Registration Dossier

Diss Factsheets

Administrative data

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
May 13 1996 to Jun 14 1996
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: done under GLP and OECD method

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1996

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
EU Method B.6 (Skin Sensitisation)
Version / remarks:
92/69/EEC Part B
GLP compliance:
yes
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
Study carried out in 1996

Test material

Constituent 1
Chemical structure
Reference substance name:
-
EC Number:
424-660-8
EC Name:
-
Cas Number:
224631-15-6
Molecular formula:
Hill formula: C18H26N4O5S CAS formula: C18H26N4O5S
IUPAC Name:
(S)-2,5-dioxopyrrolidin-1-yl 2-(3-((2-isopropylthiazol-4-yl)methyl)-3-methylureido)-3-methylbutanoate

In vivo test system

Test animals

Species:
guinea pig
Strain:
other: Crl:(HA)BR Hartley
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories Inc, Michigan
- Age at study initiation: ~ 1 month
- Weight at study initiation: 200 - 220gram
- Housing: Individual Stainless Steel ventilated cages
- Diet: Certified Guinea Pig Chow®
- Water: ad libitum
- Acclimation period: 5 days followed by an 7 day pretreatment period.

ENVIRONMENTAL CONDITIONS
- Temperature (°F): 71 - 74
- Humidity (%): Ambient
- Photoperiod (hrs dark / hrs light): 12hr daily light cycle

Study design: in vivo (non-LLNA)

Inductionopen allclose all
Route:
intradermal and epicutaneous
Vehicle:
other: corn oil for 1st induction: Petrolatum for 2nd induction and challenges.
Concentration / amount:
Concentration of test material at First Induction (Intradermal injection): 5% in corn oil.
Concentration of test material at Second Induction (topical application): 50% in petrolatum
Concentration of test material used for challenge and rechallenge (topical applications): 50% in petrolatum
Challengeopen allclose all
Route:
other: Topically
Vehicle:
other: corn oil for 1st induction: Petrolatum for 2nd induction and challenges.
Concentration / amount:
Concentration of test material at First Induction (Intradermal injection): 5% in corn oil.
Concentration of test material at Second Induction (topical application): 50% in petrolatum
Concentration of test material used for challenge and rechallenge (topical applications): 50% in petrolatum
No. of animals per dose:
10 animals assigned to the negative control group.
20 animals assigned to treatment group.
Details on study design:
MAIN STUDY

A. INDUCTION EXPOSURE
- No. of exposures: 2 - intadermal and topical
- Exposure period: 7 days for first induction and 14 days for second induction.
- Observations: 24hrs after the intradermal injections and once daily for 5 days. 24 and 48hrs after second induction.
- 0.05ml injection vol.
- Site for 2nd induction was pre-treared by massaging 0.3ml of 10% sodium dodecyl sulphate in water into the skin of animals in both groups on the day prior to topical inductionto illicit an inflammatory reaction.

B. CHALLENGE EXPOSURE
- No. of exposures: 2
- Day of first challenge: Day 21
- Day of rechallenge: Day 29
- Exposure period: 24hr occlusive bandage
- Test groups:
- Site: right flank - challenge; left flank - rechallenge
- Evaluation (hrs after challenge):24 and 48 hr after challenge and rechallenge.

Body weights were measured twice during the pretreatment period and on the days of the first and second inductions and the challenge and rechallenge and also on the final day of observations following the challenge and rechallenge treatments.
Challenge controls:
10 animals with corn oil for the 1st induction, petrolatum for the 2nd induction. Challenge and rechallenge: 50% Abbott-133816 in petrolatum.
Positive control substance(s):
no

Results and discussion

Positive control results:
n/a

In vivo (non-LLNA)

Resultsopen allclose all
Reading:
other: Challenge
Hours after challenge:
24
Group:
test chemical
Dose level:
50% in petrolatum
No. with + reactions:
11
Total no. in group:
17
Clinical observations:
slightly patchy erythema
Remarks on result:
other: Reading: other: Challenge. . Hours after challenge: 24.0. Group: test group. Dose level: 50% in petrolatum. No with. + reactions: 11.0. Total no. in groups: 17.0. Clinical observations: slightly patchy erythema.
Reading:
other: Challenge
Hours after challenge:
24
Group:
test chemical
Dose level:
50% in petrolatum
No. with + reactions:
1
Total no. in group:
17
Clinical observations:
mild erythema
Remarks on result:
other: Reading: other: Challenge. . Hours after challenge: 24.0. Group: test group. Dose level: 50% in petrolatum. No with. + reactions: 1.0. Total no. in groups: 17.0. Clinical observations: mild erythema.
Reading:
other: Challenge
Hours after challenge:
48
Group:
test chemical
Dose level:
50% in petrolatum
No. with + reactions:
6
Total no. in group:
17
Clinical observations:
slightly patchy erythema
Remarks on result:
other: Reading: other: Challenge. . Hours after challenge: 48.0. Group: test group. Dose level: 50% in petrolatum. No with. + reactions: 6.0. Total no. in groups: 17.0. Clinical observations: slightly patchy erythema.
Reading:
rechallenge
Hours after challenge:
24
Group:
test chemical
Dose level:
50% in petrolatum
No. with + reactions:
6
Total no. in group:
17
Clinical observations:
slightly patchy erythema
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 24.0. Group: test group. Dose level: 50% in petrolatum. No with. + reactions: 6.0. Total no. in groups: 17.0. Clinical observations: slightly patchy erythema.
Reading:
rechallenge
Hours after challenge:
48
Group:
test chemical
Dose level:
50% in petrolatum
No. with + reactions:
6
Total no. in group:
17
Clinical observations:
slightly patchy erythema
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 48.0. Group: test group. Dose level: 50% in petrolatum. No with. + reactions: 6.0. Total no. in groups: 17.0. Clinical observations: slightly patchy erythema.
Reading:
rechallenge
Hours after challenge:
24
Group:
test chemical
Dose level:
50% in petrolatum
No. with + reactions:
2
Total no. in group:
17
Clinical observations:
mild erythema
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 24.0. Group: test group. Dose level: 50% in petrolatum. No with. + reactions: 2.0. Total no. in groups: 17.0. Clinical observations: mild erythema.
Reading:
rechallenge
Hours after challenge:
48
Group:
test chemical
Dose level:
50% in petrolatum
No. with + reactions:
2
Total no. in group:
17
Clinical observations:
mild erythema
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 48.0. Group: test group. Dose level: 50% in petrolatum. No with. + reactions: 2.0. Total no. in groups: 17.0. Clinical observations: mild erythema.

Applicant's summary and conclusion

Interpretation of results:
other: weak to mild allergenic potency in guinea pigs treated with Abbott-133816 in this study.
Remarks:
Criteria used for interpretation of results: other: Magnusson and Kligman
Conclusions:
Abbott-133816 exhibited weak to mild allergenic potency in guinea pigs in this study.
Executive summary:

Maximum concentration not causing irritating effects in preliminary test: 50 %

Signs of irritation during induction:
First Induction (Intradermal Injection):  at injection sites
in animals that received corn oil, mild to moderate erythema
noted at 24 hours after first induction treatment and
slightly patchy to mild erythema after 48 hours.  In animals
that received A-133816 in corn oil, mild to moderate
erythema was noted 24 hours after first induction and mild
to severe erythema after 48 hours, at the intradermal
injection site.

Second Induction (Topical Application):  in animals
pretreated with sodium dodecyl sulphate on day prior to 2nd
induction, slightly patchy to mild erythema at the exposure
site was noted in animals exposed to petrolatum at 24 & 48
hours after patch removal, and in animals exposed to
A-133816 in petrolatum at 24 hours after patch removal.
Slightly patchy to mild erythema was also observed at the
exposure site in animals exposed to A-133816 in petrolatum
at 48 hours after patch removal.  A single animal showed
moderate erythema at the exposure site at this time.

Evidence of sensitisation of each challenge concentration:
Initial Challenge with A-133816; after 24 hours:

Slightly patchy erythema noted in 11 animals;

Mild erythema noted in one animal.

After 48 hours: slightly patchy erythema observed in the
exposure site in 6 of the remaining animals.

Rechallenge; after 24 & 48 hours:

slightly patchy erythema noted at the test site in 6 of the
animals exposed to A-133816, and mild erythema in a further
2 animals (these responses in animals induced with
A-133816).