Carboxylic acids, di-, C4-6

Endpoint summary

Description of key information

Dicarboxylic acid mixture did not show sensitization properties in a guinea pig maximization test.

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:

2004

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 406 (Skin Sensitisation)

Version / remarks:

1992

Qualifier:

according to guideline

Guideline:

EU Method B.6 (Skin Sensitisation)

Version / remarks:

1996

GLP compliance:

yes

Type of study:

guinea pig maximisation test

Justification for non-LLNA method:

Test was performed in 2004, long before the LLNA method was defined as preferred method for skin sensitization testing.

Specific details on test material used for the study:

the vehicle chosen was 0.9% NaCl (pyhsiological saline). A hoomogeneous dosage form preparation was obtained at the maximum concentration of 10% (w/w).

Species:

guinea pig

Strain:

Hartley

Sex:

female

Details on test animals and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, France
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 1-2 months
- Weight at study initiation: 373 ± 10g
- Diet (ad libitum)
- Water (ad libitum):
- Acclimation period: 8 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2°C
- Humidity (%): 30-70%
- Air changes (per hr): 12 cycles per hour
- Photoperiod (hrs dark / hrs light): 12h / 12h
- IN-LIFE DATES: From: March 2004 To: June 2004

Route:

intradermal

Vehicle:

physiological saline

Concentration / amount:

0.1% (w/w)

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

Concentration / amount:

10%

Day(s)/duration:

day 8 (48 hours occlusive)

Adequacy of induction:

highest technically applicable concentration used

Route:

epicutaneous, occlusive

Vehicle:

physiological saline

Concentration / amount:

5%

Day(s)/duration:

day 22 (24 hour occlusive)

Adequacy of challenge:

highest non-irritant concentration

No. of animals per dose:

test group: 10 females
control group: 5 females

Details on study design:

RANGE FINDING TESTS:
Intradermal route: 10%, 5%, 1% and 0.1% (w/w) in 0.9% NaCl (0.1 mL injection in the interscapular region)
In order to respect the criteria for the selection of concentrations (the concentration should be well-tolerated systemically and locally, intradermal injection should cause moderate irritant effects but no necrosis or ulceration of the skin) concentration chosen for the main study was 0.1% (w/w).

Cutaneous route - for induction: 10% (w/w) in 0.9% NaCl (about 8 cm² fully-loaded filter paper applied occlusively for 48 hours)
Cutaneous route - for challenge: 10% and 5% (w/w) in 0.9% NaCl (applied occlusively for 24 hours); reading 24 and 48 hours after removal of dressing
In order to respect the criteria for the selection of concentrations (the concentration should be well-tolerated systemically and locally, cutaneous application for the challence phase should be the highest concentration which does not cause irritant effect) concentration chosen for the topical application in the induction phase (day8) of main study was 10% (w/w). For the challenge application (day 22), it was 5% (w/w).

MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: intradermal injections with 0.1% test item (day 1; FCA at 50% alone, test item alone, mixture of test item and FCA) and one topical application with 10% test item for 48 hours under occlusive conditions (day 8)
- Control group: only vehicle
As the test item was shown to be non-irritant during the preliminary test, under the conditions of the topical induction phase, the animals of both groups were treated on day 7 with 0.5 mL of sodium lauryl sulfate at the concentration of 10% (w/w) in vaseline, in order to induce local irritation.

B. CHALLENGE EXPOSURE
- No. of exposures: topical application of 0.5% test item
- Day(s) of challenge: day 22
- Exposure period: 24 hours under occlusive conditions
- Control group: only vehicle
- Evaluation (hr after challenge): 24 and 48 hours after patch removal

Challenge controls:

The animals of the treated and control groups received an application of the test item (test group) and the vehicle (vehicle challenge). The vehicle was applied under the same experimental conditions to the skin of the posterior left flank as challenge control.

Positive control substance(s):

yes

Remarks:

The sensitivity of the experimental technique is regularly assessed and proven using a known moderate sensitizer, Mercaptobenzothiazole (test of September 2003)

Positive control results:

The sensitivity of the experimental technique is regularly assessed and proven using a known moderate sensitizer, Mercaptobenzothiazole (positive skin reactions in 100% (10/10) guinea pigs).

Reading:

2nd reading

Hours after challenge:

48

Group:

positive control

Dose level:

no data available

Remarks on result:

other: The sensitivity of the experimental technique is regularly assessed and proven using a known moderate sensitizer, Mercaptobenzothiazole (test of September 2003)

Reading:

1st reading

Hours after challenge:

24

Group:

positive control

Dose level:

no data available

Remarks on result:

other: The sensitivity of the experimental technique is regularly assessed and proven using a known moderate sensitizer, Mercaptobenzothiazole (test of September 2003)

Reading:

1st reading

Hours after challenge:

24

Group:

negative control

Dose level:

0

No. with + reactions:

0

Total no. in group:

5

Clinical observations:

none

Reading:

1st reading

Hours after challenge:

24

Group:

test chemical

Dose level:

5%

No. with + reactions:

1

Total no. in group:

10

Clinical observations:

erythema grade 1 in a single animal

Remarks on result:

no indication of skin sensitisation

Reading:

2nd reading

Hours after challenge:

48

Group:

negative control

Dose level:

0

No. with + reactions:

0

Total no. in group:

5

Clinical observations:

none

Reading:

2nd reading

Hours after challenge:

48

Group:

test chemical

Dose level:

5%

No. with + reactions:

1

Total no. in group:

10

Clinical observations:

erythema grade 1 in a single animal

Remarks on result:

no indication of skin sensitisation

After the challenge application, no cutaneous reactions were observed in the animals of the control group. In the treatment group, a discrete erythema was observed in 1/10 animals at the 24-hour reading and in another animal at the 48-hour reading. Dryness of the skin was also observed in 1/10 animals at the 48-hours reading only.

Interpretation of results:

not sensitising

Executive summary:

Dicarboxylic acid mixture consisting of 18.6% succinic acid, 50.9% glutaric acid, and 23.8% adipic acid, was investigated in a Guinea pig Maximization test performed according to OECD TG 406. Ten guinea pigs received 0.1% test compound  in 0.9%NaCl in the presence of Freud's complete adjuvant during the intradermal induction and 10% test compound during the following dermal induction after application of 10% sodium lauryl sulfate to induce local irritation. The challenge was performed with 5% test compound for 24 hours and skin reaction was evaluated 24 and 48 hours after removal of the dressing.

After the challenge application, no cutaneous reactions were observed in the animals of the control group. In the treatment group, a discrete erythema was observed in 1/10 animals at the 24-hour reading and in another animal at the 48-hour reading. Dryness of the skin was also observed in 1/10 animals at the 48-hours reading only. According to the evaluation criteria of the test, the dicarboxylic acid mixture is considered as not exerting skin sensitizing properties.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

Dicarboxylic acid mixture was investigated in a study according to OECD TG 406; maximization test. Ten guinea pigs received 0.1% test compound in 0.9%NaCl in the presence of Freud's complete adjuvant during the intradermal induction and 10% test compound during the following dermal induction after application of 10% sodium lauryl sulfate to induce local irritation. The challenge was performed with 5% test compound for 24 hours and skin reaction was evaluated 24 and 48 hours after removal of the dressing.

After the challenge application, no cutaneous reactions were observed in the animals of the control group. In the treatment group, a discrete erythema was observed in 1/10 animals at the 24-hour reading and in another animal at the 48-hour reading. Dryness of the skin was also observed in 1/10 animals at the 48-hours reading only. The test item is thus considered as not exerting skin sensitizing properties.

Additional sources/reviews cited in chapter "Additional Toxicological Information" support that dicarboxylic acid mixture is not sensitizing.

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information:

No experimental data concerning the respiratory sensitisation potential are available. Overall, respiratory sensitisation is not expected for dicarboxylic acid mixture.

Justification for classification or non-classification

No classification is required for skin sensitization according to the classification criteria of Regulation no. 1272/2008 (GHS).