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Toxicological information

Skin sensitisation

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Administrative data

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Remarks:
Guinea Pig
Type of information:
experimental study
Adequacy of study:
key study
Study period:
26th January 1988 to 20th February 1988
Reliability:
1 (reliable without restriction)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1988
Report date:
1988

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Qualifier:
according to guideline
Guideline:
EU Method B.6 (Skin Sensitisation)
GLP compliance:
yes
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
The testing using the guinea pig maximisation test protocol was completed on 20 February 1988. The LLNA 429 was not formally adopted by the OECD until 22 July 2010.

Test material

Constituent 1
Chemical structure
Reference substance name:
Ammonium 7-(2,6-dimethyl-8-(2,2-dimethylbutyryloxy)-1,2,6,7,8,8a-hexahydro-1-naphthyl)-3,5-dihydroxyheptanoate
EC Number:
404-520-2
EC Name:
Ammonium 7-(2,6-dimethyl-8-(2,2-dimethylbutyryloxy)-1,2,6,7,8,8a-hexahydro-1-naphthyl)-3,5-dihydroxyheptanoate
Cas Number:
139893-43-9
Molecular formula:
C25 H43 O6 N
IUPAC Name:
ammonium 7-{8-[(2,2-dimethylbutanoyl)oxy]-2,6-dimethyl-1,2,6,7,8,8a-hexahydronaphthalen-1-yl}-3,5-dihydroxyheptanoate
Test material form:
solid: particulate/powder
Specific details on test material used for the study:
Composition:
98.7% L-654,969, 0.6% lovastatin ammonium salt, 0.2% triol.

In vivo test system

Test animals

Species:
guinea pig
Strain:
Dunkin-Hartley
Sex:
female
Details on test animals and environmental conditions:
Guinea pigs were sourced from D. Hall, New Church, Staffordshire, England, weight range 386 - 482g. The animals were acclimatised to laboratory conditions. The guinea pigs were housed in suspended cages with wire mesh floors in Building R17 Room 5. Each animal was identified by ear tattoo.
Temperature: 21oC
Humidity: 30 - 70%
Light sequence: 12 hour light / 12 hour dark
Food: Vitamin C enriched Guinea Pig diet FD1 (Special Services Ltd)
Water: ad libitum

Study design: in vivo (non-LLNA)

Induction
Route:
intradermal and epicutaneous
Vehicle:
other: Freund's Complete Adjuvant for intradermal
Remarks:
Water for epicutaneous
Concentration / amount:
Intradermal injection: 0.25% w/w;
topical application, 20% w/w, in distilled water.
Day(s)/duration:
Intradermal: 7 days Epicutaneous: 48 hours
Adequacy of induction:
not specified
Challenge
No.:
#1
Route:
epicutaneous, semiocclusive
Vehicle:
water
Concentration / amount:
0.2ml
Day(s)/duration:
3
No. of animals per dose:
Number of animals in test group: 20
Number of animals in negative control group: 10
Details on study design:
Animals were randomly assigned to two groups (control and treated). There were 10 animals in the control group and 20 animals in the treated group.

Induction phase
An area of dorsal skin on the scapular region of the guinea pigs was clipped free of hair prior to each induction (approximately 4cm x 6cm). Three pairs of intradermal injections were made simultaneously into this area:
1) Freund's Complete Adjuvant diluted with an equal amount of water for irrigation
2) Test article 0.25% w/w in water for irrigation
3) Test article 0.25% w/w in 50:50 mixture Freund's Complete Adjuvant with water irrigation.

One week after injections, the area was clipped free of hair. A patch of Whatman No. 3 paper (2cm x 4cm) was saturated with test item (20% w/w in distilled water). The patch was placed on the skin and covered with a length of impermeable plastic adhesive tape. This was firmly secured by elastic adhesive bandage and left in place for 48 hours. Control animals were treated similarly to test animals with the exception that the test article was omitted.

Challenge phase
The left flanks of the guinea pigs were clipped free of hair. A patch of Whatman No. 3 paper (2cm x 2cm) was saturated with 0.2ml test item (10% w/w in distilled water). The patch was placed on the skin and covered with a length of impermeable plastic adhesive tape. This was firmly secured by elastic adhesive bandage and left in place for 24 hours.

Observations
Observations were made 24, 48, and 72 hours after the patch was removed.
Erythema and oedma scores were recorded.
Animals were weighed at the start and at conclusion of the study.
Challenge controls:
10 animals
Positive control substance(s):
no

Results and discussion

In vivo (non-LLNA)

Resultsopen allclose all
Key result
Reading:
other: 3rd reading
Hours after challenge:
72
Group:
test chemical
Dose level:
0.25% w/w
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
No adverse effect observed
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
0.25 % w/w
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
No adverse effect observed
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
0.25% w/w
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
No adverse effect observed
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
other: Freud's Treated controls
Hours after challenge:
72
Group:
negative control
Dose level:
0.1 ml Freud's complete adjuvant and water 50:50
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
none
Remarks on result:
no indication of skin sensitisation
Group:
positive control
Remarks on result:
not measured/tested

Any other information on results incl. tables

Maximum concentration not causing irritating effects in preliminary test: 10 %

Signs of irritation during induction: Not recorded

Evidence of sensitisation of each challenge concentration: 0/20

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
The test article did not produce evidence of delayed contact hypersensitivity. L654, 969 does not require labelling with the risk phrase R43 'may cause skin sensitisation by skin contact' as described in the EEC Directive 67/548/EEC Part II (D)
Executive summary:

The study was designed to determine the potential for L-654,969, to elicit a skin sensitisation reaction. The method was designed to be meet OECD Guideline 406 (Skin sensitisation). 

Thirty animals were used in the study, which included one control group (10 animals) and one treated group (20 animals). In the induction phase, three pairs of intradermal injections were made simultaneously 
1) Freund's Complete Adjuvant diluted with an equal amount of water for irrigation
2) Test article 0.25% w/w in water for irrigation
3) Test article 0.25% w/w in 50:50 mixture Freund's Complete Adjuvant with water irrigation.
In the challenge phase, 0.2ml test item (10% w/w in distilled water) was applied to the left flank of each animal in the control and treated group. 24, 48 and 72 hours after patch removal in the challenge group, the skin reactions were observed and scored. Individual animal body weights were recorded at the start and conclusion of the study.

Mortality: There were no deaths or moribund during the test. 

The test article did not produce evidence of delayed contact hypersensitivity.
L654, 969 does not require labelling or classification was per EC 1272/2008