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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:
13 July - 12 August 2005 (experimental period)
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2005
Report date:
2005

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.6 (Skin Sensitisation)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.2600 (Skin Sensitisation)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
background for conducting guinea pig maximisation test: unknown

Test material

Constituent 1
Chemical structure
Reference substance name:
-
EC Number:
472-110-0
EC Name:
-
Cas Number:
71868-15-0
Molecular formula:
C20H22O5
IUPAC Name:
2-hydroxy-1-{4-[4-(2-hydroxy-2-methylpropanoyl)phenoxy]phenyl}-2-methylpropan-1-one
Test material form:
solid: particulate/powder
Details on test material:
- Appearance: white powder

In vivo test system

Test animals

Species:
guinea pig
Strain:
Dunkin-Hartley
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- 10/5 (test/control) Hsd Poc: DH - guinea pigs (Full-Barrier), Sex: female, nulliparous, nonpregnant, bodyweight at the commencement of the study 300 - 500 g.
- 3 (range finding) Hsd Poc: DH - guinea pigs (Full-Barrier), Sex: female, nulliparous, nonpregnant, bodyweight at the commencement of the study 300 - 500 g.
- A health inspection was performed to ensure the good state of health of the animals.
- The animals were derived from a controlled full barrier maintained breeding system (SPF).
- Source: Harlan Winkelmann GmbH, Borchen, Germany.

ENVIRONMENTAL CONDITIONS
- The animals were barrier maintained (semi-barrier) in an air conditioned room.
- Temperature: 22 +/- 3 °C
- Rel. humidity: 55 +/- 10%
- Artificial light, sequence being 12 hours light, 12 hours dark
- Air change: at least 10 x / hour
- Feeding ad libitum, Altromin 3122 maintenance diet for guinea pigs, rich in crude fiber, totally-pathogen-free (TPF)
- Free access to tap water (drinking water, municipal residue control, microbiol. controlled periodically)
- The animals were kept in groups in Terluran-cages on Altromin saw fiber bedding.
- Adequate acclimatization period.

Study design: in vivo (non-LLNA)

Induction
Route:
intradermal and epicutaneous
Vehicle:
cotton seed oil
Concentration / amount:
- intradermal injection (induction - first stage): test item was applied at a 5% concentration (diluted in cotton seed oil).
- topical application (induction - second stage): test item was applied at a 50% concentration (diluted in cotton seed oil).
Day(s)/duration:
day 0: intradermal treatment; day 6: pretreatment of the test area with 0.5 ml of 10% sodium lauryl sulphate; day 7: occlusive dressing for 48 hours (test group: 0.5 mL of the prepared test item; control group: 0.5 mL of the vehicle)
Adequacy of induction:
non-irritant substance, but skin pre-treated with 10% SDS
Challenge
Route:
epicutaneous, occlusive
Vehicle:
cotton seed oil
Concentration / amount:
topical application (challenge): test item was applied at a 50% concentration (diluted in cotton seed oil).
Day(s)/duration:
day 20 (test and control group): 0.5 mL of the prepared test item was applied to the left flank of the animals and, a patch loaded with 0.5 mL vehicle to the right flank (intraspecific control); occlusive dressing for 24 hours.
No. of animals per dose:
- test group: 10 animals
- control group: 5 animals
- range finding: 3
Details on study design:
RANGE FINDING TEST:
For the justification of dose levels a preliminary test was performed. One animal was intradermally treated with 2.5 as well as 5% concentration (diluted in cotton seed oil, Lot 015K0202, Sigma) of the test item.
For the 2.5% concentration erythema grade 1 was observed (24 and 48 hours post-dose). After 72 hours no signs of irritation were observed any more.
For the 5% concentration erythema grade 1 was observed (24, 48 as well as 72 hours post-dose).
Therefore the concentration of 5% was chosen for the intradermal induction.
Two animals were topically treated with 50 as well as 100% concentration for 24 hours and 48 hours, respectively.
No signs of irritation and systemic toxicity were recorded for any concentration 24, 48 as well as 72 hours after application.
Therefore the 50% concentration was chosen for the topical induction as well as for the challenge.

MAIN STUDY
A. INDUCTION (First Stage, Intradermal Injection)

Three pairs of intradermal injections of 0.1 mL volume were given in the shoulder region which was cleared of hair by clipping so that one of each pair lies on each side of the midline.

Test group: Day 0
- Injection 1: Freund's Adjuvant complete, 1 + 1 (v/v) diluted with isotonic saline
- Injection 2: Prepared test item
- Injection 3: Prepared test item at a concentration of 50% (V/V) in Freund's Adjuvant complete, 1 + 1 (v/v) diluted with isotonic saline

Control group : Day 0
- Injection 1: Freund's Adjuvant complete, 1 + 1 (v/v) diluted with isotonic saline
- Injection 2: Vehicle at a concentration of 100%
- Injection 3: Vehicle at a concentration of 50% (V/V) in Freund's Adjuvant complete, 1 + 1 (v/v) diluted with isotonic saline
- Injections 1 and 2 were given close to each other and nearest to the head, while 3 is given toward the caudal part of the test area.

B. INDUCTION (Second Stage, Topical Application):

Test and Control Group: Day 6
Approximately twenty-four hours before the topical induction application the test area was closely clipped and painted with 0.5 mL of 10% sodium lauryl sulfat.

Test Group: Day 7
A patch was fully loaded with 0.5 mL of the prepared test item, applied to the test area and held in contact by an occlusive dressing for 48 hours.

Control Group: Day 7
A patch was fully loaded with 0.5 mL of the vehicle and applied to the test area and held in contact by an occlusive dressing for 48 hours.

C. CHALLENGE (Topical Application)

The flanks of treated and control animals were cleared of hair by closely-clipping.

Test and Control Group: Day 20
A patch loaded with 0.5 mL of the prepared test item was applied to the left flank of the animals and, a patch loaded with 0.5 mL vehicle to the right flank (intraspecific control), respectively. The patches were held in contact by an occlusive dressing for 24 hours.
Challenge controls:
A patch loaded with 0.5 mL of the prepared test item (50% in cotton seed oil) was applied to the left flank of the animals and, a patch loaded with 0.5 mL vehicle to the right flank (intraspecific control), respectively. The patches were held in contact by an occlusive dressing for 24 hours.
Positive control substance(s):
yes
Remarks:
reliability of the test system was performed in Jan./Feb. 2005 with Mercaptobenzothiazole [purity > 98%; CAS No. 149-30-4; Lot S35857 306; Merck] (15% in Vaseline)

Results and discussion

Positive control results:
Frequency of sensitisation in positive control animals:
- at 24 h 80%,
- at 48 h 80%,
- at 72 h 60%.

In vivo (non-LLNA)

Resultsopen allclose all
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
50%
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
no visible clinical symptoms over the period of observation
Remarks on result:
no indication of skin sensitisation
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
50 %
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
no visible clinical symptoms over the period of observation
Remarks on result:
no indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
50%
No. with + reactions:
0
Total no. in group:
5
Remarks on result:
no indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
50%
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
no indication of skin sensitisation
Reading:
1st reading
Hours after challenge:
24
Group:
positive control
Dose level:
15%
No. with + reactions:
8
Total no. in group:
10
Remarks on result:
positive indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
48
Group:
positive control
Dose level:
15%
No. with + reactions:
8
Total no. in group:
10
Remarks on result:
positive indication of skin sensitisation

Applicant's summary and conclusion

Interpretation of results:
other: EU-GHS criteria not met
Conclusions:
The study was performed as GLP guideline study with no deviations and is well-documented. Hence, the results are considered reliable for assessment. The test item caused no reactions identified as sensitization.
Executive summary:

A study was performed to assess the potential of the test substance to cause skin sensitisation in guinea pigs according to OECD Guideline 406, in compliance with GLP. Groups of 10 Hsd Poc: DH guinea pigs (Full-Barrier) were used for the study, along with groups of 5 controls. The maximum concentration not giving rise to irritating effects in the preliminary test corresponded to 100% test substance. The first induction was conducted with 5% test substance in cottonseed oil, the second with 50% test substance in cottonseed oil. The concentration of test substance and vehicle used at each stage of challenge was equivalent to 50%. The study results were as follows:

  • Induction I: 24 h post-dose erythema grade 1 at the injection site 2 in 8 animals; 48 h post-dose erythema grade 1 at the injection site 2 in 8 animals;
  • Induction II: No signs of irritations in any animal.
  • Challenge: No evidence of sensitization. No other effects observed.

 Under the study conditions, the test substance was considered to be non-sensitising (Brummer, 2005).