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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:
1982
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: comparable to guideline study with acceptable restrictions

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1983
Report date:
1983

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Deviations:
yes
Remarks:
- no range finding for the induction; the second induction on Day 7 was performed by intradermal injection; two challenges were performed on Day 21 and Day 35 by topical application under occlusive conditions for 6 hours each
GLP compliance:
no
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
The guinea pig maximisation test (GPMT) was an adequate in vivo skin sensitisation test at the time of performance in 1982. In addition, the GPMT is a challenge assay and more appropriate for determining skin sensitisation of highly reactive substances like diisocyanates. For this substance group the LLNA often provides over-predictive results.

Test material

Constituent 1
Chemical structure
Reference substance name:
Hexamethylene diisocyanate
EC Number:
212-485-8
EC Name:
Hexamethylene diisocyanate
Cas Number:
822-06-0
Molecular formula:
C8H12N2O2
IUPAC Name:
1,6-diisocyanatohexane
Constituent 2
Reference substance name:
Desmodur H
IUPAC Name:
Desmodur H
Details on test material:
- purity not specified

In vivo test system

Test animals

Species:
guinea pig
Strain:
other: Pirbright White
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Lippische Versuchstierzucht (Extertal, Germany)
- Age at study initiation: no data
- Weight at study initiation: mean weight ca. 253 g
- Housing: 4 or 5 animals per cage
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: no data


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 +/- 2
- Humidity (%): 40-70
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12 / 12


Study design: in vivo (non-LLNA)

Inductionopen allclose all
Route:
intradermal
Vehicle:
petrolatum
Concentration / amount:
1st induction: 10 % ;
2nd induction: undiluted ;
1st and 2nd challenge: 0.3 % and 1.0 % (application volume: 0.2 ml each)
Challengeopen allclose all
Route:
epicutaneous, occlusive
Vehicle:
petrolatum
Concentration / amount:
1st induction: 10 % ;
2nd induction: undiluted ;
1st and 2nd challenge: 0.3 % and 1.0 % (application volume: 0.2 ml each)
No. of animals per dose:
test groups: 20
control groups: 10
Details on study design:
RANGE FINDING TEST: In a pilot study for the challenge the skin irritation was examined with 0.03, 0.1, 0.3 and 1.0 % (24 hours, occlusive) using 4 animals; the animals were treated with FCA and paraffin oil like the control animals; only one animal showed skin irritation (grade 1) at the 1.0 % concentration one day after application.

MAIN STUDY
1st induction: Intradermal injections
Day 0 - treatment group
Three pairs of intradermal injections of 0.1 ml volume are given in the shoulder region which was shaved.
Injection 1 (cranial): a 1:1 mixture (v/v) Freunds Complete Adjuvans (FCA)/water
Injection 2 (medial): 10 % test substance in paraffin oil
Injection 3 (caudal): 10 % test substance formulated in FCA

Day 0 - control group
Three pairs of intradermal injections of 0.1 ml volume are given in the same sites as in the treated animals.
Injection 1 (cranial): a 1:1 mixture (v/v) FCA/water
Injection 2 (medial): paraffin oil
Injection 3 (caudal): paraffin oil in FCA

2nd induction: Intradermal injections
Day 7 - treatment group
Each animal received 2 injections of 0.025 ml undiluted test substance (ca. 0.05 ml per animal) in the shorn shoulder region of the first induction treatment.

Day 7 - control group
Control animals were not treated.

1st and 2nd challenge: Topical application under occlusive conditions
Days 21 and 35 - treatment and control groups
Patches with the test substance (application volume: 0.2 ml each) were applied in concentrations of 0.3 or 1.0 % to the left and right shorn flanks of the animals. The patches are held in contact by an occlusive dressing for 6 hours.

Observations - treatment and control groups:
0 = no visible change
1 = discrete or patchy erythema
2 = moderate and confluent erythema
3 = intense erythema and swelling

Approximately 24 hours after this observation a second observation (48 hours) and third (72 hours) is made and once again recorded. An animal is evaluated as sensitized if the treated animal showes a skin reaction graded >=1 without any evidence of irritation.
Challenge controls:
yes
Positive control substance(s):
no

Results and discussion

In vivo (non-LLNA)

Resultsopen allclose all
Reading:
other: 1st challenge on Day 21
Hours after challenge:
24
Group:
test chemical
Dose level:
0.3 % HDI in petrolatum
No. with + reactions:
15
Total no. in group:
17
Clinical observations:
erythema (mean score: 1.1)
Reading:
other: 1st challenge on Day 21
Hours after challenge:
48
Group:
test chemical
Dose level:
0.3 % HDI in petrolatum
No. with + reactions:
16
Total no. in group:
17
Clinical observations:
erythema (mean score: 1.0)
Reading:
other: 1st challenge on Day 21
Hours after challenge:
72
Group:
test chemical
Dose level:
0.3 % HDI in petrolatum
No. with + reactions:
4
Total no. in group:
17
Clinical observations:
erythema (mean score: 0.2)
Reading:
other: 1st challenge on Day 21
Hours after challenge:
24
Group:
test chemical
Dose level:
1.0 % HDI in petrolatum
No. with + reactions:
15
Total no. in group:
17
Clinical observations:
erythema (mean score: 1.5)
Reading:
other: 1st challenge on Day 21
Hours after challenge:
48
Group:
test chemical
Dose level:
1.0 % HDI in petrolatum
No. with + reactions:
16
Total no. in group:
17
Clinical observations:
erythema (mean score: 1.4)
Reading:
other: 1st challenge on Day 21
Hours after challenge:
72
Group:
test chemical
Dose level:
1.0 % HDI in petrolatum
No. with + reactions:
8
Total no. in group:
17
Clinical observations:
erythema (mean score: 0.6)
Reading:
other: 1st challenge on Day 21
Hours after challenge:
24
Group:
negative control
Dose level:
0.3 % or 1.0 % HDI in petrolatum
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
none
Reading:
other: 1st challenge on Day 21
Hours after challenge:
48
Group:
negative control
Dose level:
0.3 % or 1.0 % HDI in petrolatum
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
none
Reading:
other: 1st challenge on Day 21
Hours after challenge:
72
Group:
negative control
Dose level:
0.3 % or 1.0 % HDI in petrolatum
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
none
Reading:
other: 2nd challenge on Day 35
Hours after challenge:
24
Group:
test chemical
Dose level:
0.3 % HDI in petrolatum
No. with + reactions:
17
Total no. in group:
17
Clinical observations:
erythema (mean score: 1.5)
Reading:
other: 2nd challenge on Day 35
Hours after challenge:
48
Group:
test chemical
Dose level:
0.3 % HDI in petrolatum
No. with + reactions:
11
Total no. in group:
17
Clinical observations:
erythema (mean score: 0.8)
Reading:
other: 2nd challenge on Day 35
Hours after challenge:
72
Group:
test chemical
Dose level:
0.3 % HDI in petrolatum
No. with + reactions:
10
Total no. in group:
17
Clinical observations:
erythema (mean score: 0.7)
Reading:
other: 2nd challenge on Day 35
Hours after challenge:
24
Group:
test chemical
Dose level:
1.0 % HDI in petrolatum
No. with + reactions:
17
Total no. in group:
17
Clinical observations:
erythema (mean score: 1.9)
Reading:
other: 2nd challenge on Day 35
Hours after challenge:
48
Group:
test chemical
Dose level:
1.0 % HDI in petrolatum
No. with + reactions:
16
Total no. in group:
17
Clinical observations:
erythema (mean score: 1.5)
Reading:
other: 2nd challenge on Day 35
Hours after challenge:
72
Group:
test chemical
Dose level:
1.0 % HDI in petrolatum
No. with + reactions:
16
Total no. in group:
17
Clinical observations:
erythema (mean score: 1.1)
Reading:
other: 2nd challenge on Day 35
Hours after challenge:
24
Group:
negative control
Dose level:
0.3 % or 1.0 % HDI in petrolatum
No. with + reactions:
1
Total no. in group:
10
Clinical observations:
erythema (mean score: 0.1)
Reading:
other: 2nd challenge on Day 35
Hours after challenge:
48
Group:
negative control
Dose level:
0.3 % or 1.0 % HDI in petrolatum
No. with + reactions:
1
Total no. in group:
10
Clinical observations:
erythema (mean score: 0.1)
Reading:
other: 2nd challenge on Day 35
Hours after challenge:
72
Group:
negative control
Dose level:
0.3 % or 1.0 % HDI in petrolatum
No. with + reactions:
1
Total no. in group:
10
Clinical observations:
erythema (mean score: 0.1 and 0.3)

Any other information on results incl. tables

3 out of 20 test animals died after the second induction; at the end of the study (week 6) no relevant difference in body weight development was observed between test and control groups.

Applicant's summary and conclusion

Interpretation of results:
sensitising
Remarks:
Migrated information
Executive summary:

In a guinea pig maximization test (GPMT) similar to OECD TG 406 HDI revealed a strong skin sensitizing potential. At the topical challenges (4 and 6 weeks after the first induction treatment) 16/17 or 17/17 animals reacted with erythema according to a contact allergy after application of a 0.3 or a 1.0 % HDI formulation in petrolatum.