Scientific Committee on Consumer Products
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`SCCP
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`OPINION ON
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`Toluene
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`(its use as a solvent in nail cosmetics)
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`The SCCP adopted this opinion at its 15th plenary of 15 April 2008
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`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2193 - 1/9
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`Opinion on toluene (its use as a solvent in nail cosmetics)
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`SCCP/1170/08
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`About the Scientific Committees
`Three independent non-food Scientific Committees provide the Commission with the
`scientific advice it needs when preparing policy and proposals relating to consumer safety,
`public health and the environment. The Committees also draw the Commission's attention
`to the new or emerging problems which may pose an actual or potential threat.
`
`They are: the Scientific Committee on Consumer Products (SCCP), the Scientific Committee
`on Health and Environmental Risks (SCHER) and the Scientific Committee on Emerging and
`Newly Identified Health Risks (SCENIHR) and are made up of external experts.
`
`In addition, the Commission relies upon the work of the European Food Safety Authority
`(EFSA), the European Medicines Evaluation Agency (EMEA), the European Centre for
`Disease prevention and Control (ECDC) and the European Chemicals Agency (ECHA).
`
`
`
`SCCP
`Questions concerning the safety of consumer products (non-food products intended for the
`consumer).
`In particular, the Committee addresses questions related to the safety and allergenic
`properties of cosmetic products and ingredients with respect to their impact on consumer
`health, toys, textiles, clothing, personal care products, domestic products such as
`detergents and consumer services such as tattooing.
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`Scientific Committee members
`Claire Chambers, Gisela Degen, Ruta Dubakiene, Bozena Jazwiec-Kanyion, Vassilios
`Kapoulas, Jean Krutmann, Carola Lidén, Jean-Paul Marty, Thomas Platzek, Suresh Chandra
`Rastogi, Jean Revuz, Vera Rogiers, Tore Sanner, Günter Speit, Jacqueline Van Engelen, Ian
`R. White
`
`Contact
`European Commission
`Health & Consumer Protection DG
`Directorate C: Public Health and Risk Assessment
`Unit C7 - Risk Assessment
`Office: B232 B-1049 Brussels
`Sanco-Sc6-Secretariat@ec.europa.eu
`
` ©
`
` European Commission 2008
`(ISSN)
`
`The opinions of the Scientific Committees present the views of the independent scientists
`who are members of the committees. They do not necessarily reflect the views of the
`European Commission. The opinions are published by the European Commission in their
`original language only.
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`http://ec.europa.eu/health/ph_risk/risk_en.htm
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`

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`Opinion on toluene (its use as a solvent in nail cosmetics)
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`SCCP/1170/08
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`ACKNOWLEDGMENTS
`
`Dr. C. Chambers
`Prof. G. Degen
`Dr. B. Jazwiec-Kanyion
`Prof. V. Kapoulas
`Prof. J.-P. Marty
`Prof. T. Platzek
`Dr. S.C. Rastogi
`Prof. J. Revuz
`Prof. V. Rogiers
`Prof. T. Sanner
`Dr. J. van Engelen
`Dr. I.R. White
`
`(rapporteur)
`
`(Chairman)
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`
`
`Keywords:
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`SCCP, scientific opinion, toluene, directive 76/768/ECC, CAS 108-88-3,
`EINECS 203-625-9
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`Opinion to be cited as: SCCP (Scientific Committee on Consumer Products), Opinion on
`toluene, 15 April 2008
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`Opinion on toluene (its use as a solvent in nail cosmetics)
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`SCCP/1170/08
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`TABLE OF CONTENTS
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`5
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`ACKNOWLEDGMENTS
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`1. BACKGROUND
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`TERMS OF REFERENCE
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`2.
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`3. OPINION
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`4. CONCLUSION
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`5. MINORITY OPINION
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`6. REFERENCES
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`Opinion on toluene (its use as a solvent in nail cosmetics)
`
`
`SCCP/1170/08
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`1. BACKGROUND
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`Council Directive 2003/15/EEC amended Directive 76/768/EEC introducing Article 4b. It
`states that “the use in cosmetic products of substances classified as carcinogenic,
`mutagenic or toxic for reproduction, of category 1, 2 and 3, under Annex I to Directive
`67/548/EEC shall be prohibited. To that end the Commission shall adopt the necessary
`measures in accordance with the procedure referred to in Article 10(2). A substance
`classified in category 3 may be used in cosmetics if the substance has been evaluated by
`the SCCNFP and found acceptable for use in cosmetic products.”
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`Toluene is classified as a CMR1 category 3 substance, toxic for reproduction. The substance
`is not regulated in any Annex to the Cosmetics Directive nor has it been evaluated before
`for cosmetic usage.
`
` A
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` dossier for the continued use of toluene as a solvent in certain nail products was
`submitted by COLIPA2.
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`The Scientific Committee on Consumers products (SCCP) adopted by its 9th plenary meeting
`on 10 October 2006 an opinion (SCCP/1029/06) on toluene with the following conclusion:
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`"For the present evaluation, measurements for two situations of nail product use were
`available:
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`toluene air levels of 1 - 4 ppm
`- Home use conditions (non-ventilated rooms):
`- Client exposure in (ventilated) professional nail studios: 0.26 ppm
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`The duration of exposure is less than 30 min (typical application times 10-20 min). This
`exposure situation has been viewed in comparison to:
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`a) consumer exposure as characterized in the EU report on toluene (for two scenarios
`[U1 and U3A], for which there are at present no restrictions), and
`b) occupational exposure limits (OEL) set for continuous 8 hour exposures where risks
`from levels of 25 to 50 ppm are considered as acceptable.
`
`
`This comparison demonstrates that occasional consumer exposure to toluene present in nail
`cosmetics where the exposure may be within the range of 1 to 4 ppm can be considered as
`safe.
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`Although specific information related to the effects in children is limited and because of the
`low and occasional exposure, the SCCP is of the opinion that the presence of toluene as a
`solvent in nail cosmetics does not pose a risk to the health of all groups of consumers,
`independent of their age.
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`This conclusion is based on an exposure driven evaluation of both, acute inhalation effects
`and reproductive toxicity."
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`As part of the implementation of this opinion a discussion took place with stakeholders.
`From this discussion some questions were raised:
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`1.
`
`It is stated that "penetration through the nail plate is nil or minimal" (3.4.1. Cosmetic
`exposure p. 10). However, this assumption was questioned by member states and
`industry was asked to provide documentation to support this statement.
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`1 CMR: carcinogenic, mutagenic or toxic to reproduction
`2 COLIPA: European Cosmetic Toiletry and Perfumery Association
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`SCCP/1170/08
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`Opinion on toluene (its use as a solvent in nail cosmetics)
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`From the consumer exposure scenarios (U1 = gluing and U3A = car maintenance (car
`polishing)) in the EU Risk Assessment Report on toluene, which were used to compare
`the actual consumer exposure, when toluene is used as a solvent in nail products the
`exposure was 1.89 ppm and 2.66 ppm respectively. These exposures resulted in a
`MOS of 21 and 15 for acute effects such as headache and dizziness, and of 40 and 28
`for functional performance. For the same scenarios the MOS for reproductive toxicity
`by inhalation were 317 and 225, respectively. Questions were raised as to whether the
`MOS should be higher also for acute effects such as headache, dizziness and functional
`performance.
`3. Whether a content of 25% really was technical needed.
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`The current submission from industry is a response to questions 1 and 3 above.
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`2.
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`2. TERMS OF REFERENCE
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`1. Does the SCCP consider that the penetration through the nail plate is practically nil
`taking into account the data provided or does the SCCP have any other information
`that can document this assumption?
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`Considering that toluene is a CMR 3 substance and assuming also a MOS of 100 or
`above for the acute effects like headache, dizziness and functional performance, is it
`possible for the SCCP to calculate a concentration for the specific use in cosmetic
`products?
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`2.
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`
`Opinion on toluene (its use as a solvent in nail cosmetics)
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`SCCP/1170/08
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`3. OPINION
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`3.1. Penetration through the nail plate
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`With regard to the possibility of ungual penetration of toluene from nail products, two
`factors have to be considered: absorption though nail plate and/or skin horny layer and
`evaporation of the volatile chemical.
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`Absorption through the nail plate:
`
`In vitro subungual penetration testing using human fingernail was first published by Walters
`using a closed reservoir system in 1981 (1); and by Franz using an open reservoir system in
`1992 (2). This methodology was adapted from the in vitro percutaneous absorption test
`using human skin (3).
`
`In the scientific literature, there is only one published study on subungual penetration of
`solvents; the solvents studied were water and a series of alkanols (4). Data from this study
`suggest that the nail behaves like a hydrogel of high ionic strength to the polar and
`semipolar alcohols. The more hydrophobic a compound is, the lower are the permeability
`rates, apparently linked to decreased partitioning into the complex matrix of the nail plate.
`This was supported by research by Mertin et al. on subungual penetration of drug
`substances (5), also indicating that nail plates constitutes a hydrophilic gel membrane
`rather than a lipophilic partition membranes as it is the case for the stratum corneum.
`Another recently published study with regard to nail permeability is on the hydrophobic
`substance dibutylphthalate (6); it reports ungual penetration at the limit of chemical
`detection upon application of neat product for several days (max. mean flux 3 µg/cm2/h).
`Experimental data on the subungual penetration of toluene itself are lacking, yet it can be
`concluded from the experimental data available on other chemical substances that such a
`study would also produce little or no subungual penetration due to the hydrophobicity of the
`substance.
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`Considering this low potential of hydrophobic chemicals for nail penetration, the values
`obtained in a study on toluene absorption through human skin (7) can be regarded as a
`worst case for ungual penetration; it revealed that toluene is absorbed slowly through
`human skin, with absorption rates ranging from 14 to 23 mg/cm2-hour. In studies where
`comparisons between different exposure routes were made (e.g. 8), the amount of toluene
`absorbed through the skin was considerably less than the amount absorbed following
`inhalation exposure.
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`Evaporation:
`The assumption that penetration of toluene through the nail plate is nil or minimal, is
`further supported by consideration of its physicochemical properties. Toluene has a low
`vapour pressure (28.4 mm Hg at 25°C) that will result in extensive volatilization (9) upon
`application of toluene-containing nail products, thereby rapidly reducing the fraction of the
`substance available for ungual penetration.
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`3.2. Acute effects of toluene
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`With regard to effects of Toluene (classified toxic to reproduction, Cat. 3) on reproductive
`toxicity, a MOS value of ≥ 100 is needed to account for uncertainty in laboratory animal-to-
`human extrapolation as well as intra-individual variations. Based on a NOAEC of 600 ppm or
`2,250 mg/m3 for fertility and development (see SCCP Opinion on Toluene of 10 October
`2006, ref. 10) and the worst case of consumer exposure to toluene from nail products (4
`ppm), a MOS of 150 is calculated and considered to be clearly sufficient in light of the fact
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`SCCP/1170/08
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`Opinion on toluene (its use as a solvent in nail cosmetics)
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`that use of such products only leads to short-term exposure.
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`With regard to the acute effects of toluene, the SCCP does not see the need to set an MOS
`of 100 or above for the following reasons:
`– Such a MoS would contain an uncertainty factor to account for laboratory animal-to-
`human interspecies differences, which is not necessary because the evaluation is
`based on human data.
`– These human data were used to set occupational exposure limits (OEL) to protect
`against the most sensitive endpoint, i.e. effects on the central nervous system under
`regular prolonged exposure. OELs for toluene of 25 and 50 ppm are now in force in
`various countries for an 8-hour work-shift (time weighted average). Exposure to
`toluene in nail products is infrequent and short by comparison, and toluene levels
`during home use of such products containing 25% Toluene do not exceed 4 ppm.
`– There are no recommendations for restrictions of consumer exposure made in the EU
`report on toluene (11) for two scenarios [U1 for gluing and U3A for car
`maintenance/polishing]. These exposures of 7.1 and 10 mg/m³ [corresponds to 1.9
`and 2.7 ppm] resulted in a MOS of 21 and 15 for acute effects such as headache and
`dizziness, and of 40 and 28 for functional performance and where not considered to
`be of concern.
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`As a consequence, the short term exposure from nail products containing 25% toluene is
`not considered to be of concern with regard to acute neurological effects.
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`4. CONCLUSION
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`1.
`
`Taking into account the available data on ungual penetration of chemical substances
`and the physico-chemical properties of toluene, the SCCP is of the opinion, that the
`penetration of toluene can reasonably be expected to be practically nil .
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`2.
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`
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`Taking into account the available scientific data, the short-term exposure to toluene
`from nail products containing 25% toluene is not considered to be of concern with
`regard to acute neurological effects. Since the risk assessment is based on human
`data, a MoS of ≥10 is acceptable.
`
`
`In summary, the SCCP is of the opinion that inclusion of toluene up to 25% is safe from the
`general toxicological view in nail cosmetics used as intended in adults and children.
`However, the SCCP would like to point out that there is a foreseeable risk of increased
`inhalation by children as part of the normal playing behaviour from cosmetics promoted as
`children's toys. Therefore, the use of toluene in such products is not considered appropriate.
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`5. MINORITY OPINION
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`Not applicable
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`6. REFERENCES
`
`1. Walters KA et al. (1981) Physicochemical characterization of the human nail: I.
`Pressure sealed apparatus for measuring nail plate permeabilities. J Invest. Dermatol.
`76: 70-79.
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`2.
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`3.
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`SCCP/1170/08
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`Opinion on toluene (its use as a solvent in nail cosmetics)
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`Franz TJ (1992) Absorption of amorolfine though human nail. Dermatol. 184 (suppl 1):
`18-20.
`Franz TJ (1975) Percutaneous absorption: on the relevance of in vitro data. J Invest.
`Dermatol. 64: 190-195
`4. Walters KA et al. (1983) Physicochemical characterization of the human nail:
`permeation pattern for water and the homologous alcohols and differences with
`respect to the stratum corneum. J Pharm Pharmacol 35: 28-33.
`
`5. Mertin D, Lippold BC (1997) In-vitro permeability of the human nail and of a keratin
`membrane from bovine hooves: influence of the partition coefficient octanol/water and
`the water solubility of drugs on their permeability and maximum flux. J Pharm
`Pharmacol. 49: 30-34
`Jackson EM (2008). Subungual penetration of dibutyl phthalate in human fingernails.
`Skin Pharmacol Physiol. 21(1):10-14.
`7. Dutkiewicz T, Tyras H (1968) Skin absorption of toluene, styrene and xylene by man.
`Br J Ind Med 25:243.
`8. Sato A, Nakajima T (1978) Differences following skin or inhalation exposure in the
`absorption and excretion kinetics of trichlorethylene and toluene. Br J Ind Med 35:43-
`49.
`EPA: TOXICOLOGICAL REVIEW OF TOLUENE (CAS No. 108-88-3) In Support of
`Summary Information on the Integrated Risk Information System (IRIS) September
`2005, U.S. Environmental Protection Agency, Washington D.C., EPA/635/R-05/004
`10. SCCP opinion on Toluene (its use as a solvent in nail cosmetics), 10. October 2006
`
`European Union Risk Assessment Report. Toluene. Final report. Volume 30. Institute for
`Health and Consumer Protection, European Chemicals Bureau, EUR 20539, 2003
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`9.
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