Registration Dossier

Administrative data

Description of key information

The test substance CBS did not cause skin sensitization in guinea pigs (Monsanto Co. 1982). In contrast, there was one human patch testing study which demonstrated contact sensitization in humans (Monsanto Co. 1982). Data from epidemiological studies are difficult to assess, but also indicate some skin sensitizing potential of CBS. 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:
supporting study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Principles of method if other than guideline:
S-Duplex was dermally applied to 20 (10m + 20f) guinea pigs, for a total of 3 six-hour insult periods at a 25% concentration. An additional group of 10 (5m + 5f) guinea pigs were treated with 1-chloro-2,4-dinitrobenzene (DNCB). The positive control and negative control also were treated for a total of 3 six-hours insult period. Fourteen days after the last induction period, all animals were challenged at a native site.
GLP compliance:
yes
Type of study:
Buehler test
Justification for non-LLNA method:
The test was conducted in the year 1982.
Species:
guinea pig
Strain:
Hartley
Sex:
male/female
Route:
epicutaneous, occlusive
Vehicle:
other: ethanol (80%)
Concentration / amount:
25%
Route:
epicutaneous, occlusive
Vehicle:
other: ethanol (80%)
Concentration / amount:
25%
No. of animals per dose:
20 (10 per dose/sex)
Details on study design:
Main experiment
Treatment-group: 20 animals (10 males, 10 females) were dermally exposed for a total of three six-hour insults periods with 25% test substance.
Positive control: 10 animals (10 males, 10 females) were treated for a total of three six-hour insult periods with 1 -chloro-2,4 -dinitrobenzene (DNCB).
Negative/vehucle control: 4 animals (2 males, 2 females) were treated for a total of three six-hours insult periods with 80% ethanol.
Positive control substance(s):
yes
Remarks:
1-chloro-2,4-dinitrobenzene (DNCB).
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:
18
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: 18.0. Clinical observations: no effects.

Positive control (1-chloro-2,4 -dinitrobenzene) showed positive response (1st reading: 8/9, 2nd reading: 8/9)

Vehicle control: no effects (1st reading: 0/3, 2nd reading: 0/3).

Interpretation of results:
GHS criteria not met
Executive summary:

The test substance CSB has not demonstrated any delayed hypersensitivity in a Buehler test with guinea pigs. Based upon the results of a dose-range-finding study with guinea pigs, the highest non-irritating dose chosen for induction was 25 %. The test substance CBS was dermally applied to twenty guinea pigs (10 males and 10 females) for a total of three-6-hour insult periods at a concentration of 25 %. An additional group of 10 guinea pigs was treated with 1-chloro-2,4-dinitrobenzene (DNCB), positive control). In order to assess the influence of the vehicle on sensitization, four guinea pigs were treated with 80 % ethanol during the induction period. Fourteen days after the last induction period, all animals were challenged at a naive site. A positive response was elicited in the animals receiving DNCB, no response was observed in the vehicle induced animals challenged with the test substance at a 25 % concentration, no response was observed in the experimental group receiving the test substance at 25 % concentration (Monsanto Co 1982).

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:
no
Type of study:
patch test
Justification for non-LLNA method:
Study was conducted in the year 1982 on human volunteers.
Species:
human
Sex:
male/female
Route:
epicutaneous, occlusive
Vehicle:
petrolatum
Concentration / amount:
70% in petrolatum
Route:
epicutaneous, occlusive
Vehicle:
petrolatum
Concentration / amount:
70% in petrolatum
No. of animals per dose:
51 human volunteers
Details on study design:
Induction: Weeks #1, #2, and #3. A series of 12 applications, each of 24 hours' duration was scheduled to be carried out during weeks #1, #2, and #3.
Rest period: Weeks #4 and #5
Challenge: Week #6: A series of 4 applications on virgin sites was scheduled to be carried out during the challenge week.
Positive control substance(s):
no
Reading:
1st reading
Hours after challenge:
24
Group:
test group
Dose level:
70%
No. with + reactions:
5
Total no. in group:
51
Clinical observations:
In five (5/51) individuals Grade 3 response were discovered (clear distinguished from individuals with irritations); these responses were typical of an allergic contact dermatitis, indicating that the test material had successfully sensitized these five
Remarks on result:
other: see Remark
Remarks:
Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 70%. No with. + reactions: 5.0. Total no. in groups: 51.0. Clinical observations: In five (5/51) individuals Grade 3 response were discovered (clear distinguished from individuals with irritations); these responses were typical of an allergic contact dermatities, indicating that the test material had successfully sensitized these five .
Group:
negative control
Remarks on result:
other: Human patch test - no negative control group was included
Group:
positive control
Remarks on result:
other: Human patch test - no positive control group was included

Induction phase:

The test material produced irritation in eight (8/51) individuals during the induction phase

In 5 of these individuals, minimal erythema was observed sporadically and was not considered of any significance.

In 3 indivuduals intense erythema was present when the thenth application was removed. In panelist no. 37 and 39, the intense irritation was not discovered until several days after the twelfth application had been removed.

Challenge phase:

The test material produced in seven (7/51) individuals during the course of these applications. A minimal solitary irritation was observed in two (2) individuals. These response were not considered of any significance. In five (5/51) individuals, including the three (3/51) discussed during the induction phase, Grade 3 response were discovered. These responses were typical of an allergic contact dermatities, indicating that the test material had successfully sensitized these five (5/51) individuals.

during the course of this evalaution, not only were the sites occupied by this material involved but the effect was manifested as a"spill-over" phenomenon on adjacent sites occupied by innocuous materials.

Interpretation of results:
Category 1 (skin sensitising) based on GHS criteria
Executive summary:

In a repeated insult patch test with 51 volunteers using a 70 % test substance preparation in petrolatum, CBS acted as a sensitizer in 5/51 individuals. These five individuals, showed Grade 3 responses (erythema). The authors concluded, that these responses were typical of an allergic contact dermatitis, indicating that the test material had successfully sensitized these five (5/51) individuals. (Monsanto company 1982).

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

Non-human information

The test substance CSB (CAS 95-33-0) has not demonstrated any delayed hypersensitivity in a Buehler test with guinea pigs. Based upon the results of a dose-range-finding study with guinea pigs, the highest non-irritating dose chosen for induction was 25 %. The test substance CBS was dermally applied to twenty guinea pigs (10 males and 10 females) for a total of three-6-hour insult periods at a concentration of 25 %. An additional group of 10 guinea pigs was treated with 1-chloro-2,4-dinitrobenzene ((DNCB), positive control). In order to assess the influence of the vehicle on sensitization, four guinea pigs were treated with 80 % ethanol during the induction period. Fourteen days after the last induction period, all animals were challenged at a naive site. A positive response was elicited in the animals receiving DNCB, no response was observed in the vehicle induced animals challenged with the test substance at a 25 % concentration, no response was observed in the experimental group receiving the test substance at 25 % concentration (Monsanto Co. 1982).

 

Human information

In a repeated insult patch test (modified Shelanski 4 x 4 method) with 51 volunteers using a 70 % test substance preparation in petrolatum (approximately 200 mg of test material per patch), CBS acted as a sensitizer in 5/51 individuals. These five individuals showed Grade 3 responses (erythema). The authors concluded, that these responses were typical of an allergic contact dermatitis, indicating that the test material had successfully sensitized these five (5/51) individuals. (Monsanto company 1982).

In several human patch tests with contact dermatitis patients, the test substance CBS reacted positive. In a patch test study 34 of 686 contact dermatitis patients reacted positive, when tested with 1 % CBS in petrolatum (Conde-Salazar 1993). A second study revealed that 11 of 46 patients with occupational rubber dermatitis had a positive patch test result with CBS (Kiec-Swierczynska 1995). In another study 1.8 % of patients with occupational contact dermatitis, were tested positive with CBS (Geier 2003).

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 Monsanto study a high amount of test material 200 mg/patch was used. Additional the number of subjects tested was low (approx. 50 volunteers). The number of subjects tested was low (approx. 50 volunteers) in the repeated insult patch test (modified Shelanski 4 x 4 method).

The purity/content of the Monsanto test from 1982 is not available in the study report. No information of impurities or other compounds is available.

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 thePredictive 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.  

 

Additionally, 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: Report on the plant’s experience concerning the sensitizing potential of N-cyclohexy-2-benzothiazolesulfenamide, August 2018.

 

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 CZ-EG-c ( N-cyclohexy-2-benzothiazolesulfenamide) were reported by Lanxess. The number of eczema related to sulfenamides 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 CBS as Skin Sens 1 B (moderate hazard band according to ECHA guidance on information requirements and chemical safety assessment Part E: Risk characterisation , 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 data available.


Data on sensitization caused by inhalation are not available. As no cases of respiratory sensitization after occupational exposure have been reported yet, it can be assumed that CBS dose not induce sensitization via the inhalation route.

Justification for classification or non-classification

The test substance CBS did not cause skin sensitization in guinea pigs (Monsanto Co. 1982). In contrast, there was one human patch testing study which demonstrated contact sensitization in humans (Monsanto Co. 1982). Data from epidemiological studies are difficult to assess, but also indicate some skin sensitizing potential of CBS. 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.