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Toxicological information

Skin sensitisation

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Administrative data

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
other: Read across from supporting substance
Adequacy of study:
key study
Study period:
1993
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Justification for type of information:
Sandospace S can be considered a close analogue to Spansospace R, in which a Clorine atom is substituted by an isopropylether functionality. The two substances have a very high structural similarity and very similar toxicological pattern. Despite the dilution of the test material, the sensitizing properties are clearly demonstrated and support the controversial results of the similar substance.

Data source

Reference
Title:
Unnamed
Year:
1993
Report date:
1993

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Version / remarks:
July 17, 1992
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
The study was performed before the LLNA guideline implementation

Test material

Constituent 1
Reference substance name:
Sodium 4-[[4-chloro-6-isopropoxy-1,3,5-triazin-2-yl]amino]benzenesulphonate
EC Number:
270-226-4
EC Name:
Sodium 4-[[4-chloro-6-isopropoxy-1,3,5-triazin-2-yl]amino]benzenesulphonate
Cas Number:
68413-55-8
Molecular formula:
C12H12ClN4NaO4S
IUPAC Name:
Sodium 4-[[4-chloro-6-isopropoxy-1,3,5-triazin-2-yl]amino]benzenesulphonate

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:
Standard Laboratory Conditions
Air-conditioned with 10-15 air changes per hour and continuously monitored environment with a temperature of 22 ± 3 degrees centigrade, a relative humidity between 40-70 %, 12 hours artificial fluorescent light (approx. 100 lux) /12 hours dark, music during the light period.

Accommodation:
Individually in Makrolon type-3 cages (size: 22x37x15 cm) with standard softwood bedding ("Lignocel", Schill AG, CH-4132 Muttenz).

Diet:
Pelleted standard Kliba 342, Batch Nos. 79/93 and 80/93 (from acclimatization start at October 29, 1993) and 80/93 (from October 30 to November 16, 1993) guinea pig breeding/ maintenance diet ("Kliba11, KlingentalmOhle AG, CH-4303 Kaiseraugst), ad libitum. Results of analyses for contaminants are included in this report.

Water:
Community tap water from Fullinsdorf, ad libitum. Once weekly additional supply of ascorbic acid (1 g/1) via the drinking water. Results of bacteriological, chemical and contaminant analyses are included in this report.

Study design: in vivo (non-LLNA)

Induction
Route:
intradermal and epicutaneous
Vehicle:
water
Concentration / amount:
5 %
Day(s)/duration:
7
Adequacy of induction:
highest concentration used causing mild-to-moderate skin irritation and well-tolerated systemically
Challenge
No.:
#1
Route:
epicutaneous, semiocclusive
Vehicle:
water
Concentration / amount:
75 %
Day(s)/duration:
24 and 48
Adequacy of challenge:
highest non-irritant concentration
No. of animals per dose:
MALE NUMBER OF ANIMAL PER GROUP

1 Control Group 10
2 Test Group 20
3 Intracutaneous Pretest 2
4 Epicutaneous Pretest 4
Details on study design:
TEST ARTICLE PREPARATION
The test article and vehicle were placed into a glass beaker on a tared Mettler PM 200 balance and weight/weight dilutions were prepared. Homogeneity of the test article in a suitable vehicle was maintained during treatment using a magnetic stirrer. The preparations were made immediately prior to each dosing.

PRETEST/ performed during the acclimatization period
The objective of this investigation was to identify a maximally tolerated concentration of the test article suitable for the induction phase of the main study. In addition, a suitable non-irritant concentration of the test article, by the topical route of administration, was identified for the challenge application.
The procedure employed for these investigations was as follows:

INTRADERMAL INJECTIONS:
Intradermal injections (0.1 ml/site) were made into the clipped flank of two guinea-pigs at concentrations of 5, 3 and 1% of the test article in bi-dist_illed water. The resulting dermal reactions were assessed 24 hours later. For intradermal induction application a 5 % test article dilution was selected.

EPIDERMAL APPLICATIONS:
Both flanks of each of 4 guinea pigs were clipped and shaved just prior to the application. Thereafter, patches of filter paper (2 x 2 cm) were saturated with concentrations of 100% and 75 %, 50 %, 25 % of the test article in bi-distilled water and applied to the clipped and shaved flanks. The patches were covered by a strip of aluminum foil and firmly secured by elastic plaster wrapped around the trunk and covered with impervious adhesive tape. This procedure ensured the intensive contact of the test article. The dressings were removed after an exposure period of 24 hours and the reaction sites were assessed 24 and 48 hours after removal of the bandage for erythema and oedema on a numerical basis according to Oraize described above.
The allocation of the different test sites- on the animals was alternated in order to minimize site to site variation in responsiveness.
For the epidermal induction a 100 % and for the challenge a 75 and 100 % test substance concentrations were selected.

MAIN STUDY

INDUCTION

Intradermal injections/ performed on test day 1:
An area of dorsal skin from the scapular region (approximately 6 x 8 cm) was clipped free of hair. Three pairs of intradermal injections (0.1 ml/site) were made at the border of a 4 x 6 cm area in the clipped region as follows:

Test group:

1) 1:1 (v/v) mixture of Freund's Complete Adjuvant and physiological saline.
2) The test article, diluted to 5 % with bi-distilled water.
3) The test article diluted to 5 % by emulsion in a 50:50 mixture of Freund's complete adjuvant
and physiological saline.

Control Group:

1) 1:1 (v/v) mixture of Freund's Complete Adjuvant and physiological saline.
2) Bi-distilled water.
3) 1:1 (w/w) mixture of bi-distilled water in a 1:1 (v/v) mixture of Freund's complete adjuvant and
physiological saline.

Epidermal applications

On test day 7 and approximately 24 hours prior to the epidermal application the scapular area (approximately 6 x 8 cm) was clipped, shaved free of hair and the test area was pretreated with 10 % Sodium-Lauryl-Sulfate (SLS) in paraffinum perliquidum as no primary irritation had been observed in the pretest. The SLS was massaged into the skin with a glass rod without bandaging. This 10% concen­ tration of SLS enhances sensitization by provoking a mild inflammatory reaction.
On test day 8, a 2 x 4 cm patch of filter paper was saturated with the test article (100 %) and placed over the injection sites of the test animals. The patch was covered with aluminum foil and firmly secured by an elastic plaster wrapped around the trunk of the animal and secured with impervious adhesive tape. The dressings were left in place for approximately 48 hours. The epidermal application procedure described ensured intensive contact of the test article.
The guinea-pigs of the control group were treated as described above with bi­ distilled water).
Reaction sites were assessed for erythema and oedema 24 and 48 hours after removal of the dressing, using the numerical grading system according to Oraize.


CHALLENGE/ performed on test day 22
The test and control guinea-pigs were challenged two weeks after the epidermal induction application. The test and control guinea-pigs were treated in the same way.
Hair was clipped and shaved from a 5 x 5 cm area on the left and right flank of each guinea-pig just prior to the application. Three patches (2 x 2 cm) of filter paper were saturated with the highest non-irritant concentration of 75 % (left flank) with the undiluted test article (applied to the left cranial flank) and the vehicle only (bi-distilled water applied to right flank) using the same method as for the epidermal application.
Approximately 24 and 48 hours after the removal of the dressing the application sites were assessed for erythema and oedema using the numerical scoring system according the Draize.


Positive control substance(s):
yes
Remarks:
2-MERCAPTOBENZOTHIAZOLE

Results and discussion

Positive control results:
50% of positivity: 5 animal over 10.

In vivo (non-LLNA)

Resultsopen allclose all
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
100% in distilled water
No. with + reactions:
0
Total no. in group:
20
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
100% in distilled water
No. with + reactions:
18
Total no. in group:
20
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
100% in distilled water
No. with + reactions:
0
Total no. in group:
20
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
100% in distilled water
No. with + reactions:
16
Total no. in group:
20
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
75% in distilled water
No. with + reactions:
0
Total no. in group:
20
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
75% in distilled water
No. with + reactions:
20
Total no. in group:
20
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
75% in distilled water
No. with + reactions:
0
Total no. in group:
20
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
75% in distilled water
No. with + reactions:
13
Total no. in group:
20

Applicant's summary and conclusion

Interpretation of results:
Category 1 (skin sensitising) based on GHS criteria
Conclusions:
In the challenge, 90 respectively 80 % of the animals showed erythematous reactions after the 24- and 48-hour reading when treated with the undiluted test article. 100 respectively 65% of the animals showed erythematous reactions after the 24- and 48-hour reading when treated with the test article at 75% in bi­ distilled water. No reactions were noted in the control group treated in the same way.
These results indicate a strong to extreme allergenic potency of the test article SANDOSPACE S LIQUID according to the rating of Magnusson and Kligman (1969).
According to EEC (European Economic Community) classification criteria described in guidelines 93/21/EEC (EEC Official Journal Nr. L. llOA, May 4, 1993), this test article treated in the described conditions is considered to be a sensitizer.
Executive summary:

To assess the allergenic potential of SANDOSPACE S LIQUID in albino guinea pigs the Maximization-Test of B. Magnusson and A.M. Kligman (1969) was used. Ten males were used as control group and 20 males were used as test group.


Due to unequivocal findings after the first challenge, no second challenge was performed.


The highest non-irritating test article concentration used for challenge application was 75 %. The undiluted test article was additionally applied in the challenge because only one out of 4 animals of the epidermal pretest was observed with a very slight erythematous reaction at the 24-hour reading.