Methyl salicylate

Endpoint summary

Key value for chemical safety assessment

Skin sensitisation

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (sensitising)

Additional information:

Studies in Animals:

Table 1 summarises the data from skin sensitisation studies on MeS in animals according to a variety of protocols. Concentrations tested ranged from those likely to be used in consumer products up to the undiluted test substance. All maximisation studies in guinea pigs reported MeS as not sensitising. According to the Substance Evaluation (SEV) Conclusion document from March 2021, the Evaluating Member State (France) has considered that the negative Maximisation studies available on MeS had methodological limitations, in particular a low number of animals tested that could decrease the sensitivity of the Maximisation tests (RIFM, 1981, cited in CIR, 2003 and in Lapczynski et al., 2007; Kimber et al., 1991; Klecak et al., 1977).

All LLNA studies at concentrations up to 20% reported MeS as not sensitising. Three studies reported that MeS is sensitising at the higher concentrations of 25% (Montelius, 1994), 50% (Montelius, 1998), or 80% (Adenuga et al., 2012). On the other hand, two studies (Ashby, 1995; Arts, 1996) reported MeS as not sensitising at 25%, while another (Basketter, 1998) reported MeS as not sensitising even at 100%.

The majority of the published LLNA studies describe testing of sets of chemicals during the validation of the LLNA as a regulatory test protocol. MeS was included in such studies as an irritant substance, rather than as a sensitiser. Although MeS is not classified as a skin irritant, it does exhibit a mild degree of skin irritancy. Skin irritancy is reported to be one possible cause of “false positive” results in the LLNA (Basketter et al, 1998; Basketter & Kimber, 2007). Some variation in test results could be due to the different solvent vehicle used in the studies, the concentrations tested and some variations in the protocols used. Overall, the animal studies indicate that MeS can be considered to have at most a weak sensitising potential.

 

Table 1: Skin Sensitisation studies on MeS in animals

Method	Concentration	Species	Result	Reference
Maximisation	Intradermal induction: 2.5% in DOBS/FCA Topical induction: 100% Challenge: 10% in acetone/PEG	Guinea pig	Not sensitising	Kimber, 1991 Basketter, 1992
Maximisation (screening)	Intradermal induction: 5% in water Topical induction: 60% in water Challenge: 20% in water	Guinea pig	Not sensitising	Longobardi, 2001
Maximisation	Intradermal induction: 1% in FCA Topical induction: 40% in acetone Challenge: 10% in acetone	Guinea pig	Not sensitising	RIFM, 1981 (Cited in CIR, 2003)
Maximisation	Intradermal induction: 5% in FCA Topical induction: 25% in petrolatum Challenge: sub-irritant in petrolatum	Guinea pig	Not sensitising	Klecak, 1977
Open epicutaneous	Induction: up to at least 30% Challenge: 1% vehicle not stated	Guinea pig	Minimum sensitising conc. 30%	Klecak, 1977
Open epicutaneous	8%	Guinea pig	Not sensitising	Klecak, 1979, 1985
Closed epicutaneous	Induction: 30% Challenge: 1%	Guinea pig	Not sensitising	Ishihara, 1986
Draize	Induction & challenge: 0.1% in isotonic saline	Guinea pig	Not sensitising	Klecak, 1977
Freund’s Complete Adjuvant	50% in FCA	Guinea pig	Not sensitising	Klecak, 1977
Optimization	Induction: 0.1% in saline or FCA/saline Intradermal challenge: 0.1% in saline Topical challenge: 10% in petrolatum	Guinea pig	Intradermal challenge: 2/20 sensitisation reactions Topical challenge: no sensitisation	Maurer, 1980
LLNA	25, 50, 100% (vehicle not specified)	Mouse	Not sensitising	Basketter, 1998
LLNA	10, 20, 25, 50, 100% in DMF or MEK	Mouse	Sensitising 50% EC3: 28% (DMF)	Montelius, 1994
LLNA	5, 12.5, 25% in AOO	Rat	Not sensitising	Arts, 1996
LLNA	1, 10, 25% in DMF or MEK	Mouse	Sensitising 25% SI 3.0 with DMF SI 7.5 with MEK	Montelius, 1994
LLNA	5, 10, 25% in AOO	Mouse	Not sensitising	Ashby, 1995
LLNA	20% in AOO	Mouse	Not sensitising	Kimber,1998
LLNA	10%	Mouse	Not sensitising	Maurer, 1980
LLNA	5%	Mouse	Not sensitising	Gerberick, 1992
LLNA	20, 40, 80% in 4:1 mixture of acetone and olive oil	Mouse	Sensitising 80% SI > 3 EC3: 48.15	Adenuga, 2012

Studies in Humans:

Volunteer Induction Studies

Results of human volunteer induction studies conducted by RIFM and summarised in Lapczynski et al. (2007) are shown in Table 2. No instances of positive reactions were reported.

 

Table 2: Human Volunteer Sensitisation Studies on MeS

Method	Concentration	Result	Reference
Maximisation	12% in petrolatum	0/25	RIFM, 1976
Maximisation	8% in petrolatum	0/27	RIFM, 1973
HRIPT	1.25% (vehicle not stated)	0/39	RIFM, 1964

Diagnostic Studies

Consumer use of preparations containing low concentrations of MeS has been widespread over many years. A number of diagnostic studies in patients with skin conditions have been reported and summarised in Lapczynski et al. (2007). The results are shown in Table 3. Only very low percentages of positive reactions to MeS were reported in patients with pre-existing dermatitis/eczema. In contrast, the SEV has concluded that 7 out of the 8 diagnostic studies demonstrated positive reactions after patch testing (Romaguera, 1980; de Groot et al., 2000; Rudner, 1977; Ferguson, 1984; Mitchell et al., 1982; Nethercott et al., 1989; Addo et al., 1982; Stingeni et al., 1995). In addition, two individual cases of skin sensitisation to MeS are reported in the literature (Oiso et al., 2004; Hindson, 1977).

 

Table 3: Human Diagnostic Studies on MeS

Number of patients	Tests	MeS Concentration	No. +ve reaction	% +ve reaction	Ref.
4600: (2784 contact dermatitis; 189 dermatitis of hands; 135 photoallergy; 1491 healthy	Patch tests in which ICDRG series were included	2% in petrolatum	6	0.13 (0.19 excluding healthy subjects)	Romaguera, 1980
183	A1 Test® strips or Finn Chambers®	2%		1.6	Rudner, 1977, 1978
241	Finn Chambers®	2% in yellow soft paraffin	3	1.2	Ferguson, 1984
585 eczema patients	Not specified	2% in petrolatum,		3	Mitchell, 1982
19 with eyelid dermatitis	A1 Test® strips or Finn Chambers®	1% in petrolatum		0	Nethercott, 1989
70 with dermatitis other sites	A1 Test® strips or Finn Chambers®	1% in petrolatum		1.4	Nethercott, 1989
197	Closed patch tests	0.05-0.5% in base cream or 99% ethanol	4	2	Takenaka, 1986
1825	“Internationally accepted criteria”	2% in petrolatum	7	0.4	De Groot, 2000
50 with photosensitivity dermatitis with actinic reticuloid syndrome	Closed patch test	2% in paraffin	1	2	Addo, 1982
32 with polymorphic eruption	Closed patch test	2% in paraffin	0	0	Addo, 1982
457 with contact dermatitis	Closed patch test	2% in paraffin	0	0	Addo, 1982
267 health care employees with contact dermatitis	Patch test	2% in petrolatum	0	0	Stingeni, 1995
4	Patch test	2% in olive oil or arachis oil	1	25	Hindson, 1977
1	Closed patch test	2% in olive oil	1	100	Oiso, 2004

Conclusion:

Overall, the weight of evidence from both animal tests and human data suggests that MeS may have, at most, weak skin sensitisation potential. However, the evaluating Member State Competent Authority (MSCA) has considered MeS as a skin sensitiser. In this context, a C&L proposal to classify methyl salicylate as Skin Sens. 1B based on animal and human data was submitted, and then agreed by the Risk Assessment Committee (RAC). Therefore, the substance MeS is now subject to a harmonised classification as Skin Sens. 1B in accordance with the Commission delegated regulation (EU) 2021/849 of 11 March 2021 (i.e., the 17th adaptation to technical and scientific progress). The available studies are considered sufficient to fulfil this endpoint.

 

Short description of key information:

The skin sensitisation potential of MeS has been examined in many studies in several test systems. All maximisation studies in guinea pigs, the majority of studies by other protocols in guinea pigs and the majority of LLNA studies in mice give a non-sensitising result, however three LLNA studies indicated MeS as a moderate sensitiser. No key study has been chosen for this endpoint. Instead, an assessment has been made by weight of evidence, taking into account the most relevant studies in animals as well as human induction and diagnostic studies.

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

There have been no reports of respiratory sensitisation from either the manufacture or the use of MeS over many years of human experience. No experimental information is available or required for this endpoint

 

Short description of key information:

There are no data which indicate that MeS has respiratory sensitisation potential.

Justification for classification or non-classification

Skin sensitisation:

All studies in guinea pigs and all LLNA studies at concentrations up to 20% reported MeS as not sensitising. Three LLNA studies reported MeS as sensitising at higher concentrations of 25, 50 or 80%. On the other hand, two studies reported MeS as not sensitizing at 25%, and another reported MeS as not sensitising even at 100%.

Human volunteer induction studies reported no instances of positive reactions. Consumer use of preparations containing low concentrations of MeS is widespread. In diagnostic studies on patients with skin conditions, only very low percentages of positive reactions to MeS were reported. In contrast, the SEV has concluded that 7 out of the 8 diagnostic studies demonstrated positive reactions after patch testing. In addition, two individual cases of skin sensitisation to MeS are reported in the literature.

The weight of evidence from both animal tests and human data suggests that MeS may have, at most, weak skin sensitisation potential. However, in the context of CLH proposal, the evaluating MSCA has considered MeS as a skin sensitiser.

A harmonised classification as Skin Sens. 1B (H317: may cause an allergic skin reaction) based on animal and human data was submitted, and then agreed by the RAC. Therefore, the substance MeS is now subject to a harmonised classification as Skin Sens. 1B according to the Commission delegated regulation (EU) 2021/849 of 11 March 2021 (i.e., the 17^th ATP) and in accordance with the criteria of UN/EU GHS.

 

Respiratory sensitisation:

There have been no reports of respiratory sensitisation from either the manufacture or the use of MeS over many years of human experience. MeS is therefore not classified for respiratory sensitisation according to the criteria of UN/EU GHS.