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Description of key information

Propargite was determined to be non-sensitising; study conducted in accordance with EPA OPP 81-6; Kiplinger (1993e). A concentration of 0.1 % was determined to be non-irritant.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records
Reference
Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
12th December 1991 to 18th January 1992
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
EPA OPP 81-6 (Skin Sensitisation)
Deviations:
no
Qualifier:
equivalent or similar to guideline
Guideline:
EPA OTS 798.4100 (Skin Sensitisation)
Deviations:
no
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Deviations:
no
GLP compliance:
yes
Type of study:
Buehler test
Justification for non-LLNA method:
The study was conducted prior to the LLNA becoming the preferred method in the EU.
Species:
guinea pig
Strain:
Hartley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Kuiper Rabbit Ranch, Gary, Indiana, USA
- Age at study initiation: young adult
- Weight at study initiation: 361-457 g
- Housing: individual suspended wire-mesh cages
- Diet: Purina® Guinea Pig Chow® #5025 ad libitum
- Water: tap water ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature: 66-73 ºF
- Humidity: 30-74 %
- Photoperiod: 12 hours light/12 hours dark
Route:
epicutaneous, occlusive
Vehicle:
other: ethanol and acetone for primary irritation phase and ethanol for induction phase
Concentration / amount:
0.1 % w/v
No.:
#1
Route:
epicutaneous, occlusive
Vehicle:
other: acetone for challenge phase
Concentration / amount:
0.2 % w/v at challenge
No.:
#2
Route:
epicutaneous, occlusive
Vehicle:
other: acetone for rechallenge
Concentration / amount:
0.1 and 0.2 % w/v at rechallenge
No. of animals per dose:
Fifteen animals of each sex in the main study and eight animals of each sex in the primary irritation phase.
Details on study design:
RANGE FINDING TESTS:
0.4 mL of the test material was applied to animals at concentrations of 0.025, 0.05, 0.1, 02, 0.4, 0.8 and 1.5 % to determine the primary irritation index. Test material was applied for six hours occluded exposure.

MAIN STUDY
A. INDUCTION EXPOSURE
- Exposure period: 6 hours
- Test groups: two (one with ethanol as vehicle and one with acetone as vehicle)
- Frequency of applications: once per week
- Duration: three weeks
- Concentrations: 0.2 % w/v

B. CHALLENGE EXPOSURE
- No. of exposures: two (challenge and rechallenge a week later)
- Exposure period: 6 hours
- Test groups: one
- Control group: two (challenge and rechallenge)
- Concentrations: 0.2 % w/v (challenge); 0.1 and 0.2 % w/v (rechallenge)
- Dose: 0.4 mL/site
Positive control substance(s):
yes
Remarks:
0.25 % w/v dinitrochlorobenzene in 80 % ethanol
Key result
Reading:
other: challenge
Hours after challenge:
48
Group:
test chemical
Dose level:
0.2 % w/v test material.
Remarks on result:
other: sensitisation incidence index of 8 %
Key result
Reading:
rechallenge
Hours after challenge:
48
Group:
test chemical
Dose level:
0.1 and 0.2 % w/v
Remarks on result:
other: sensitisation incidence index of 0 %

None of the animals died and there were no remarkable changes or differences observed in body weights.

Primary irritation phase

In the primary irritation phase, 0.1 and 0.2 % w/v were the highest concentrations tested that caused no or slight irritation. They were therefore selected as the doses to be used in the main study.

Induction phase

The first induction dose caused slight patchy erythema in six animals. The second dose caused slight patchy erythema in five animals and moderate patchy erythema in one animal. The third dose caused slight patchy erythema in ten animals and moderate patchy erythema (with eschar) in one animal. The responses in the induction phase to the positive control substance were significantly more marked.

Challenge phase

In the test group, slight patchy erythema and moderate patchy erythema was noted in five animals and one animal, respectively, 24 hours after the challenge dose with 0.2 % w/v test material. At 48 hours, slight patchy erythema was seen in five animals. Slight patchy erythema was seen in three of the naive control animals at 24 and 48 hours post-dose. The responses in the challenge phase to the positive control material were significantly more marked. In this phase, only 1/12 animals in the test group (previously exposed) exhibited a grade 1 (moderate patchy erythema) response. Since all responses in the naive control group (previously unexposed) were less than grade 1, a sensitisation incidence index of 8 % was apparent for the test group. The sensitisation incidence index for the positive control group was 100 % in this phase.

Rechallenge phase

Following rechallenge with 0.1 % w/v test material, slight patchy erythema was noted in four animals and three animals, 24 and 48 hours post-dose, respectively. There were no irritation responses in the naive control animals following rechallenge with 0.1 % w/v test material. Following rechallenge with 0.2 % w/v test material, slight patchy erythema was noted in eight animals at 24 hours, with one animal exhibiting moderate patchy erythema (a Grade 1 response). This Grade 1 response was not considered indicative of sensitisation, however, as a grade 1 response was also observed in the naive group at this dose and time point. At 48 hours, slight patchy erythema was seen in five and one animals in the 0.2 % w/v and naive groups, respectively. In this phase, no animals in the 0.1 and 0.2 % w/v test groups (previously exposed) exhibited equal to/greater than grade 1 responses, the only exception being in one animal as discussed, but this was matched by a concurrent Grade 1 response in the naive control group. There were no other grade 1 responses in the naive control group. Therefore, a sensitisation incidence index of 0 % was apparent for the test group at rechallenge.

Interpretation of results:
other: Not classified in accordance with EU criteria
Conclusions:
Based solely on the sensitisation index of 8 % at challenge dosing, the test material could be considered to be a weak sensitiser. However, there was no evidence of sensitisation at re-challenge. Moreover, the single grade 1 response seen in the test group at the first challenge could have been due to primary irritation rather than sensitisation. This hypothesis is supported by the fact that the 0.2 % w/v dose employed at first challenge was clearly minimally irritating to both test and nalive control animals. Therefore, taken together, the results indicate that the test material is non-sensitising to guinea pigs under the conditions of this study.
Executive summary:

Six male and female guinea pigs were dosed topically with the test material once per week for three weeks for a total of three induction exposures. Two weeks after the last induction exposure, animals were challenge dosed for detection of sensitisation by topical application of known non-irritating concentration of the test material to previously unexposed areas of the skin. One week after challenge dosing, animals were rechallenged to confirm the initial challenge results.

Two naive groups of three male and three female guinea pigs each were dosed only at challenge and rechallenge respectively, in the same manner as the test group and served as irritation controls.

Reactions to challenge and rechallenge were evaluated at approximately 24 and 48 hours after completion of exposure. Body weights and clinical observations were recorded just prior to study initiation and at termination.

There were no deaths, test material related clinical findings or remarkable body weight changes during the study.

Following the initial challenge with a 0.2 % concentration of test material, there was a single grade 1 reaction in the test group at 24 hours that exceeded the highest reaction in the naive control I group. There were five and three grade ± (slight patchy erythema) reactions at 24 and 48 hours in the test and naive control groups respectively.

Following the rechallenge with both a 0.1 and 0.2 % concentration of test material, there were no reactions in the test group that could be attributed to sensitisation. The 0.1 % concentration induced four and three grade ± reactions in the test group at 24 and 48 hours, respectively, and no reactions in the naive control II group. The 0.2 % concentration induced a single grade 1 reaction in both the test and naive control II groups at 24 hours. There were eight and five grade ± reactions in the test group at 24 and 48 hours, respectively, and a single grade ± reaction at 24 and 48 hours in the naive control II group.

The incidence of grade ± reactions in both naive control groups and the grade 1 reaction in the naive control II group indicate that the 0.2 % concentration of the test material was minimally irritating. The single grade 1 reaction in the test group following challenge dosing could not clearly be ascribed to sensitisation due to the low levels of irritation caused by the test material. The substance was therefore found to be non-sensitising.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

Six male and female guinea pigs were dosed topically with the test material once per week for three weeks for a total of three induction exposures. Two weeks after the last induction exposure, animals were challenge dosed for detection of sensitisation by topical application of known non-irritating concentration of the test material to previously unexposed areas of the skin. One week after challenge dosing, animals were rechallenged to confirm the initial challenge results.

Two naive groups of three male and three female guinea pigs each were dosed only at challenge and rechallenge respectively, in the same manner as the test group and served as irritation controls.

Reactions to challenge and rechallenge were evaluated at approximately 24 and 48 hours after completion of exposure. Body weights and clinical observations were recorded just prior to study initiation and at termination.

There were no deaths, test material related clinical findings or remarkable body weight changes during the study.

Following the initial challenge with a 0.2 % concentration of test material, there was a single grade 1 reaction in the test group at 24 hours that exceeded the highest reaction in the naive control I group. There were five and three grade ± (slight patchy erythema) reactions at 24 and 48 hours in the test and naive control groups respectively.

Following the rechallenge with both a 0.1 and 0.2 % concentration of test material, there were no reactions in the test group that could be attributed to sensitisation. The 0.1 % concentration induced four and three grade ± reactions in the test group at 24 and 48 hours, respectively, and no reactions in the naive control II group. The 0.2 % concentration induced a single grade 1 reaction in both the test and naive control II groups at 24 hours. There were eight and five grade ± reactions in the test group at 24 and 48 hours, respectively, and a single grade ± reaction at 24 and 48 hours in the naive control II group.

The incidence of grade ± reactions in both naive control groups and the grade 1 reaction in the naive control II group indicate that the 0.2 % concentration of the test material was minimally irritating. The single grade 1 reaction in the test group following challenge dosing could not clearly be ascribed to sensitisation due to the low levels of irritation caused by the test material. The substance was therefore found to be non-sensitising.

Justification for selection of skin sensitisation endpoint:

Two skin sensitisation studies have been submitted. Kiplinger (1993e) was performed with the Buehler test and determined that propargite was non-sensitising; Morris (2003) was performed with the more stringent Magnusson and Kligman test and determined that propargite was a sensitiser. The exposure conditions of the Buehler test are considered to be more representative of the exposure conditions from the use of the substance and so this study has been selected as the key study. This is consistent with the existing harmonised classification for propargite in Annex VI of Regulation 1272/2008 as non-sensitising. In this study, a concentration of 0.1 % was determined to be non-irritant and is used at the relevant NOEL for local effects.

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

In accordance with the criteria for classification as defined in Annex I, Regulation (EC) No 1272/2008, the substance does not require classification with respect to skin sensitisation.

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