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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Description of key information

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:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: acceptable documented publication which meets basic scientific principles
Principles of method if other than guideline:
Method: other: according to Magnusson & Kligman (1969)
GLP compliance:
not specified
Type of study:
guinea pig maximisation test
Species:
guinea pig
Strain:
Hartley
Sex:
female
Route:
intradermal and epicutaneous
Vehicle:
other: 1% vaseline
Concentration / amount:
induction (intradermal: 0.5 % in olive oil, epicutaneous: 1% vaseline),
Route:
other: epicutaneous
Vehicle:
other: 1% vaseline
Concentration / amount:
induction (intradermal: 0.5 % in olive oil, epicutaneous: 1% vaseline),
No. of animals per dose:
20
Details on study design:
1st application: Induction 0.5 % intracutaneous
2nd application: Challenge 0.05 % open epicutaneous
3rd application: Challenge 0.5 % open epicutaneous
Reading:
1st reading
Hours after challenge:
48
Group:
negative control
Dose level:
0.05%
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
no data
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 48.0. Group: negative control. Dose level: 0.05%. No with. + reactions: 0.0. Total no. in groups: 20.0. Clinical observations: no data.
Reading:
1st reading
Hours after challenge:
48
Group:
negative control
Dose level:
0.5 %
No. with + reactions:
4
Total no. in group:
20
Clinical observations:
no data
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 48.0. Group: negative control. Dose level: 0.5 %. No with. + reactions: 4.0. Total no. in groups: 20.0. Clinical observations: no data.
Reading:
1st reading
Hours after challenge:
48
Group:
test chemical
Dose level:
0.05 %
No. with + reactions:
10
Total no. in group:
20
Clinical observations:
no data
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 48.0. Group: test group. Dose level: 0.05 %. No with. + reactions: 10.0. Total no. in groups: 20.0. Clinical observations: no data.
Reading:
1st reading
Hours after challenge:
48
Group:
test chemical
Dose level:
0.5%
No. with + reactions:
18
Total no. in group:
20
Clinical observations:
no data
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 48.0. Group: test group. Dose level: 0.5%. No with. + reactions: 18.0. Total no. in groups: 20.0. Clinical observations: no data.

RS-Freetext:
TS concentration   % sensitization   sensitizing potential
0.05 % TS               50 %              medium
0.5  % TS               90 %              very high
controls                 0 %                 -
Potency categorisation based on GPMT:strong
-Clinical signs: not reported

The authors also noted a cross-sensitization to
N-phenyl-N'-cyclohexyl-p-phenylenediamine (CPPD): 30 % of animals  sensitized to 

6PPD showed cross-sensitization to 0.05 % CPPD in vaseline.  Animals sensitized 

to p-phenylenediamine (PPD) or to  N-isopropyl-N'-phenyl-p-phenylenediamine 

showed also cross-sensitization  to 6PPD (see table).

Table: Cross-Sensitization in guinea pigs (% animals cross-sensitized)
      Cross-reaction product tested (0.05 % in vaseline):
Sensitizer:  CPPD    6PPD     PPD     IPPD
CPPD             50       5         15         nd
6PPD             30      50         nd         nd
PPD             100      95         80         95
IPPD             90      85        100         10

Interpretation of results:
sensitising
Remarks:
Migrated information
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (sensitising)
Additional information:

The skin sensitizing potential of 6PPD was evaluated with the guinea pig maximization test. For induction treatment groups of 20 female guinea pigs were intradermally injected with 0.05% or 0.5 % 6PPD in olive oil with complete FCA followed one week later by cutaneous application of 1 % 6PPD in petrolatum. According to the grading system of Magnusson and Kligman 50 and 90 %, respectively, of the guinea pigs challenged by epicutaneous application of 0.05 and 0.5 % 6PPD in petrolatum reacted positive. The sensitizing potential was classified as medium for the 0.05 % and very high for the 0.5 % challenge concentration. 30 % of animals sensitized to 6PPD showed cross-sensitization to 0.05 % N-phenyl-N' cyclohexyl-p-phenylenediamine (CPPD) in vaseline. Animals sensitized to p-phenylenediamine (PPD) or to N-isopropyl-N‘-phenyl-p-phenylenediamine (IPPD) showed also cross-sensitization to 6PPD (Herve-Bazin et al., 1977). The skin sensitizing potential of 6PPD was confirmed in a more recent guinea pig maximization test and local lymph node assay (Yamano 2009). Female Hartley guinea pigs challenged with 50 ppm (0.005%) and 5000 ppm (0.5%) 6PPD showed positive skin reactions (4/4). Moreover, female BALB/c mice treated with 6PPD showed a significant increase in the Stimulation Index (SI: 2.34 and 5.06 at 1 % and 3 %, respectively) at a non-irritant dose-range and thus was considered to be a positive skin sensitizer in the local lymph node assay.

Human information

"A range of older studies performed by chemical industry report from patch-tests in humans applying a repeated insult patch test (method of Shelanski) or a modified Schwartz patch test. In healthy volunteers not previously exposed to test rubber formulations, no sensitization or only a low sensitization rate to 6PPD was noted, while the sensitization rate was much higher in persons who had been previously sensitized to rubber samples" (OECD SIDS 2005).

The positive patch-test reactions to 6PPD may be a consequence of para-group cross-sensitization:

9 farmers with contact allergy due to rubber boots were patch-tested with 19 rubber additives according to ICDRG criteria. 5/9 contact dermatitis patients showed a positive reaction to 6PPD besides cross-sensitization to N-isopropyl-N'-phenyl-p-phenylenediamine, p-phenylenediamine and p-aminoazobenzene (Nishioka 1996). Positive patch-test results were also reported in 6/135 patients partly with cross-sensitzation to other rubber additives (Heise 1997). 15 patients that had been tested positive to IPPD also showed a reaction to 6PPD (Herve-Bazin et al., 1977).

Over a period of 32 years data from one 6PPD manufacturing site were collected and analyzed to determine the skin sensitizing potential of 6PPD. 70 workers were examined at regular intervals by the company medical department over the years (Oberthür, 2012). The results showed no evidence of 6PPD induced skin sensitization.


Migrated from Short description of key information:
The skin sensitisation potential of 6PPD was evaluated in guinea pigs and in early studies with human volunteers; in addition patch test results are available. 6PPD was sensitizing in guinea pigs and was found to reveal positive reactions in humans. According to criteria published in REACH guidance document chapter R. 8, 6PPD was categorized as a moderate to strong skin sensitizer.

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

Based on the criteria defined in the 2. ATP (EU Regulation No 286/2011 of March 2011) the available animal and human data on 6PPD are not sufficient for 1A or 1B sub-categorization.

Animal experiments:

A non-guideline local lymphe node assay with 6PPD used a non-radioactive read out for cell proliferation, 5-bromo-2’-deoxyuridine (BrdU), instead of3H-methyl thymidine. The reported “Stimulation index” (SI) was calculated by multiplying the cellularity index by the BrdU incorporation index.Without method validation data as requested in the OECD TG 429 for a new, non-radioactive, readout no quantitative comparison to a potential radioactive EC3 value can be made. No conclusion on the quantitative sensitization potency can be derived from a limited guinea pig maximization test in which groups of 4 animals were challenged “all at once” with 6 different sensitizes. In a second guinea pig maximization test 50-90% of the animals were sensitized at an intradermal concentration of 0.5% 6PPD in an early study with limited documentation.

Human data with 6PPD:

No or only a low sensitization rate to 6PPD was noted in different limited human studies summarized in the OECD SIDS Initial Assessment Report for 6PPD.In human studies with 6PPD the sensitization rate was much higher in persons who had been previously sensitized to rubber samples. An examination of the skin sensitization potential of 6PPD in 70 workers over 32 years in one manufacturing site showed no evidence of a sensitation effects related to the exposure to 6PPD.

In conclusion: It is proposed to classify 6PPD as skin sensitizer Category 1 without sub-categorization.