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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:
23 Jan - 04 Mar 2002
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP-Guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2002
Report date:
2002

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
EU Method B.6 (Skin Sensitisation)
Deviations:
no
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Deviations:
no
GLP compliance:
yes
Remarks:
incl certificate of RCC Ltd, Itingen from Swiss Federal Office of Public Health
Type of study:
guinea pig maximisation test

Test material

Constituent 1
Chemical structure
Reference substance name:
-
EC Number:
441-100-8
EC Name:
-
Cas Number:
351197-46-1
Molecular formula:
Hill formula: C24 H48 N4 O6 CAS formula: C24 H48 O6 N4
IUPAC Name:
2-[2-(dimethylamino)ethoxy]ethyl N-{[1,3,3-trimethyl-5-(9-methyl-2-oxo-3,6-dioxa-1,9-diazadecan-1-yl)cyclohexyl]methyl}carbamate
Constituent 2
Reference substance name:
Carbamic acid, [[5-[[[2-[2- (dimethylamino)ethoxy]ethoxy]carbonyl]amino]-1,3,3- trimethylcyclohexyl]methyl]-,2-[2- (dimethylamino)ethoxy]ethyl ester
IUPAC Name:
Carbamic acid, [[5-[[[2-[2- (dimethylamino)ethoxy]ethoxy]carbonyl]amino]-1,3,3- trimethylcyclohexyl]methyl]-,2-[2- (dimethylamino)ethoxy]ethyl ester
Details on test material:
- Name of test material (as cited in study report): UAX-1179
- Physical state / appearance: pale, amber liquid
- Analytical purity: >99% proprietary tertiary amines
- Lot/batch No.: M. 17-08.01
- Expiration date of the lot/batch:19-Sep-2003
- Stability of test item dilution: Stable in the purified water for at least 7 days (determined at RCC Ltd, Environmental Chemistry & Pharmanalytics Division, under RCC study number 838563). Stable in FCA/NaCI 0.9 % for at least 2 hours.
- Storage condition of test material: In the original container, at room temperature (range of 20 +/- 3 °C), away from direct sunlight, heat and moisture. Stored under dry air (nitrogen).
- Safety precautions: Routine hygienic procedures were used to ensure the health and safety of the personnel.

In vivo test system

Test animals

Species:
guinea pig
Strain:
other: Ibm: GOHI; SPF-quality guinea pigs (Himalayan spotted)
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: RCC Ltd, Biotechnology & Animal Breeding Division, Wolferstrasse 4, CH-4414 Füllinsdorf, Switzerland
- Age at study initiation:3 - 6 weeks
- Weight at study initiation: Pretest group at pretest start: 386 - 411g, control and test group at beginning of acclimatization period: 409 - 445 g
- Housing: Individually in Makrolon type-4 cages with standard softwood bedding ("Lignocel", Schill AG, CH-4132 Muttenz).
- Diet (e.g. ad libitum): Pelleted standard Provimi Kliba 3418, batch nos. 93/01 and 116/01, guinea pig breeding / maintenance diet, containing Vitamin C (Provimi Kliba AG, CH-4303 Kaiseraugst), ad libitum.
- Water (e.g. ad libitum): Community tap water from Füllinsdorf, ad libitum.
- Acclimation period: one week (no acclimatization for the animals of the pretest)

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 +/- 3 °C
- Humidity (%): 30 - 70%
- Air changes (per hr): 10 - 15
- Photoperiod (hrs dark / hrs light): 12
- Music was played during the daytime light period.

Study design: in vivo (non-LLNA)

Inductionopen allclose all
Route:
intradermal and epicutaneous
Vehicle:
water
Remarks:
purified water (deionised water)
Concentration / amount:
Concentration of test material and vehicle used at intradermal induction: Intradermal injection (0.1 mL/site)

a) 1:1 (v/v) mixture of Freund's Complete Adjuvant and physiological saline.
b) Test item at 10% in purified water.
c) Test item at 10% in a 1:1 (v/v) mixture of Freund's Complete Adjuvant and physiological saline.


Epidermal applications:
Test item 75% in purified water used for epidermal induction.

Concentration of test material and vehicle used for each challenge: 75% in purified water, 0.2 mL
Challengeopen allclose all
Route:
epicutaneous, occlusive
Vehicle:
water
Remarks:
purified water (deionised water)
Concentration / amount:
Concentration of test material and vehicle used at intradermal induction: Intradermal injection (0.1 mL/site)

a) 1:1 (v/v) mixture of Freund's Complete Adjuvant and physiological saline.
b) Test item at 10% in purified water.
c) Test item at 10% in a 1:1 (v/v) mixture of Freund's Complete Adjuvant and physiological saline.


Epidermal applications:
Test item 75% in purified water used for epidermal induction.

Concentration of test material and vehicle used for each challenge: 75% in purified water, 0.2 mL
No. of animals per dose:
Number of animals in test group: 10
Number of animals in negative control group: 5
Details on study design:
RANGE FINDING TESTS: intradermal (10, 15 and 25% were tested : the concentration selected for the main study was 10% with discrete or patchy erythema) and epidermal pretest (15 - 75% were tested, no irritation up to 75%, technically, 75% test item concentration was the highest which could be applied to the skin to ensure optimal skin contact)

MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: 2 (see any other information on materials and methods)
- Test groups: FCA/NaCl or Test item 10% in purified water or in 1:1 FCA/NaCl [intradermal]; 75% in purified water after 10% SLS [epidermal] (see any other information on materials and methods)
- Control group: vehicle and or auxiliary compounds, 10% SLS before epidermal induction
- Site: dorsal skin
- Frequency of applications: 2, first intradermal on day 1 , second epidermal on the test day 8
- Concentrations: 10% intradermal (0.1 mL/site), 75% (0.3 mL) epidermal; see any other information on materials and methods

B. CHALLENGE EXPOSURE
- No. of exposures: 1
- Day(s) of challenge: day 22
- Test groups: Test item 75% in purified water and one patch with water only (after 10% SLS)
- Control group: 75% in purified water and one patch with water only (after 10% SLS)
- Site: left flank for test item, right flank for control (purified water)
- Concentrations: 0.2 mL
- Evaluation (hr after challenge):24 h and 48h after removal of the bandage
Challenge controls:
75% in purified water (0.2 mL)
Positive control substance(s):
yes
Remarks:
2-Mercaptobenzothiazole (performed from 14 May - 21 Jun 2001)

Results and discussion

Positive control results:
For validation of sensitivity of the GPMT test / test system used a study was performed with 15 (10 test and 5 control) male albino guinea pigs according to OECD 406. 2-Mercaptobenzothiazole was selected as positive control.
No toxic symptoms were evident in the guinea pigs of the control or test group. No deaths occurred. All 10 test animals showed discrete/patchy to intense erythema and swelling at the 24- and 48-hour reading after the challenge treatment with 2-MERCAPTOBENZOTHIAZOLE at 0.5 % (w/w) in mineral oil. No skin effect was observed in the control group.
Based on the mentioned findings in this adjuvant sensitization test the positive control 2-Mercaptobenzothiazole is a skin senitizer in guinea pigs.

In vivo (non-LLNA)

Resultsopen allclose all
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
75 %
No. with + reactions:
9
Total no. in group:
9
Clinical observations:
one animal of the test group was found dead on test day 1 (after intradermal induction)
Remarks on result:
other: see Remark
Remarks:
Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 75 %. No with. + reactions: 9.0. Total no. in groups: 9.0. Clinical observations: one animal of the test group was found dead on test day 1 (after intradermal induction).
Reading:
1st reading
Hours after challenge:
24
Group:
other: right flank (challenge control) of test group
Dose level:
0 %
No. with + reactions:
0
Total no. in group:
9
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: other: right flank (challenge control) of test group. Dose level: 0 %. No with. + reactions: 0.0. Total no. in groups: 9.0.
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
75 %
No. with + reactions:
9
Total no. in group:
9
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 75 %. No with. + reactions: 9.0. Total no. in groups: 9.0.
Reading:
2nd reading
Hours after challenge:
48
Group:
other: right flank (challenge control) of test group
Dose level:
0 %
No. with + reactions:
0
Total no. in group:
9
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: other: right flank (challenge control) of test group. Dose level: 0 %. No with. + reactions: 0.0. Total no. in groups: 9.0.
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
75 %
No. with + reactions:
0
Total no. in group:
4
Clinical observations:
one animal of the control group was found dead on test day 11 (induction phase)
Remarks on result:
other: see Remark
Remarks:
Reading: 1st reading. . Hours after challenge: 24.0. Group: negative control. Dose level: 75 %. No with. + reactions: 0.0. Total no. in groups: 4.0. Clinical observations: one animal of the control group was found dead on test day 11 (induction phase).
Reading:
1st reading
Hours after challenge:
24
Group:
other: right flank (challenge control) of negative control group
Dose level:
0 %
No. with + reactions:
0
Total no. in group:
4
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: other: right flank (challenge control) of negative control group. Dose level: 0 %. No with. + reactions: 0.0. Total no. in groups: 4.0.
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
75 %
No. with + reactions:
0
Total no. in group:
4
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: negative control. Dose level: 75 %. No with. + reactions: 0.0. Total no. in groups: 4.0.
Reading:
2nd reading
Hours after challenge:
48
Group:
other: right flank (challenge control) of negative control group
Dose level:
0 %
No. with + reactions:
0
Total no. in group:
4
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: other: right flank (challenge control) of negative control group. Dose level: 0 %. No with. + reactions: 0.0. Total no. in groups: 4.0.

Any other information on results incl. tables

Maximum concentration not causing irritating effects in preliminary test: 75 %

Signs of irritation during induction: The expected and common findings were observed in the control and test group after the different applications using FCA intradermally. These findings consisted of erythema, oedema, necrotizing dermatitis, encrustation and exfoliation of encrustation.
Ventral recumbency and tremor were observed in 4 test animals approximately 3 hours after the intradermal induction application.

The 75% concentration of the test item used for the challenge application was non-irritant and was the maximum concentration attainable.


The animals of the test and control groups were all pretreated with 10% SLS approx. 21 hours before the epidermal induction. After the epidermal induction application, discrete/patchy to moderate/confluent erythema in the test (all animals) and control (2 animals) group was observed.
Evidence of sensitisation of each challenge concentration: Concentration 75%: 9/9 (100%) of the animals showed sensitisation. Discrete/patchy to moderate/confluent erythema were observed in all animals at the 24- and 48-hour reading after treatment with the test item at 75% in purified water. No skin reactions were observed in the animals when treated with purified water only.
Other observations:
One animal of the control group was found dead on test day 11 just prior to the 24 -hour reading in the epidermal induction phase and one animal of the test group was found dead on test day 1 after the intradermal induction.No macroscopic findings were noted. The cause of death could not be established.

The animal of the test group found dead on day 1 showed a loss of body weight (8%) during the acclimatization period. The body weight of the other animals was within the range commonly recorded for animals of this strain and age.

Table 1: Test group; Skin response after the challenge application of UAX-1179, 75% in purified water (left flank) and application of purified water (right flank)

 

Left flank

Right flank

Male animals

Reaction readings after removal of bandage

Animal No.

24 hours

48 hours

24 hours

48 hours

302

2

2

0

0

303

1

1

0

0

304

2

2

0

0

305

2

2

0

0

306

1

1

0

0

307

2

2

0

0

308

2

2

0

0

309

2

2

0

0

310

1

1

0

0

311

exitus

 

 exitus

 

Table 2: Positive control; Skin response after the challenge application of 2 -Mercaptobenzothiazole, 0.5% in mineral oil (left flank) and mineral oil (right flank)

 

Left flank

Right flank

Male animals

Reaction readings after removal of bandage

Animal No.

24 hours

48 hours

24 hours

48 hours

44

1

2

0

0

45

2

2

0

0

46

2

2

0

0

47

1

1

0

0

48

2

2

0

0

49

3

3

0

0

50

3

3

0

0

51

2

2

0

0

52

1

2

0

0

53

2

3

0

0

Table 3: Negative control; Skin response after the challenge application of UAX-1179, 75% in purified water (left flank) and purified water (right flank)

 

Left flank

Right flank

Male animals

Reaction readings after removal of bandage

Animal No.

24 hours

48 hours

24 hours

48 hours

297

0

0

0

0

298

0

0

0

0

299

0

0

0

0

300

exitus

 

exitus

 

301

0

0

0

0

Applicant's summary and conclusion

Interpretation of results:
sensitising
Remarks:
Migrated information
Conclusions:
UAX-1179 is considered to be a skin sensitizer.
Executive summary:

The cutaneous allergenic potential of UAX-1179 was investigated by the GPMT. The study was performed in 15 male albino guinea pigs in accordance with OECD Guideline No. 406. Discrete/patchy to moderate/confluent erythema were observed in all animals at the 24- and 48-hour reading after treatment with the test item at 75% in purified water. No skin effect was observed in the control group. (One animal of the control group and one animal of the test group were found dead during the study. The cause of death could not be established.) Based on the findings of this adjuvant sensitization test UAX-1179 is considered to be a skin sensitizer.