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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:
From January 10th, 1995 to February 10th, 1995
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1995
Report date:
1995

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
EU Method B.6 (Skin Sensitisation)
Version / remarks:
acording to EEC directive 92/69 B6 maximization test
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Qualifier:
according to guideline
Guideline:
other: "Allergic Contact Dermatitis in the Guinea-Pig: Identification of Contact Allergensu Magnusson B. Kligman A.M., 1970 published by C.C. Thomas, Springfield, Illinois , USA.
GLP compliance:
yes
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
An LLNA study was not performed because there is an existing reliable study for skin sensitisation using the Guinea Pig Maximisation test method.

Test material

Constituent 1
Chemical structure
Reference substance name:
5-amino-2,4,6-triiodo-1,3-benzenedicarbonyldichloride
EC Number:
417-220-1
EC Name:
5-amino-2,4,6-triiodo-1,3-benzenedicarbonyldichloride
Cas Number:
37441-29-5
Molecular formula:
C8H2Cl2I3NO2
IUPAC Name:
5-amino-2,4,6-triiodobenzene-1,3-dicarbonyl dichloride
Test material form:
solid: particulate/powder

In vivo test system

Test animals

Species:
guinea pig
Strain:
Dunkin-Hartley
Remarks:
(HA)BR albino guinea pig (SPFquality)
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River, Germany
- Females (if applicable) nulliparous and non-pregnant: not specified
- Age at study initiation: Approx. 6-7 weeks
- Weight at study initiation: 376 - 500 grams
- Housing: Group housing of 2 animals, except for 1 control animal, per labelled metal cage with wire-mesh floors and equipped with an automatic drinking system (ITL, Bergen, The Netherlands).
- Diet: Free access to standard guinea pig diet, including ascorbic acid (1600 mglkg); LC 23-0, pellet diameter 4mm (Hope farms, Woerden, The Netherlands). In addition, hay (B.M.I., Helmond, The Netherlands) was provided once a week.
- Water: Free access to tap water, diluted with decalcif ied water.
- Acclimation period: At least 5 dayes before start of treatment
- Indication of any skin lesions: no

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21°C
- Humidity (%): 50%
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12 hours artificial fluorescent light and 12 hours dark per day

Study design: in vivo (non-LLNA)

Inductionopen allclose all
Route:
intradermal
Vehicle:
corn oil
Concentration / amount:
2.5 % (w/w) intradermal injection
Adequacy of induction:
not specified
Route:
epicutaneous, open
Vehicle:
corn oil
Concentration / amount:

50% epidermal application
Challenge
No.:
#1
Route:
epicutaneous, open
Vehicle:
corn oil
Concentration / amount:

0, 10, 25, 50 % (w/w)
No. of animals per dose:
Number of animals in test group 10
number of animals in negative control group 5
Details on study design:
PRELIMINARY STUDY
Intradermal injections (one animals):
A 5% and 1% test substance concentration were injected in one animal into two injection sites (0.1 ml each) in the left and right clipped.shoulder regions respectively. The resulting dermal reactions were assessed 24 and 48 hours later for erythema , necrosis and diameter of necrosis.

Epidermal-application (the same animal as mentioned before):
A 50% test substance concentration (0.5 m l ) was applied epidermally on a shaved flank of one animal, using a Scotchpak-non-woven patch (2.5 x 2.2 cm) on Micropore tape and held in place by Coban elasticbandage. After 24 hours, the dressings was removed and the skin cleaned of residual test substance. The treated skin was assessed 24 and 48 hours later according to the scale described below.

Epidermal applications (three animals):
Four concentrations o f the test substance (50%, 25%, 10% and 5%, 0.05 ml each) were applied occlusively on a shaved flank of each of the animals using Square chambers, mounted on Micropore tape and held in place by Coban elastic bandage. After 24 hours, the dressings were removed and the skin cleaned of residual tes t substance. The treated sites were assessed 24 and 48 hours later according to the scale described below.

Erythema and eschar formation:
No erythema .............................................................................0
Slight erythema (barely perceptible) ................................................1
Well-defined erythema ................................................................... 2
Moderate erythema ....................................................................... 3
Severe erythema (beet redness) to s l i g h t eschar formation (injuries in depth) ........... 4

Oedena formation:
No oedema ............................................................................... 0
Slight oedema (barely perceptible) ...................................................... 1
Well-defined oedema (edges of area well-defined by definite raising) ................... 2
Moderate oedema (raised approximately 1 millimeter) ...................................... 3
Severe oedema (raised more than 1 millimeter and extending beyond the area of exposure) . 4

MAIN STUDY
A. INDUCTION EXPOSURE
Day 1
Three pairs of intradermal injections (0.1 ml/site) were made in the clipped scapular region as follows:
A) Freunds' Complete Adjuvant (Difco, Detroit, U.S.A.), 50:50 with water for injection (Ferensius AG, Bad Homburg, Germany).
B) A 2.5% test substance concentration corn oil .
C) The test substance, at twice the concentration used in (B), emulsified in a 50:50 mixture of Freunds' Complete Adjuvant.
Note: One of each pair was on each side of the midline and from cranial A) to caudal C).

Day 3
The dermal reactions caused by the intradermal injections were examined in a similar manner as described for the preliminary study.

Day 7
The clipped scapular area was rubbed with 10% sodium-dodecyl-sulfate in vaseline using a spatula. This concentration of SDS provokes a mild inflammatory
reaction.

Day 8
The clipped area between the injection sites was treated with 0.5 ml f a 50% test substance concentration using a Scotchpak-non-woven patch (2 x 4
cm) mounted on Micropore tape and secured with Coban elastic bandage.

Day 10
After 48 hours, the dressings were removed and the skin cleaned of residual test substance. The skin reactions were assessed immediately after bandage
removal.


B. CHALLENGE EXPOSURE
Day 22
All animals were treated epidermally with 0.05 ml of each of a the following test substance concentrations, 50%, 25% and 10% and the vehicle on a clipped and
shaved flank, using Square chambers, attached to Micropore tape and secured with Coban elastic bandage.

Day 23
After approximately 24 hours, the dressings were removed and the skin cleaned of residual test substance and vehicle. The treated sites were
assessed for redness and swelling 24 and 48 hours after removal of the dressings, using the numerical grading system below. After the first
reading, the test sites were shaved with an electric razor.

At the end of the study period all animals were killed by oxygenlcarbon dioxide asphyxiation.

OBSERVATIONS
Mortality/Viability: Twice daily
Toxicity:At least once daily
Body weights: Prior to start and at termination of the study.

INTERPRETATIONS
The results for the experimental animals at the challenge application(s) were compared with the results for the control animals. Positive skin reactions (grade1 or more) were considered signs of sensitisation, provided that such reactions are not observed in the control group. A sensitisation rate (%) was calculated for each concentration as follows: the number of sensitised animals to one concentration in proportion to the total number of animals of the experimental group. The highest sensitisation rate calculated was used to assign a classification according to Kligman (J. Invest . Dermatol. 47, 393-409, 1966).

Sensitisation rate Grade Classification
0-8 I weak
9-28 II mild
29-64 III moderate
65-80 IV strong
81-100 V extreme
Positive control substance(s):
not specified

Results and discussion

In vivo (non-LLNA)

Resultsopen allclose all
Group:
positive control
Remarks on result:
other: no data
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
50%
No. with + reactions:
7
Total no. in group:
10
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
25%
No. with + reactions:
7
Total no. in group:
10
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
10%
No. with + reactions:
7
Total no. in group:
10
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
0%
No. with + reactions:
1
Total no. in group:
10
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
50%
No. with + reactions:
9
Total no. in group:
10
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
25%
No. with + reactions:
9
Total no. in group:
10
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
10%
No. with + reactions:
9
Total no. in group:
10
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
0%
No. with + reactions:
3
Total no. in group:
10
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
50%
No. with + reactions:
0
Total no. in group:
5
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
25%
No. with + reactions:
1
Total no. in group:
5
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
10%
No. with + reactions:
1
Total no. in group:
5
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
0%
No. with + reactions:
0
Total no. in group:
5
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
50%
No. with + reactions:
0
Total no. in group:
5
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
25%
No. with + reactions:
1
Total no. in group:
5
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
10%
No. with + reactions:
1
Total no. in group:
5
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
0%
No. with + reactions:
0
Total no. in group:
5

Any other information on results incl. tables

Preliminary study:

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

Main study - Induction

In the experimental animals, signs of necrosis (diameter between 2 -6 mm) and well defined or moderate erythema was observed after intradermal injection of a 2.5% test substance concentration. Injection of corn oil only resulted in slight or well defined erythema in the control animals. All experimental animals showed slight to well defined erythema after the 48 h occluded epidermal induction exposure. Light brown staining of the treated skin by the test substance was noted. No skin reactions were noted in the control animals after exposure to corn oil.

Main Study - Challenge

In the control group one animal showed discrete or patchy erythema in response to the 25% and 10% test substance concentrations. No skin reactions were evident in the other animal after the challenge exposure.

In the experimental group all ten animals showed skin recations in response to all the three test substance concentrations during the challenge phase. These reactions were characterised by erythema (grade 1 oe 2) and/or scaliness.

Discrete or patchy erythema and/or scaliness was also noted in resposne to corn oil in four experimental animals.

Toxicity symptoms/ Mortality

No mortality occurred and no symptoms of systemic toxicity were observed in the animals of the main study during the study period.

Body weights

The average body weight gain in experiemntal annimals was higher than of the control animals. Non reason can be given for the cause of the difference.

other observations:

The response to corn oil noted in the experimental animals was considered to have happened by accident. Leakage from adjacent treated sites might possibly have occured. Since the control animals received corn oil treatment in the induction phase, sensitisation to corn oil was ruled out, based on the absence of responses in the control group to vehicle.

Applicant's summary and conclusion

Interpretation of results:
sensitising
Conclusions:
The results lead to a sensitisation rate of 100%, which indicates that the test substance has extreme sensitizing properties in this test applying the rating of allergenicity described by Kligman A.M. (1966).
Executive summary:

Assessment for Contact Hypersensitivity to test substance in the Albino Guinea Pig (Maximization Test).


The study was carrIed out in accordance with the OECD Guideline No. A06, "Skin Sensitisation", the EU Method B.6, and based on the method described by Magnusson and Kligman, " Allergic Contact Dermatitis in the Guinea Pig - Identification of Contact Allergens".


Based on a test substance pretest , corn oil was selected as the most suitable vehicle for the test substance. Test substance concentrations selected for the Main study were based on the results of a preliminary study using four animals.


In the Main study, ten experimental animals were intradermally injected with a 2.5% concentration and epidermally exposed to a 50% concentration. Five control animals were similarly treated, but with omission of the test substance.


Approximately 24 hours before the epidermal induction exposure all animals were treated with 10% SDS. Two weeks after the epidermal application all animals were challenged with a 50%, 25% and 10% test substance concentration and corn oil .


The skin reactions observed in response to the 50% test substance concentration in all ten experimental animals in the challenge phase were considered indicative of sensitisation, based on the absence of responses in the control animals to this concentration. Furthermore, all experimental animals showed responses to the 25% and 10% concentrations, whereas a response was noted in one control animal.


Taking into acount this difference in frequency it was concluded that the test susbtance had induced contact hypersensitivity in all experimental animals to all three concentrations.


These results lead to a sensitisation rate of 100 per cent, which indicates that the test substance has extreme sensitizing properties in this test applying the rating of allergenicity described by Kligman A.M. (1966).