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Diss Factsheets

Administrative data

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
11 July 1995 to 10 September 1995
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study

Data source

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

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
EU Method B.6 (Skin Sensitisation)
Deviations:
no
GLP compliance:
yes
Type of study:
guinea pig maximisation test

Test material

Constituent 1
Chemical structure
Reference substance name:
Bis(dimethyl-(2-hydroxyethyl)ammonium) 1,2-ethanediyl-bis(2-hexadecenylsuccinate)
EC Number:
421-660-1
EC Name:
Bis(dimethyl-(2-hydroxyethyl)ammonium) 1,2-ethanediyl-bis(2-hexadecenylsuccinate)
Molecular formula:
Hill formula: C50 H96 N2 O10 CAS formula: C42 H74 O8. 2(C4 H11 N O)
IUPAC Name:
bis((2-hydroxyethyl)dimethylazanium) (4E)-3-{[2-({3-carboxylato-3-[(2E)-hexadec-2-en-2-yl]propanoyl}oxy)ethoxy]carbonyl}-4-methyloctadec-4-enoate
Constituent 2
Reference substance name:
BIS(DIMETHYL-(2-HYDROXYETHYL)AMMONIUM) 1,2-ETHANEDIYL-BIS (2-HEXADECENYLSUCCINATE)
IUPAC Name:
BIS(DIMETHYL-(2-HYDROXYETHYL)AMMONIUM) 1,2-ETHANEDIYL-BIS (2-HEXADECENYLSUCCINATE)

In vivo test system

Test animals

Species:
guinea pig
Strain:
Dunkin-Hartley
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: D. Hall, Newchurch, Staffordshire
- Age at study initiation: approximately 4-5 weeks
- Weight at study initiation: 342 - 414 g
- Housing: Suspended metal cages with wire mesh floors
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 6 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): approximately 21
- Humidity (%): 30 - 70
- Air changes (per hr): approximately 15
- Photoperiod (hrs dark / hrs light): 12 hours dark / 12 hours light

Study design: in vivo (non-LLNA)

Inductionopen allclose all
Route:
intradermal and epicutaneous
Vehicle:
other: Alembicol D
Concentration / amount:
Concentration of test material and vehicle used at induction:
Intradermal injection: 0.25% v/v in Alembicol D
Topical application: 60.0% v/v in Alembicol D

Concentration of test material and vehicle used for each challenge:
40.0% and 20.0% v/v in Alembicol D
Challengeopen allclose all
Route:
epicutaneous, occlusive
Vehicle:
other: Alembicol D
Concentration / amount:
Concentration of test material and vehicle used at induction:
Intradermal injection: 0.25% v/v in Alembicol D
Topical application: 60.0% v/v in Alembicol D

Concentration of test material and vehicle used for each challenge:
40.0% and 20.0% v/v in Alembicol D
No. of animals per dose:
Number of animals in test group: 20
Number of animals in negative control group: 10
Details on study design:
RANGE FINDING TESTS: Based on the results of the preliminary investigations, the following concentrations of OS 114451A were selected:

Induction intradermal injection - 0.25% v/v in Alembicol D - this was the highest concentration that caused irritation but did not adversely affect the animals.

Induction topical application - 60% v/v in Alembicol D - the concentration of 70% was an irritant level and the concentration of 50% was a sub-irritant level. For this reason 60% was considered to be the most appropriate concentration for use in the main study.


MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: 2 - one intradermal injection follwed by topical application one week later
- Exposure period: Topical application - 48 hours
- Test groups: 1 group of 20
- Control group: 1 group of 10
- Site: Dorsal skin on the scapular region
- Frequency of applications: once per exposure route
- Duration: Topical application - 48 hours
- Concentrations: Injection - 0.25% v/v in Alembicol D, Topical application - 60% v/vin Alembicol D


B. CHALLENGE EXPOSURE
- No. of exposures: 4 - two topical applications at different doses, followed by two further topical applications at the same two doses three weeks later
- Day(s) of challenge: NDA
- Exposure period: 24 hours per challenge
- Test groups: 1 group of 20
- Control group: 1 group of 10
- Site: Dorsal skin on the scapular region. First challenge on left flank, 40% v/v dose on anterior site, 20% v/v dose on posterior site. Second challenge on right flank, 40% v/v dose on anterior site, 20% v/v dose on posterior site.
- Concentrations: 40% v/v and 20% v/v
- Evaluation (hr after challenge): 24, 48 and 72 hours after removal of the patches


OTHER: None
Challenge controls:
- No. of exposures: 4 - two topical applications at different doses, followed by two further topical applications at the same two doses three weeks later
- Day(s) of challenge: NDA
- Exposure period: 24 hours per challenge
- Test groups: 1 group of 20
- Control group: 1 group of 10
- Site: Dorsal skin on the scapular region. First challenge on left flank, 40% v/v dose on anterior site, 20% v/v dose on posterior site. Second challenge on right flank, 40% v/v dose on anterior site, 20% v/v dose on posterior site.
- Concentrations: 40% v/v and 20% v/v
- Evaluation (hr after challenge): 24, 48 and 72 hours after removal of the patches
Positive control substance(s):
yes
Remarks:
hexyl cinnamic aldehyde

Results and discussion

Positive control results:
The sensitivity of the guinea-pig strain used is checked periodically at the testing laboratory with hexyl cinnamic acid, a known sensitiser. The results of recent tests are presented in the report and adequately demonstrate a positive sensitisation response.

In vivo (non-LLNA)

Resultsopen allclose all
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
40 %
No. with + reactions:
14
Total no. in group:
20
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 40 %. No with. + reactions: 14.0. Total no. in groups: 20.0.
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
20 %
No. with + reactions:
8
Total no. in group:
20
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 20 %. No with. + reactions: 8.0. Total no. in groups: 20.0.
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
40 %
No. with + reactions:
14
Total no. in group:
20
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 40 %. No with. + reactions: 14.0. Total no. in groups: 20.0.
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
20 %
No. with + reactions:
11
Total no. in group:
20
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 20 %. No with. + reactions: 11.0. Total no. in groups: 20.0.
Reading:
rechallenge
Hours after challenge:
24
Group:
test chemical
Dose level:
40 %
No. with + reactions:
17
Total no. in group:
20
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 24.0. Group: test group. Dose level: 40 %. No with. + reactions: 17.0. Total no. in groups: 20.0.
Reading:
rechallenge
Hours after challenge:
24
Group:
test chemical
Dose level:
20 %
No. with + reactions:
6
Total no. in group:
20
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 24.0. Group: test group. Dose level: 20 %. No with. + reactions: 6.0. Total no. in groups: 20.0.
Reading:
rechallenge
Hours after challenge:
48
Group:
test chemical
Dose level:
40 %
No. with + reactions:
17
Total no. in group:
20
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 48.0. Group: test group. Dose level: 40 %. No with. + reactions: 17.0. Total no. in groups: 20.0.
Reading:
rechallenge
Hours after challenge:
48
Group:
test chemical
Dose level:
20 %
No. with + reactions:
8
Total no. in group:
20
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 48.0. Group: test group. Dose level: 20 %. No with. + reactions: 8.0. Total no. in groups: 20.0.
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
40 %
No. with + reactions:
2
Total no. in group:
10
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: negative control. Dose level: 40 %. No with. + reactions: 2.0. Total no. in groups: 10.0.
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
20 %
No. with + reactions:
1
Total no. in group:
10
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: negative control. Dose level: 20 %. No with. + reactions: 1.0. Total no. in groups: 10.0.
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
40 %
No. with + reactions:
1
Total no. in group:
10
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: negative control. Dose level: 40 %. No with. + reactions: 1.0. Total no. in groups: 10.0.
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
20 %
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: negative control. Dose level: 20 %. No with. + reactions: 0.0. Total no. in groups: 10.0.
Reading:
rechallenge
Hours after challenge:
24
Group:
negative control
Dose level:
40 %
No. with + reactions:
3
Total no. in group:
10
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 24.0. Group: negative control. Dose level: 40 %. No with. + reactions: 3.0. Total no. in groups: 10.0.
Reading:
rechallenge
Hours after challenge:
24
Group:
negative control
Dose level:
20 %
No. with + reactions:
2
Total no. in group:
10
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 24.0. Group: negative control. Dose level: 20 %. No with. + reactions: 2.0. Total no. in groups: 10.0.
Reading:
rechallenge
Hours after challenge:
48
Group:
negative control
Dose level:
40 %
No. with + reactions:
4
Total no. in group:
10
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 48.0. Group: negative control. Dose level: 40 %. No with. + reactions: 4.0. Total no. in groups: 10.0.
Reading:
rechallenge
Hours after challenge:
48
Group:
negative control
Dose level:
20 %
No. with + reactions:
4
Total no. in group:
10
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 48.0. Group: negative control. Dose level: 20 %. No with. + reactions: 4.0. Total no. in groups: 10.0.

Any other information on results incl. tables

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

Signs of irritation during induction:
Intradermal: Slight irritation in both test and control animals, and necrosis at sites receiving Freund's complete
adjuvant.
Topical: Test and control animals had slight erythema on the dosed areas.

Evidence of sensitisation of each challenge concentration:
First Challenge Dose (40.0%):

A total of 14/20 test animals exhibited reactions greater than the controls (ranging from slight erythema and edema towell-defined erythema with or without edema) at the 24, 48 and/or 72 hr observation periods.

First challenge dose (20.0%): Nine of 20 test animals had
reactions greater than that observed in the controls(ranging, as described above, from slight erythema and edema
to well-defined erythema with or without edema).


Second challenge dose (40.0%):  Two control animals out of10 showed well defined erythema at either 24 or 48 hours.Twelve test animals out of 20 showed well defined erythemaat either 24 or 48 hours. Well defined erythema was still present at 72 hours in 10 test animals. Two animals had
necrosis on the dosed area.

Second challenge dose (20.0%): Four of 10 control animals
had reactions at 24, 48, and/or 72 hr. These reactions
ranged from slight, localized erythema to slight erythema
and edema. Three test animals had well-defined erythema with
slight edema.

Other observations:
Other skin irritation:  Most test animals also exhibited
dryness, sloughing and/or thickening of the epidermis at 24,
48 and/or 72 hr following the first and second challenge
doses.

Bodyweight:  All animals exhibited a bodyweight increase
during the study.

Clinical signs:  There were no signs of clinical toxicity
observed for any animal during the study.

Applicant's summary and conclusion

Interpretation of results:
sensitising
Remarks:
Migrated information
Conclusions:
In this study, OS 114451A produced evidence of skin sensitisation (delayed contact hypersensitivity) in three of the twenty test animals.
Executive summary:

In a dermal sensitization study (LBL 16/952362/SS) withOS 114451A in Alembicol D, thirty 4-5 week old Dunkin/Hartley male guinea pigs were tested using the method of EC Directive 92/69/EEC, Method B6 skin sensitisation. The positive control material was hexyl cinnamic aldehyde. No signs of ill health or toxicity were observed.

 

In this study, OS 114451A produced evidence of skin sensitisation (delayed contact hypersensitivity) in three of the twenty test animals.