exposure, the animals were treated with a challenge application applied 6 hours to a new site. Twenty-four hours after the challenge, all animals were treated with depilatory at the test site for 30 minutes. At approximately 2 hours after washing, the response of the test site was graded. The grading was repeated 48 hours after the challenge. A severity index was calculated based on the scores reported following the challenge application.

A group of 5 male and 5 female guinea pigs were treated as described above with 0.3% dinitrochlorobenzene the positive control. A solvent (negative) control was treated with 80 % ethanol during the induction period and test material during the challenge period to determine if the solvent would contribute to any observed response during the study.

The test substance, when applied at a concentration of 25% in ethanol, did not cause delayed hypersensitivity in guinea pigs.

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Principles of method if other than guideline:
The test material Santocure NS/Santocure Dryer material was applied at a concentration of 25 % in ethanol to the shaved skin of 10 male and ten female guinea pigs. Test material was administered for one six-hour insult period in each of three consecutive weeks. Each site was examined for irritation at 24 and 48 hours after treatment. Fourteen days after the last induction exposure, the animals were treated with a challenge application applied 6 hours to a new site. Twenty-four hours after the challenge, all animals were treated with depilatory at the test site for 30 minutes. At approximately 2 hours after washing, the response of the test site was graded. The grading was repeated 48 hours after the challenge. A severity index was calculated based on the scores reported following the challenge application.
GLP compliance:
yes
Type of study:
Buehler test
Species:
guinea pig
Strain:
Hartley
Sex:
male/female
Route:
epicutaneous, semiocclusive
Vehicle:
other: ethanol
Concentration / amount:
induction: 25%, challenge: 25 %
Route:
epicutaneous, semiocclusive
Vehicle:
other: ethanol
Concentration / amount:
induction: 25%, challenge: 25 %
No. of animals per dose:
10 animals per dose and sex, positive control: 10 animals, negative control: 4 animals
Details on study design:
The test material Santocure NS/Santocure Dryer material was applied at a concentration of 25 % in ethanol to the shaved skin of 10 male and ten female guinea pigs.
Positive control substance(s):
yes
Remarks:
dinitrochlorobenzene
Reading:
1st reading
Hours after challenge:
24
Group:
test group
Dose level:
25%
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
no effects
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 25%. No with. + reactions: 0.0. Total no. in groups: 20.0. Clinical observations: no effects.
Reading:
2nd reading
Hours after challenge:
48
Group:
test group
Dose level:
25%
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
no effects
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 25%. No with. + reactions: 0.0. Total no. in groups: 20.0. Clinical observations: no effects.

In the pilot study, all treated animals showed severe irritation with the application of 50 % test material; no irritation was noted at the 10% concentration. On basis of these results a concentration of 25% was used for induction and challenge applications.

For the induction period, no irritation was noted for any of the animals treated with 25% test material or for the sovent controls. The positive controls did show responses during this period. For test material-induced or solvent induced animals, no positive responses were seen during the 24 or 48 hour periods following the challenge application of the test material. Positive responses were noted in all positive control animals.

Conclusion: Santure NS/Santocure dryer material, when applied at a concentration of 25% in ethanol, did not cause delayed hypersensitivity in guinea pigs.

Interpretation of results:
GHS criteria not met
Conclusions:
Santure NS/Santocure dryer material, when applied at a concentration of 25% in ethanol, did not cause delayed hypersensitivity in guinea pigs.
Executive summary:

The test material Santocure NS/Santocure Dryer material was applied at a concentration of 25 % in ethanol to the shaved skin of 10 male and ten female guinea pigs. Test material was administered for one six-hour insult period in each of three consecutive weeks. Each site was examined for irritation at 24 and 48 hours after treatment. Fourteen days after the last induction exposure, the animals were treated with a challenge application applied 6 hours to a new site. Twenty-four hours after the challenge, all animals were treated with depilatory at the test site for 30 minutes. At approximately 2 hours after washing, the response of the test site was graded. The grading was repeated 48 hours after the challenge. A severity index was calculated based on the scores reported following the challenge application.

Santure NS/Santocure dryer material, when applied at a concentration of 25% in ethanol, did not cause delayed hypersensitivity in guinea pigs.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (sensitising)
Additional information:

Non-human information

The sensitisation potential of the test substance TBBS was evaluated in a guinea pig assay, which was conducted in accordance to OECD TG 406 (Monsanto Co. 1982). The test substance was applied at a concentration of 25 % in ethanol to the shaved skin of 10 male and ten female guinea pigs. Test material was administered for one six-hour insult period in each of three consecutive weeks. Each site was examined for irritation at 24 and 48 hours after treatment. Fourteen days after the last induction exposure, the animals were treated with a challenge application applied 6 hours to a new site. Reading was done ca. 24 and 48 hours after the challenge. For the induction period, no irritation was noted for any of the animals treated with 25% test material. No positive response was seen during 24 or 48 hour periods following the challenge application of the test material. In conclusion, the test substance, when applied at a concentration of 25% in ethanol, did not cause delayed hypersensitivity in guinea pigs. The test substance was also negative in another guinea pig study (Monsanto Co. 1982b).

Human information

The test substance TBBS was evaluated in a human Repeated Insult Patch test (modified Shelanski method) with 54 volunteers (Monsanto 1983). The test substance was tested as a 60 % preparation in petrolatum. Using a specially prepared, occlusive adhesive bandage, 200 mg of the test material was placed in contact with a selected site on the back of each subject for 24 hours. Following this exposure, the test material was removed and the reaction of the site of application was evaluated and graded (scores 0 through 4) by the clinical investigator. The test material was applied in this manner for four consecutive 24 hours periods each week (Monday through Friday) for three consecutive weeks (induction phase). Subjects were then allowed a two week rest period, during which no exposures to the test material occurred. During the sixth week of the study, each subject was to receive a series of four consecutive 24 hour applications of the test material. Due to the responses noted in subjects during the induction phase, subjects were treated with test material only for one 24 hour period. The application site was examined and scored at 24, 48, and 72 hours following removal of the test material. 45 subjects completed the study. During the induction period, eleven subjects demonstrated intense irritation consisting of erythema and indurations. These responses were considered indicative of an allergic reaction. Due to the severity of reaction during the induction period, these eleven subjects were not tested during the portion of the induction phase which followed their response. Following the single 24 hour challenge application, six subjects demonstrated slight to moderate erythema. Twenty-four hours after removal of the test material, mild to intense inflammatory changes were observed in 15 individuals. At 48 hours after removal, responses were still noted in 13 subjects. These responses were considered characteristic for allergic contact dermatitis.

In conclusion, the test substance TBBS, tested as a 60 % preparation in petrolatum, produced sensitization in 13/45 subjects who completed the study. No evidence of primary irritation was observed.

This finding was confirmed in an earlier study (Shelanski  human patch test ) with human volunteers (Monsanto 1970). In this study 9 out of 55 volunteers showed an allergic skin reaction after treatment with TBBS.

Altogether the number of exposures of the Shelanski  human patch test (15 x) is very high, compared with other human patch tests (Schwartz-Peck (1 x) , (modified ) Draize (10 x), Voss-Griffith (9x)).  In the latest test (Monsanto 1983) a high amount of test material 200 mg/patch was used.  Additional the number of subjects tested was low (approx. 50 volunteers). In the older test the test material was applied as a dry powder directly to the skin. The number of subjects tested was low (approx. 50 volunteers) in both tests.

For the Monsanto test 1983 the test material had a purity of 97.4%. No information of impurities or other compounds is available. The purity/content of the Monsanto test from 1970 is not available in the study report.

The relative number of volunteers who reacted positive was noticeable higher in the Monsanto test 1983 than in the Monsanto test 1970. No visible skin changes consistent with the criteria deemed characteristic of a primary irritant were found in the Monsanto test 1970 whereas in the Monsanto test 1983 during the induction period, eleven subjects demonstrated intense irritation consisting of erythema and induration.

The human sensitisation tests require great experience in design and execution of the test and a number of artefacts are possible (SCCNFP opinions – see link).

http://ec.europa.eu/health/scientific_committees/consumer_safety/opinions/sccnfp_opinions_97_04/sccp_out102_en.htm

No international agreed test protocols for the Predictive human skin sensitisation assays are available.

According to Guidance to Regulation (EC) No 1272/2008 on classification, labelling and packaging (CLP) of substances and mixtures, Version 5.0 , July 2017 human induction studies such as HRIPT (Human Repeat Insult Patch Test ) or HMT (Human Maximisation Test ) must not be performed, although historical data may be used as weight of evidence for the sub-categorisation.  

Additional, human data should be incorporated with animal data to decide on the sub-categorisation (CLP Regulation).

In conclusion, based on the limitations of the human studies, especially the difficult interpretation of the results, the studies cannot be regarded independently, instead the studies have to be assessed in the context of other available studies.

Occupational Reports

There are several reports on the skin sensitizing potential of sulfonamides and thiazoles from the major manufacturers (General Quimica, Lanxess – in alphabetical order) and a downstream user (Michelin) available (please see Chapter 13 for the full reports).

•General Quimica: Report on the skin sensitizing potential of sulfonamides and Thiazoles during manufacture, 2018-08-27.

•Michelin: Report on the skin sensitizing potential of sulfonamides and thiazoles during the production of Michelin’s tyres (as down-stream user of these substances), 2018.

•Lanxess: Sensitization of N-tert-butyl-2-benzothiazolesulfenamide (TBBS, CAS: 95-31-8), January 2019.

 

No cases of skin sensitisation related with professional activities derived from contact with sulfenamides and thiazoles were reported (General Quimica). No known cases about skin sensitization which can be linked to product contact with Vulkacit NZ-EG-c ( N-tert-butyl-2-benzothiazolesulfenamide) were reported by Lanxess. The number of eczema related to sulfonamides and thiazoles was negligible compared to other etiology (Michelin).

A comprehensive examination was conducted and described in the Michelin report: ‘The case of the city of Clermont-Ferrand is interesting because the high number of workers between the year 1960 and 1990. There were up to 30 000 employees working in this city, so that Clermont Ferrand is a pool of employment very interesting for studying epidemiological issue regarding the rubber industry. Clermont Ferrand Michelin entity has his own medical service and every employee had a systematic medical visit every year and in case of illness such as a dermatitis disease. Furthermore, Michelin worked with the university hospital of Clermont-Ferrand and specifically with the dermatology consultation of the occupational health service. As a fact, the rubber industry is known to be an “allergic” industry due both to the latex and the rubber additives used in the fabrication of tyres. So a specific focus has been done on this type of disease.  Each hand dermatosis has been explored in this consultation with the realization of patch tests with standard European rubber battery comprising rubber additives. The number of eczema related to Sulfenamides and thiazoles was negligible compared to other etiology’.

The applied RMMs (Risk Management Measures) and OCs (Operational conditions) in these factories  correspond  with the moderate hazard band, which applies for substances having a moderate hazard profile i.e. moderate sensitisers, categorized as Skin Sens. 1 B (H 317).

This means, a catergorisation as Skin Sens 1 B (and the following subsequent applied RMMS and OCs) are sufficient to prevent workers from skin sensitization maybe induced by Sulfenamides and thiazoles.

Conclusion:

Due to the negative results of the Guinea pig sensitization tests, the human patch tests which are not fully valid, on a weight-of-evidence consideration, a classification for TBBS as  Skin Sens 1 B  (moderate hazard band according to ECHA guidance on information requirements and chemical safety assessment Part E: Risk charaterisation , May 2016) is justified.

The Occupational reports from several producers demonstrate, that the RMMs and OCs for the moderate hazard band are sufficient to effectively protect workers from skin sensitization possibly caused by Sulfenamides and thiazoles.


Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available
Additional information:

No study available.

Justification for classification or non-classification

The skin sensitisation potential of TBBS was evaluated in guinea pigs and in studies with human volunteers. No skin sensitization was noted in guinea pigs after treatment with TBBS (Monsanto Co 1982). However, an allergic response (13/54) was noted in a Repeated Insult Patch test with human volunteers (Monsanto Co. 1983). No cases of skin sensitisation related with professional activities derived from contact with Sulfenamides and Thiazoles were reported from several companies with RMMs and OCs for the moderate hazard band. On a weight-of-evidence consideration, according to CLP classification criteria (Regulation (EC) No 1272/2008) a classification as Skin Sens.1B (H317: May cause an allergic skin reaction) is justified.