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Diss Factsheets

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:
1995-07-04 to 1995-07-28
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:
dated 29 December 1992
Deviations:
no
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Version / remarks:
adopted 17 July 1992
Deviations:
yes
Remarks:
see "Principles of method if other than guideline"
Principles of method if other than guideline:
Only in 18 animals a topical challenge was administered. OECD guidelines states: ‘when fewer than 20 test guinea pigs have been used in a maximisation test and it is not possible to conclude that the test substance is a sensitiser, testing in additional animals to give a total of at least 20 test and 10 control animals is strongly recommended.’ Since the test substance was very toxic, no further testing is required. The study is considered acceptable. The test substance is considered not sensitising to the skin of guinea pigs.
GLP compliance:
yes (incl. QA statement)
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
This study was conducted due to non-REACH regulatory requirements. With the existing data from this study not only being acceptable but of good quality (Klimisch Score 1), this study precludes the need for an additional LLNA study. In addition, a supplementary LLNA study would violate the ECHA objectives with regards to animal welfare.

Test material

Constituent 1
Chemical structure
Reference substance name:
Fenamiphos
EC Number:
244-848-1
EC Name:
Fenamiphos
Cas Number:
22224-92-6
Molecular formula:
C13H22NO3PS
IUPAC Name:
{ethoxy[3-methyl-4-(methylsulfanyl)phenoxy]phosphoryl}(propan-2-yl)amine
Test material form:
solid: crystalline

In vivo test system

Test animals

Species:
guinea pig
Strain:
other: SPF-bred guinea pigs of the strain Hsd Win:DH (previously termed BonDHPW)
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Winkelmann GmbH Laboratory Animal Breeders in 33176 Borchen
- Microbiological status of animals, when known: SPF
- Age at study initiation: 5-6 weeks
- Weight at study initiation: 331-335 g
- Housing: IV Makrolon® cages with low-dust wood shavings, in groups of five
- Diet (ad libitum): Altromin®3020 - Maintenance Diet for Guinea Pigs supplied by Altromin GmbH in Lage
- Water (ad libitum): tap water
- Acclimation period: at least 7 days
- Indication of any skin lesions: no

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 +/-1.5
- Humidity (%): 40-70
- Air changes (per hr): 12-15
- Photoperiod (hrs dark / hrs light): 12/12

Study design: in vivo (non-LLNA)

Inductionopen allclose all
Route:
intradermal
Vehicle:
physiological saline
Remarks:
containing 2 % v/v Cremophor EL®
Concentration / amount:
2.5 %
Day(s)/duration:
Day 1/ -
Adequacy of induction:
highest concentration used causing mild-to-moderate skin irritation and well-tolerated systemically
Route:
epicutaneous, occlusive
Vehicle:
physiological saline
Remarks:
containing 2 % v/v Cremophor EL®
Concentration / amount:
25 %
Day(s)/duration:
Day 7/ 48 h
Adequacy of induction:
non-irritant substance, but skin pre-treated with 10% SDS
Challengeopen allclose all
No.:
#1
Route:
epicutaneous, occlusive
Vehicle:
physiological saline
Remarks:
containing 2 % v/v Cremophor EL®
Concentration / amount:
12%
Day(s)/duration:
Day 21/ 24 h
Adequacy of challenge:
highest non-irritant concentration
No.:
#2
Route:
epicutaneous, occlusive
Vehicle:
physiological saline
Remarks:
containing 2 % v/v Cremophor EL®
Concentration / amount:
25 %
Day(s)/duration:
Day 21/ 24 h
Adequacy of challenge:
highest non-irritant concentration
No. of animals per dose:
18 animals in test substance group (9 animals/ challenge concentration)
10 animals in control group (5 animals/ challenge concentration)
Details on study design:
RANGE FINDING TESTS:

MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: intradermal: 2, topical and intradermal
- Exposure period: topical 48 h
- Test groups:
intradermal:
1. Injection site: cranial/bilateral: complete Freund's adjuvant (DIFCO LAB.) diluted 1:1 with physiological NaCI solution (sterile).
2. Injection site: medial/bilateral: 1 % SRA 3886 formulated in sterile physiological saline solution containing 2% v/v Cremophor EL®
3. Injection site: caudal/bilateral: 1% SRA 3886 formulated at equal parts in sterile physiological NaCI solution containing 2% v/v Cremophor EL® and complete Freund's adjuvant.

topical:
0.5 ml SRA 3886 25% in physiological saline solution containing 2% v/v Cremophor EL®.


- Control group:
intradermal:
The animals of the control groups were treated in the same manner as the animals of the test substance group; however, the formulations for injection site pairs 2 and 3 did not contain any test substance but a corresponding amount of sterile physiological NaCI solution containing 2% v/v Cremophor EL®.
topical:
0.5 ml sterile physiological saline solution containing 2% v/v Cremophor EL®.

- Site: dorsal region and the flanks
- Frequency of applications: 3
- Concentrations: intradermal: 2.5 %, topical: 25 %



B. CHALLENGE EXPOSURE
- No. of exposures: 2
- Day of challenge: Day 21
- Exposure period: 24 h
- Test groups: 2
- Control group: 2
- Site: dorsal region and the flanks
- Concentrations: 12 and 25 %
- Evaluation (hr after challenge): 48 and 72

Results and discussion

In vivo (non-LLNA)

Resultsopen allclose all
Key result
Reading:
1st reading
Hours after challenge:
48
Group:
positive control
Dose level:
0
No. with + reactions:
0
Total no. in group:
0
Key result
Reading:
2nd reading
Hours after challenge:
72
Group:
positive control
Dose level:
0
No. with + reactions:
0
Total no. in group:
0
Key result
Reading:
1st reading
Hours after challenge:
48
Group:
negative control
Dose level:
12 %
No. with + reactions:
0
Total no. in group:
18
Key result
Reading:
2nd reading
Hours after challenge:
72
Group:
negative control
Dose level:
12 %
No. with + reactions:
0
Total no. in group:
18
Key result
Reading:
1st reading
Hours after challenge:
48
Group:
negative control
Dose level:
25 %
No. with + reactions:
0
Total no. in group:
18
Key result
Reading:
2nd reading
Hours after challenge:
72
Group:
negative control
Dose level:
25 %
No. with + reactions:
0
Total no. in group:
18
Key result
Reading:
1st reading
Hours after challenge:
48
Group:
test chemical
Dose level:
12 %
No. with + reactions:
0
Total no. in group:
18
Clinical observations:
none at surviving animals
Key result
Reading:
2nd reading
Hours after challenge:
72
Group:
test chemical
Dose level:
12 %
No. with + reactions:
0
Total no. in group:
18
Clinical observations:
none at surviving animals
Key result
Reading:
1st reading
Hours after challenge:
48
Group:
test chemical
Dose level:
25 %
No. with + reactions:
4
Total no. in group:
18
Clinical observations:
none at surviving animals
Key result
Reading:
2nd reading
Hours after challenge:
72
Group:
test chemical
Dose level:
25 %
No. with + reactions:
1
Total no. in group:
18
Clinical observations:
none at surviving animals

Any other information on results incl. tables

Table 1: Results summary
































































































































































Animal no.



Callenge: 25 %



Callenge: 12 %



 



48 h



72 h



48 h



72 h



21



0



0



0



0



22



0



0



0



0



23



0



0



0



0



24



0



0



0



0



25



+



+



+



+



26



1



0



0



0



27



0



0



0



0



28



1



0



0



0



29



0



0



0



0



30



1



1



0



0



31



0



0



0



0



32



0



0



0



0



33



+



+



+



+



34



0



0



0



0



35



0



0



0



0



36



1



0



0



0



37



0



0



0



0



38



0



0



0



0



39



0



0



0



0



40



0



0



0



0



+ animal died after the first induction (intradermal)


 


MORTALITY


Two animals of the test group died after intradermal induction. The macroscopic examination revealed paleness of the liver, lungs and kidneys and the stomach was filled with liquid.


 


SKIN REACTIONS


After 48 h slight skin redness (grade 1) was observed at the 25 % challenge concentration in 4/18 test animals, After 72 h a slight skin redness was observed only in 1 animal. No skin reactions were found at the 12 % challenge concentration in test group and control group animals after 48 and 72 hours.

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
Under the conditions of this study, the test substance is considered not sensitising to the skin of guinea pigs.
Executive summary:

The study was performed in accordance with OECD 406. There were no deviations from the current regulatory guideline considered to compromise the scientific validity of the study. In a skin sensitisation study, according to Magnusson and Kligman (GPMT), the potential of the test item was evaluated to provoke sensitization reactions in guinea pigs. The dose levels were based on the results of range-finding studies. On day 0, three pairs of intradermal injections of 0.1 mL volume were given in the left and the right side of the spinal column:



(1) a 1:1 mixture (v/v) Freund's complete adjuvant with NaCI,


(2) the test item (1% suspension of the test item in physiological saline containing 2% v/v Cremophor EL®), (3) 1% of the test item in a 1:1 mixture (v/v) of Freund's complete adjuvant with NaCI solution containing 2% v/v Cremophor EL®.


 


Seven days after the intradermal induction, the test substance was applied to the test area at a concentration of 25% in physiological saline containing 2% v/v Cremophor EL®, and held in place for 48 hours. Three weeks after the intradermal induction, two hypoallergic patches loaded with 12% and 25% of the test substance were placed on the left flank of the animals and held in contact for 24 hours. The skin reactions were assessed 48 and 72 hours after the initiation of the challenge exposure, according to Magnusson and Kligman grading scale. The animals were observed for clinical signs at least once daily throughout the entire study period.


Two animals of the test group died after intradermal induction. The macroscopic examination revealed paleness of the liver, lungs and kidneys and the stomach was filled with liquid.


 


In the surviving animals, after 48 h slight skin redness (grade 1) was observed at the 25 % challenge concentration in 4/18 test animals, after 72 h a slight skin redness was observed only in 1 animal. No skin reactions were found at the 12 % challenge concentration in test group and control group animals after 48 and 72 hours.


Based on the obtained results, it can be concluded that the test item has no potential to induce skin sensitization.