Registration Dossier

Administrative data

Description of key information

Key value for chemical safety assessment

Skin sensitisation

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (sensitising)
Additional information:

Sensitisation assays in test animals

The sensitising potential of hydroquinone was investigated in two mouse local lymph node assays [Reliability 2] comparable to standard conditions of the OECD Guideline 429 (Key studies: Kimber et al., 1998; Lea et al., 1999).

In an interlaboratory evaluation with participation of five test laboratories test concentrations were 0.10, 0.25, 0.50, 1.00, and 2.50% HQ in acetone/olive oil (4:1) as vehicle. A strong sensitising activity of hydroquinone was indicated by a mean EC3 value of 0.073% or 18 µg/cm2as based on the most reliable test data (Key study: Kimber et al., 1998).In the second LLNA study, possible vehicle effects on the sensitising potential of hydroquinone were investigated by two laboratories. The different vehicles were acetone/olive oil (4:1) (AOO), methylethylketon (MEK), dimethyl formamide (DMF), propylene glycol (PG), dimethyl sulfoxide (DMSO), acetone/physiological saline (1:1) (APS), and acetone and the tested concentration range was 0.1 – 1.0%. PEG and APS were retested at higher concentrations ranging from 2.5 - 10% (results from one laboratory). The following mean EC3 values were found: for acetone 0.08%, for MEK 0.09%, for AOO 0.15%, for DMF 0.21%, for DMSO 0.35%, for PG and APS 1 - 2%. Calculated as µg HQ/cm2 the following EC3 values resulted: for acetone 20, for MEK 22.5, for AOO 37.5, for DMF 52.5, for DMSO 87.5, for PG and APS 250 – 500 µg/cm2. Consequently the sensitising potential was highly dependent on the vehicle covering a range of EC3 values from 0.08 to up to 1 – 2 % (Key study: Lea et al., 1999). Based on both key studies, the EC3 value of 0.07% or 18 µg/cmis considered to be the NOAEL for skin sensitisation. Based on criteria of CLP, the skin sensitisation potency of HQ would be classified as extreme, sensitiser sub-category 1A, under CLP criteria [due to EC3 < 2%].

Further, the sensitising potential of hydroquinone was investigated in a guinea pig maximization test comparable to standard conditions of the OECD Guideline 406. Intradermal induction was performed with a test concentration of 2% followed by a 48-hour occlusive patch with 10% hydroquinone seven days later. After a 14-day interval, challenge was performed by application of an occlusive chamber with 5% hydroquinone to a prepared flank for 24 hrs. A positive skin reaction was observed in seven of the 10 guinea pig maximization test, giving a sensitisation rate of 70% (Key study: Goodwin et al., 1981). Because more than 30% of the animals responded at > 1% injection dose, the results correspond to sub-category 1B, strong sensitiser. Similar results were obtained in another maximisation assay, using an intradermal injection at 2%, topical induction at concentrations of 0.2, 2.0 or 20% hydroquinone on day 7, before an open application challenge with the same concentrations.

The results are relatively consistent with prior publications using the M&K assay (reported in RSS-overview). Based on the doses and % responses reported, the 3 studies would also correspond to a sub-category 1B, as the injection concentration was always > 1% with responses in > 30% of the animals

Overview of available study results

Test type

Species

Result

Conclusion

Test doses

Reference

Key studies

LLNA

Mouse

Positive

Sensitiser, EC3=0.073%

0.1, 0.25, 0.50, 1.0, 2.5% in acetone/olive oil (4:1)

Kimber et al., 1998

LLNA

mouse

Positive

Sensitiser, EC3=0.08% to 1-2%

1sttest: 0.05, 0.1, 0.25, 0.50, 1.0% in various vehicles

2ndtest 2.5, 5.0, 10%

Lea et al., 1999

GPMT

Guinea pig

Positive

Sensitisation rate 70%

Induction: 2% inj, 10% topical

Challenge: 5%

Goodwin et al., 1981

GPMT

Guinea pig

Positive

Sensitisation rate 75% to 100%

Induction: 2% inj, 0.2%, 2% or 20% topical (in 80% acetone)

Challenge: 0.2%, 2% or 20% (in 80% acetone), open application

To-o et al., 2010

Supporting studies

GPMT

Guinea pig

Positive

Sensitisation rate 50%, grading 3a

0.5M inj- 1M ind., (i.e. 5 and 10%)

Van der Walle et al., 1982

GPMT

Guinea pig

Positive

Strong sensitizer

Induction: 2% inj, 1% topical

Challenge: 0.5%.

Response: Strong, 65-80% incidence (M&K, 1969)

Basketter and Goodwin, 1988

GPMT

Guinea pig

Positive

Sensitisation rate 100%

Induction: 2% inj, 1% topical Challenge: 0.5%.

Basketter and Scholes, 1992

a according to Magnusson and Kligman         

The sensitising potential of hydroquinone indicated in the key studies is supported by further positive test results in the Local Lymph Node Assay (LLNA) (Basketter and Scholes, 1992; Kimber et al., 1994), in the Guinea Pig Maximization Test according to Magnusson and Kligman (Van der Walle et al., 1982; Basketter and Goodwin, 1988; Basketter and Scholes, 1992), in the Freund’s Complete Adjuvant Test (FCAT) (Van der Walle et al., 1982), in the Cumulative Contact Enhancement Test (CCET) (Basketter and Goodwin, 1988), the Single Injection Adjuvant Test (SIAT) and the modified Draize test (Goodwin et al., 1981) (all supporting data compiled without detailed evaluation).

 

Human Experience

Human experience on a possible sensitising effect of HQ can be evaluated in a weight of evidence approach.

Several publications report on patch tests performed according to standardized conditions, generally with 48 h application via Finn chambers and reading according to ICDRG criteria after 48 and 72 h, and 4 to 6 days. There was no indication of sensitisation to HQ in patch tests with patients of Finnish dermatology clinics (populations partly overlapping covering a total study period of 1985 to 1996: Tarvainen et al. 1995; Kanerva et al. 1997, 1999), or a group of 54 Finnish hairdressers with work-related skin and respiratory symptoms (Leino et al. 1998). From 65 persons working at a film laboratory (number with exposure to HQ not known) 4 (6.2%) showed a positive patch test reaction to 1% HQ. The vehicle was found to influence the outcome of findings. Whereas no skin reaction was observed with 1% HQ in petrolatum, 1% HQ in water provoked erythema (irritant reaction) and staining possibly due to instability of HQ in aqueous solution (Liden 1989).

After a skin bleaching procedure with a 7-day treatment with a skin bleaching cream (5% HQ, 10% glycolic acid) a 47-year old woman developed an allergic contact dermatitis. Patch test reactions were positive both to the bleaching cream (++) and to 1% HQ (+). In the observed case, presumably an increased skin permeation of HQ existed due to a cosmetic keratolytic pretreatment of the skin, which could have favoured sensitisation (Barrientos et al., 2001).

Overall, despite a long history of use, observations of exposure-related skin sensitisation in humans are not frequent. The literature data on human clinical studies (human patch tests for diagnosis purpose, usually conducted with 1% HQ as part of a standard allergen series) or case reports have been reviewed in section 7.10.4 of the IUCLID, and indicate that hydroquinone is not a significant skin contact allergen in humans. Additional sources (German publications) have been also discussed by the MAK commission (The MAK Collection for Occupational Health and Safety, Volume 10, 1994, http://onlinelibrary.wiley.com/doi/10.1002/3527600418.mb12331e0010/pdf).

The positive levels in patch tests were usually observed at 1% or higher, and were dependent on vehicle used. Irritation reactions were also observed when HQ was applied in water.

The prevalence in professional users (in particular hair-dressers) has been reported in the past to be below 1%.

Other adverse skin effects (ochronosis, irritation) have been associated with high concentrations or overuse, especially in medicinal uses.

Migrated from Short description of key information:
Local lymph node assay (comparable to OECD Guideline 429): mean EC3 0.07% or 18 µg/cm2 (Kimber et al., 1988); the sensitising potential was highly dependent on the vehicle covering a range of EC3 values from 0.08 to up to 1 – 2 % (Lea et al., 1999)
Guinea pig maximization test (comparable to OECD Guideline 406): sensitization rate 70% following intradermal injection at 2%. In another study, similar to OECD 406, with reduced animal numbers, incidence was 75 to 100% depending on the concentration at challenge after an intradermal induction concentration of 2%
Human data (patch tests for diagnosis purpose, case reports, history of use) indicate a low frequency of exposure-related sensitization cases despite a long history of use.
By weight of evidence considering the experimental data in animals, clinical studies in humans and history of use, the substance is considered a skin sensitiser sub-category 1B (see discussion).

Justification for selection of skin sensitisation endpoint:
Positive effects observed in various animals studies and case reports in humans indicate a sensitisation potential. By weight of evidence considering the experimental data in animals, clinical studies in humans and history of use, the substance is considered to be a skin sensitiser sub-category 1B.

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

The experimental results in the mice LLNA and in the guinea-pig M&K indicate a clear sensitizing potential, however the potency seems to differ between both test methods. The LLNA model assesses the ability of the substance to simulate the lymphocyte proliferative response during the induction phase, while the Maximisation test assessed both the induction and the elicitation phases, and may be more reliable in assessing the sensitisation potency of Hydroquinone.

Furthermore the human data (mainly diagnostic patch test data) tend to support that hydroquinone is not a significant human skin sensitizer.

Results in humans and Maximisation assay support classification in sub-category 1B.

According to the criteria of EC directive 1272/2008 and GHS, Hydroquinone is classified as Skin Sensitiser Sub-Category 1B; H317: May cause an allergic skin reaction, based on a weight of evidence.