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Toxicological information

Skin sensitisation

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Administrative data

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
08/01/1997 - 09/12/1997
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP, Guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1997
Report Date:
1997

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Version / remarks:
(1992)
Deviations:
no
Qualifier:
equivalent or similar to
Guideline:
EU Method B.6 (Skin Sensitisation)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPP 81-6 (Skin Sensitisation)
Version / remarks:
(1982)
Deviations:
no
Qualifier:
according to
Guideline:
other: JMAFF 59 NohSan no. 4200 (1985)
Deviations:
no
GLP compliance:
yes
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
This study was conducted in 1997, which is prior to adoption in 2002 of the LLNA OECD TG 420. The study is submitted in the context of this REACH dossier as it provides key information non the non-sensitising classification of dinotefuran and remains adequate; this study was generated for product registration purposes in other countries.

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Remarks:
powder

In vivo test system

Test animals

Species:
guinea pig
Strain:
other: Crl:[HA]BR
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: 4 - 8 weeks old
- Weight at study initiation: 372 - 500 g

Study design: in vivo (non-LLNA)

Inductionopen allclose all
Route:
intradermal and epicutaneous
Vehicle:
other: Carboxyl Methyl Cellulose (CMC)/distilled water and Freund's Complete Adjuvant (FCA) for the intradermal injection phase and as a mixture in petrolatum for the topical induction application and challenge phase of the definitive study.
Concentration / amount:
1 % v/w, 5 % v/w, 10 % v/w, 15 % v/w
Challengeopen allclose all
Route:
epicutaneous, occlusive
Vehicle:
other: Carboxyl Methyl Cellulose (CMC)/distilled water and Freund's Complete Adjuvant (FCA) for the intradermal injection phase and as a mixture in petrolatum for the topical induction application and challenge phase of the definitive study.
Concentration / amount:
1 % v/w, 5 % v/w, 10 % v/w, 15 % v/w
No. of animals per dose:
20 test animals (dinotefuran): exposed to the test substance at inductions and challenge.

Details on study design:
PRELIMINARY STUDY:
- A preliminary irritation study in which 2 groups of 4 guinea pigs were exposed by occluded topical application for 24 hours to dinotefuran at concentrations of 5, 10, 15 and 25% w/w in petrolatum, or intradermally at concentrations of 1, 5, 10 and 15% in aqueous carboxymethylcellulose. Dermal reactions were evaluated 24 and 48 hours after treatment.

MAIN STUDY
A. INDUCTION EXPOSURE
- Concentration of test substance: 5% w/v
- Induction vehicle: 0.5% CMC/distilled water and FCA for the intradermal injection phase and as a 25% (w/w) mixture in petrolatum for the topical induction application and challenge phase of the definitive study.
- No. of doses administered: On day 1, the test group received 3 pairs of intradermal injections of 50% FCA in water, 5% w/v dinotefuran in aqueous carboxymethylcellulose and 10% w/v dinotefuran in aqueous carboxymethylcellulose diluted 1:1 with FCA (i.e 5% dinotefuran with FCA). The control group received similar injections but without dinotefuran. On day 7, the application sites of both groups of animals were treated topically with 10% sodium lauryl sulfate which was massaged into the skin. On day 8, the animals were treated topically, over the injection sites, under occlusive dressing for 48 hours with 25% w/w dinotefuran in petrolatum (treated group) or petrolatum alone (irritation control group).

B. CHALLENGE EXPOSURE
- No. of exposures: Two weeks after day 8, both groups were challenged topically, under occlusive dressing for 24 hours, with 25% w/w dinotefuran in petrolatum (right side) and petrolatum alone (left side). The challenge sites were shaved and then scored for dermal reactions 24 and 48 hours after removal of the challenge dressings.

The substance was removed 24 hours after challenge.

GRADING SYSTEM USED: Performed according to the method of Magnusson & Kligman (Magnusson, B. and Kligman, A. (1970): Allergic Contact Dermatits in the Guinea Pig, Charles C. Thomas, pp. 113-117, 120).

No statistical analyses were employed.
Challenge controls:
20 irritation control animals (for dinotefuran): exposed to the test substance only at challenge.
Positive control substance(s):
yes
Remarks:
hexylcinnamaldehyde

Results and discussion

Positive control results:
The positive control study was conducted within six months of the conduct of this study. The positive reaction of the challenge skin of all 10 positive control (hexylcinnamaldehyde) animals was observed, whereas all scores in the negative control group were zero. Therefore, hexylcinnamaldehyde was considered to be an extreme dermal sensitizer.

In vivo (non-LLNA)

Resultsopen allclose all
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
test group
Dose level:
25 % w/w
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
1 animal exhibited thin appearance on days 1-19, hypoactivity and nonformed faeces on days 1-20 and 22-28. None after challenge
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
test group
Dose level:
25 % w/w
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
1 animal exhibited thin appearance on days 1-19, hypoactivity and nonformed faeces on days 1-20 and 22-28. None after challenge
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
0
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
None
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
positive control
Dose level:
50% w/v
No. with + reactions:
10
Total no. in group:
10
Clinical observations:
1 animal exhibited nonformed stool on day 14 and 15 after challenge
Remarks on result:
positive indication of skin sensitisation
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
positive control
Dose level:
50% w/v
No. with + reactions:
10
Total no. in group:
10
Clinical observations:
1 animal exhibited nonformed stool on day 14 and 15 after challenge

Any other information on results incl. tables

Preliminary study:

No dermal irritation occurred at any concentration of dinotefuran administered by topical application, up to 25% w/v. Therefore, all dermal reactions were scored as zero. In the 4 animals treated by intradermal injection, dinotefuran produced mild erythema (grade 1) at 1% w/v, mild-moderate diffuse erythema (grade 1 - 2) reactions at 5% w/v and moderate-marked erythema (grade 2 - 3) at 10 and 15% w/v (Table 7.4.1).

Main study:

There were no treatment-related clinical signs or adverse effects on body weight with the exception of one animal in the test group that appeared thin from day 20.

None of the test and control group animals exhibited a dermal response to the challenge application of the test or control articles either 24 or 48 hours after patch removal. Therefore, all dermal reaction scores were zero.

Table 7.4.1: Individual dermal reaction scores in the irritation screening study - intradermal injection

Animal

Dermal reaction score at:

number

1% w/v

5% w/v

10% w/v

15% w/v

 

24hr

48hr

24hr

48hr

24hr

48hr

24hr

48hr

1

1

1

2

2

3

3

3

3

2

1

1

2

2

2

2

3

3

3

1

1

1

1

2

2

2

2

4

1

1

1

1

2

2

3

3

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Remarks:
Migrated information
Conclusions:
Based on a skin reaction incidence of 0 %, which is below the 30 % threshold of significance specified in Commission Directive 93/21/EEC, dinotefuran is not a dermal sensitiser in the guinea pig, and no EU classification is required (category IV according to EPA classification criteria and not classified according to GHS criteria). Dinotefuran does not induce skin sensitisation at concentrations ≤ 25%.