Registration Dossier

Toxicological information

Skin sensitisation

Currently viewing:

Administrative data

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
no stated
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Important aspects (intradermal induction, intradermal/epidermal challenge) in line with and induction period longer than current OECD guideline. The deviations from the regarding guideline (OECD406) lead to an even more rigid study design.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1980

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Deviations:
yes
Remarks:
induction: 10 intradermal injections, no dermal application; 2 challenges: 1 intradermal (14 days after last induction), 1 by epidermal route (24 days after last induction)
Principles of method if other than guideline:
n.a.
GLP compliance:
no
Remarks:
performed before GLP-guideline
Type of study:
Maurer optimisation test

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Methylparaben

In vivo test system

Test animals

Species:
guinea pig
Strain:
other: Pribright white
Sex:
male/female
Details on test animals and environmental conditions:
For details on conditions please refer to Th. Maurer, P. Thomann, E.G. Weirich and R. Hess, Contact Dermatitis, 4 (1978) 321

Study design: in vivo (non-LLNA)

Inductionopen allclose all
Route:
intradermal
Vehicle:
no data
Concentration / amount:
0.1% intradermal induction
0.1% intradermal challenge
5% epidermal challenge
Challengeopen allclose all
Route:
intradermal and epicutaneous
Vehicle:
no data
Concentration / amount:
0.1% intradermal induction
0.1% intradermal challenge
5% epidermal challenge
No. of animals per dose:
20 (10 males/10 females)
Details on study design:
- Induction period: 3 weeks (10 intracutaneous applications)
- Intradermal challenge (week 6)
- epidermal challenge (week 8)

Induction:
The animals received 1 injection into the skin every other day of a freshly prepared 0.1 % methyl parabene suspension. During the first week the skin fold thickness at the injection site was measured before the application with a skinfold caliper. During the second and third weeks the test compound was incorporated at 0.1 % in a mixture of Freund´s complete adjunvant and physiological saline (adjuvant/saline 1:1 v/v).

Challenges:
The animals were challenged with methyl parabene 14 days after the last induction application using the same procedure as that during the first induction week. After a further rest period of 10 days the animals were again challenged, but this time by epidermal route. In this case the maximal subirritant concentration (5 %) of the test compound was applied in soft white petrolatum under occlusive dressings. The filter patches were removed 24 h after application.

Assessment of reactions after intradermal application:
24 h after the application during the first induction week as well as after the intradermal challenge the reaction sites were chemically depilated; 3 h later the reactions were assessed. The 2 greatest perpendicular diameters and the skinfold thickness were measured (in mm). By multiplying the diameters with the increase in skinfold thickness an approx. "reaction volume" (in µL) was obtained for each reaction in each animal. For the individual animal the mean reaction volume for the first induction week was calculated and one standard deviation added. The value thus obtained, the individual threshold value, represented the skin irritation reactivity of each animal to the induction applications. Any challenge reaction greater than the induction threshold value was considered an allergic reaction, and the animal was termed "positive". The number of positive animals in the test group was compared statistically with the number of "pseudo positive" animals in the control group treated with the vehicle alone using the Fisher test.

Assessment of reactions after epidermal challenge:
At 21 h after removing the bandages, the reaction sites were also chemically depilated. 3 h later the epidermal reactions were evaluated according to the Draize scale for primary irritation. The significance of differences in the number of positive animals between the treated group and the controls was assessed by the Fisher test.

Negative control: sodium chloride solution
Challenge controls:
no data
Positive control substance(s):
yes
Remarks:
other substances (e.g. cinnamic aldehyde, chlorocresol etc) were tested in parallel

Results and discussion

Positive control results:
Cinnamic aldehyde (0.1 % intradermal; 3 % epidermal applied)
- incidence after intradermal challenge: 20 of 20 animals positive
- incidence after epidermal challenge: 19 of 20 animals positive

In vivo (non-LLNA)

Resultsopen allclose all
Reading:
other: reading after intradermal challenge
Hours after challenge:
24
Group:
test group
Dose level:
0.1 %
No. with + reactions:
3
Total no. in group:
20
Clinical observations:
no data
Remarks on result:
other: Reading:
Reading:
other: reading after epidermal challenge
Hours after challenge:
24
Group:
test group
Dose level:
5 %
No. with + reactions:
4
Total no. in group:
20
Clinical observations:
no data
Remarks on result:
other: Reading:
Reading:
other: reading after intradermal challenge
Hours after challenge:
24
Group:
negative control
Dose level:
no data
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
no data
Remarks on result:
other: Reading:
Reading:
other: reading after epidermal challenge
Hours after challenge:
24
Group:
negative control
Dose level:
no data
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
no data
Remarks on result:
other: Reading:

Applicant's summary and conclusion

Interpretation of results:
not sensitising
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
In a guinea pig sensitization study according to Maurer Optimization Test Methylparaben caused allergic reactions in a few animals (4/20). The number of affected guinea pigs was not high enough to be significant. Methylparaben is not considered to be a skin sensitiser.
Based on a read-across approach, Sodium Methylparaben is not considered to be a skin sensitiser and is therefore not subjected for labelling and classification requirements according to regulatory requirements.
Executive summary:

Testing for sensitising properties of Methylparaben was performed in male and female guinea pigs according to the Maurer Optimization Test. Intradermal induction was performed using 0.1 % Methylparaben (10 injections). The first challenge was carried out with 0.1% Methylparaben (intradermal) 14 days after the last induction application and the second challenge was conducted with 5% Methylparaben (epidermal) in soft white petrolatum after further 10 days rest.

Methylparaben induced allergic reactions in a few animals, but according to the standard evaluation, not significant and therefore the test substance is not considered to have sensitising properties.