4-methoxybenzyl alcohol

Endpoint summary

Description of key information

Based on the results of the LLNA assay accoroding to OECD 429, the test item is considered to be a skin sensitizer.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Reference 1

Endpoint:

skin sensitisation: in vivo (LLNA)

Type of information:

experimental study

Adequacy of study:

key study

Study period:

09 July 2004 and 25 January 2005

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 429 (Skin Sensitisation: Local Lymph Node Assay)

Version / remarks:

2002

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.2600 (Skin Sensitisation)

Version / remarks:

2003

Deviations:

no

GLP compliance:

yes

Type of study:

mouse local lymph node assay (LLNA)

Species:

mouse

Strain:

CBA

Sex:

female

Details on test animals and environmental conditions:

TEST ANIMALS
- Source: Harlan Interfauna UK Limited, Blackthorne, Bicester, Oxon, UK
- Age at study initiation: 8-12 weeks
- Housing: a maximum of 4 mice was housed per cage
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3
- Humidity (%): 30-70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Vehicle:

other: 1:3 ethanol/diethyphthalate (EtOH/DEP)

Concentration:

2.5, 5.0, 10, 25 and 50% (w/w)

No. of animals per dose:

4

Details on study design:

MAIN STUDY
ANIMAL ASSIGNMENT AND TREATMENT
- Name of test method: local lymph node assay
- Criteria used to consider a positive response: One or more concentrations of the test substance should elicit a 3-fold or greater increase in isotope incorporation relative to the vehicle control group.

TREATMENT PREPARATION AND ADMINISTRATION:
- All dose preparations were used within 24 hours of preparation.
- Approximately, 25 µL of the test substance in vehicle was applied, using a variable volume micro-pipette, to the dorsal surface of each ear. The procedure was repeated daily for 3 consecutive days. Three days after the third application, all animals were injected, via the tail vein, with approximately 250 µL of phosphate buffered saline (PBS) containing 20µCi of a 2.0Ci/mmol specific activity 3H-methyl thymidine. Approximately 5 hours later, the animals were humanely killed.

Positive control substance(s):

hexyl cinnamic aldehyde (CAS No 101-86-0)

Positive control results:

A greater than 3-fold increase in isotope incorporation was observed at both 10% and 25% concentrations of positive control in acetone:olive oil (4.1).

Key result

Parameter:

EC3

Value:

5.9

Key result

Parameter:

SI

Value:

1.8

Test group / Remarks:

2.5% test item

Key result

Parameter:

SI

Value:

2.8

Test group / Remarks:

5% test item

Key result

Parameter:

SI

Value:

3.9

Test group / Remarks:

10% test item

Key result

Parameter:

SI

Value:

5.1

Test group / Remarks:

25% test item

Key result

Parameter:

SI

Value:

5.3

Test group / Remarks:

50% test item

Cellular proliferation data / Observations:

CELLULAR PROLIFERATION DATA
The following disintegrations per minute (DPM) were determined:
vehicle: 2651 dpm
2.5% test item: 4620 dpm
5.0% test item: 7319 dpm
10 % test item: 10242 dpm
25% test item: 13609 dpm
50% test item: 14025 dpm

EC3 CALCULATION: EC3 = [(3-d)/(b-d)] x (a-c) + c with a: concentration giving the SI immediately above 3), b: SI of a, c: concentration giving the SI immediately below 3, d: SI of c

Interpretation of results:

Category 1B (indication of skin sensitising potential) based on GHS criteria

Conclusions:

The test item is likely to be a skin sensitiser under the conditions of the test. The EC3 value was calculated to be 5.9% w/v (1475 µg/cm2).

Executive summary:

The test substance was assessed for its skin sensitisation potential using the mouse Local Lymph Node Assay: The assay determines the level of T lymphocyte proliferation in the lymph nodes draining the site of chemical application, by measuring the amount of radiolabelled thymidine incorporated into the dividing cells. The test item was applied as 2.5, 5, 10, 25 or 50% w/v preparations in 1:3 ethanol:diethylphthalate. A vehicle control was similarly treated using 1:3 EtOH:DEP alone. The test substance caused skin sensitisation when applied as a 10, 25 and 50% (w/v) preparation in 1:3 EtOH:DEP. The EC3 value giving rise to a 3 fold increase in lymphocyte proliferation was calculated to be 5.9% w/v (1475 µg/cm2). The positive control, hexycinnamaldehyde caused skin sensititsation when applied as 10% or 25% preparations in acetone:olive oil (4:1), confirming the validity of the test. In conclusion, the test substance is considered to be a skin sensitiser under the test conditions.

Reference 2

Endpoint:

skin sensitisation: in vitro

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (sensitising)

Additional information:

Key study

The test substance was assessed for its skin sensitisation potential using the mouse Local Lymph Node Assay: The assay determines the level of T lymphocyte proliferation in the lymph nodes draining the site of chemical application, by measuring the amount of radiolabelled thymidine incorporated into the dividing cells. The test item was applied as 2.5, 5, 10, 25 or 50% w/v preparations in 1:3 ethanol:diethylphthalate. A vehicle control was similarly treated using 1:3 EtOH:DEP alone. The test substance caused skin sensitisation when applied as a 10, 25 and 50% (w/v) preparation in 1:3 EtOH:DEP. The EC3 value giving rise to a 3 fold increase in lymphocyte proliferation was calculated to be 5.9% w/v (1475 µg/cm2). The positive control, hexycinnamaldehyde caused skin sensititsation when applied as 10% or 25% preparations in acetone:olive oil (4:1), confirming the validity of the test. In conclusion, the test substance is considered to be a skin sensitiser under the test conditions.

 

Supporting studies

Two guinea pig sensitization studies using a modified Draize procedure (Sharp et al., 1978) and an open epicutaneous test (Klecak, 1985), respectively, were conducted. No positive reactions were observed when the test substance was intradermally injected at concentration of 0.25% on one flank and topical applied at a concentration of 10% on the other flank (Sharp et al., 1978). No sensitization was determined in the open epicutaneous test when the guinea pigs were treated with 5% of the test substance at the challenge phase. Thus, both studies support the result of the key study even if the result of the key study already indicated a sensitizing effect at 10% of the test substance. This difference is most likely attributed to the different experimental procedure.

 

In addtion, there are existing three reliable human patch tests performed with the test substance.In the study by Kligman (1971) a maximization test was carried out with 5% of the test substance under occlusion patch test for five 48 -hour exposures following pretreatment with 5% SLS on 25 male subject. As a result, no positive reactions were observed.

Larsen et al (1996) applied 5% of the test susbtance to the upper backs of 167 patients who were established to be fragrance sensitive based on historical and clinical grounds or had previously reacted to fragrance materials in previous patch tests. The exposure duration was 48 or 72 hours. Allergic reactions were reported in 1.8% of 167 patients. Schnuch et al. (2007) also observed one allergic reaction when the 1% of the test substance was patch tested for 24 or 48 hours on 2004 patients. In conclusion, the test substance showed the tendency to induce skin sensitization in humans at low concentrations. However, a positive reactions was only observed in subjects who were fragrance sensitive.

 

Overall conclusion

Considering the most reliable and suitable study, the Local Lymph Assay, the test substance is considered to be a skin sensitizer when applied to 10, 25 and 50% (w/v) preparation.

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008

Based on the available experimental data, the substance is considered to be classified for skin sensitisation cat. 1B and labelled with H317 (May cause an allergic skin reaction) under Regulation (EC) No 1272/2008, as amended for the eighth time in Regulation (EC) No 2016/918.