INTERA Stakeholder Workshop 18 th of November 2011 Brussels Dimethylfumarate (DMF) case study Araceli Sánchez Jiménez, Eelco Kuipers and Karen S Galea

INTERA Stakeholder Workshop 18 th of November 2011 Brussels In outbreak of contact dermatitis in EU, linked to exposure to DMF Introduction: ‘ the sofa scandal’

INTERA Stakeholder Workshop 18 th of November 2011 Brussels So what is DMF? Used as a biocide to kill moulds, sprayed or in sachets –Leather furniture, shows, clothing Reported to be allergic sensitizer at low levels DMF conc. >0.1ppm banned under Article 13 of the General Product Safety Directive (GPSD) Production of DMF treated products in EU (all concentrations) banned since Still used to treat psoriasis and necrobiosis lipoidica (orally) in EU

INTERA Stakeholder Workshop 18 th of November 2011 Brussels Skin reactions Rantanen et al Gimenez-Arnau et al. 2009

INTERA Stakeholder Workshop 18 th of November 2011 Brussels Why use DMF as a case study pollutant? DMF very topical at the time of pollutant selection –Widespread press coverage –Ongoing court cases Not a ‘classic’ indoor environment pollutant Assess application of integrated approach for dermal exposure

INTERA Stakeholder Workshop 18 th of November 2011 Brussels Full chain for DMF

INTERA Stakeholder Workshop 18 th of November 2011 Brussels Step 1: Define scope of case study: No. people affected by DMF

INTERA Stakeholder Workshop 18 th of November 2011 Brussels Step 1: Health outcome of interest Health effectDermalRespiratoryBothOtherMissing Count78%1%3%0.09%27% No long-term health effects from DMF exposure identified Common health effects - contact dermatitis, skin irritation or acute allergic dermatitis no specific dose-response functions for DMF. contact dermatitis selected as health endpoint Did not consider inhalation or oral routes of exposure.

INTERA Stakeholder Workshop 18 th of November 2011 Brussels Step 2: Identify the main sources of emission (products) Sources - Leather furniture predominates, footwear to a lesser extent, reports also from toys, helmets and other items of clothing. Also from cross-contaminated products Patterns of use - exposure period and frequency dependent on concentration at the time of exposure and sensitivity of individual. Most subjects exposed during short-periods. VariableN totalN missingMeanMedianMinMax Exposure time of sofas (days)

INTERA Stakeholder Workshop 18 th of November 2011 Brussels Step 2: continued DMF exposure modifiers: –Clothes –Body temperature –Perspiration (heat and sweating) –Pressure contact (occlusion and body weight)

INTERA Stakeholder Workshop 18 th of November 2011 Brussels Step 3b: Exposed area, uptake factor and dermal loading mechanism modelling Amount found highly variable, not evenly distributed Due to the inhomogeneous distribution, results are presented in ppm (i.e. μg DMF/gr of product analysed) instead of surface concentration. The material analysed not always layer in contact with skin Concentrations at time of exposure may possibly be higher Ambient factors, temperature and pressure, will affect the release of DMF from the product, with increase amounts released at higher temperatures and pressures.

INTERA Stakeholder Workshop 18 th of November 2011 Brussels DMF concentrations in footwear products Mean of GM=58 ppm

INTERA Stakeholder Workshop 18 th of November 2011 Brussels DMF conc. contaminated furniture Mean of GM=58 ppm

INTERA Stakeholder Workshop 18 th of November 2011 Brussels DMF in products in contact with contaminated furniture 76 % (n=25) < LOD (0.02 ppm) NMeanMinMax Direct Indirect

INTERA Stakeholder Workshop 18 th of November 2011 Brussels Exposure dose –Qp is the mass of the product in contact with the skin (mg). Default values for each body area (A) have been estimated for exposure to leather or textile sofa or leather or textile footwear. –Fc is the concentration of DMF in the product (mg.kg-1). Default factors have been estimated for the concentration of DMF in sofas and footwear. –MF is the modification factor related to the thickness of the clothes worn. We estimated 0.9 for wearing a thick layer (0.4 cm) and 0.99 for wearing a thin layer of clothes (0.1). For bare skin MF=1. –A is the fraction of the body exposed. –time is the number of hours a day exposed to DMF.

INTERA Stakeholder Workshop 18 th of November 2011 Brussels Exposure modelling

INTERA Stakeholder Workshop 18 th of November 2011 Brussels Step 5: Internal dose modelling Two approaches might be considered for internal dose modeling to DMF. –PBPK modeling –Estimations from the uptake factor PBPK modeling –conclude will not be possible for the DMF case study due to the lack of data. Estimations from the uptake factor –Alternatively, the internal dose could be estimated from the uptake factor. –KMS contains skin permeation calculator were skin permeation can be calculated for different substances using molecular weight (144.13) and the LogKoW (0.74).

INTERA Stakeholder Workshop 18 th of November 2011 Brussels Summary Information requiredComments Source of DMFFurniture (sofas) and footwear Amount of DMF in the product Estimated based on limited data from the peer-reviewed literature and AFSSET Exposure modifiersClothing (ignored body T & weight, perspiration rate) Exposure timeEstimated using data from the UK and literature Population exposedLimited data availability Migration rate Assumed 100% of product in contact with skin the can be transferred Surface areaData obtained from the KMS. Uptake fraction Penetration rate based on MW and octanol-water partition coefficient PBTK modellingNo data