Toxicology Letters 199 (2010) 364–371 Contents lists available at ScienceDirect Toxicology Letters journal homepage: www.elsevier.com/locate/toxlet Dermal uptake and excretion of 14 C-toluene diisocyante (TDI) and 14 C-methylene diphenyl diisocyanate (MDI) in male rats. Clinical signs and histopathology following dermal exposure of male rats to TDI H.D. Hoffmann a,∗ , E. Leibold b , C. Ehnes b , E. Fabian a , R. Landsiedel a , A.Gamer a,1 , A. Poole c a Experimental Toxicology and Ecology, BASF SE, 67056 Ludwigshafen, Germany b Product Safety, BASF SE, 67056 Ludwigshafen, Germany c DOW Europe GmbH, Bachtobelstrasse 3, 8810 Horgen, Switzerland article info Article history: Received 8 June 2010 Received in revised form 27 September 2010 Accepted 28 September 2010 Available online 7 October 2010 Keywords: 4,4 ′ -methylene diphenyl diisocyanate 2,4-Toluene diisocyanate 2,6-Toluene diisocyanate Dermal uptake Skin pathology abstract Polyurethanes (PU) are polymers made with diisocyanates such as MDI (4,4 ′ -methylene diphenyl diiso- cyanate) and TDI (2,4-toluene diisocyanate and 2,6-toluene diisocyanate). Investigations have been undertaken with MDI and TDI to assess dermal uptake and resulting systemic exposure. Absorption, distribution and excretion of MDI was studied in rats using a single dermal administration of 14 C-MDI dissolved in acetone at nominal 165 mg/kg body weight and 15 mg/kg bw (4.0 and 0.4 mg/cm 2 ) and intra- dermal injection of 14 C-MDI dissolved in corn oil at nominal 1.4 mg/kg bw. Dermal absorption of 14 C-MDI (at both doses) was low; at or below 1% of the applied dose. Considerable amounts of the applied radioac- tivity were found at the application site which could not be washed off. By intradermal administration of 14 C-MDI approximately 66% of applied radioactivity remained at the application site with approximately 26% recovered in excreta, cage wash, tissues and carcass. The absorption, distribution and excretion of 2,4-TDI was studied in rats following a single dermal administration of radiolabelled 14 C-2,4-TDI at nom- inal 350 mg/kg body weight (12 mg/cm 2 ). Dermal absorption of 14 C-2,4-TDI was at or below 1% of the applied dose. Considerable amounts of the applied radioactivity were found at the application site which could not be washed off. In summary the results show that dermal uptake of MDI and TDI is very low. Due to the chemical reactivity of isocyanates it can be expected that small amounts which might be absorbed will react with tissue constituents directly at the exposed skin area, or will be converted to adducts with biomacromolecules or to biologically inactive oligoureas. Overall it is concluded that, following dermal exposure to MDI and TDI, systemic exposures and resulting toxicity, other than the known sensitization, can be expected to be very low. In addition studies were performed with dermal application of unlabelled 2,4 and 2,6 TDI to check the availability and fate of this chemical on rat skin surface and to assess possible tissue damage. These experiments showed that unchanged test material can be detected on rat skin for up to 8 h if not washed off. Dermal treatment with 2,4 or 2,6 TDI was associated with irritation with increased severity over a 48 h period after washing with a decontaminant solution. © 2010 Elsevier Ireland Ltd. All rights reserved. 1. Introduction MDI (4,4 ′ -methylene diphenyl diisocyanate) and TDI (2,4- toluene diisocyanate and 2,6-toluene diisocyanate) are reactive chemicals used to make a large variety of polymers including polyurethanes (Allport et al., 2003a). The technical use of these compounds provides some potential for exposure at the workplace ∗ Corresponding author at: BASF SE, Experimental Toxicology, Germany; Mandel- ring 32, 67157 Wachenheim, Germany. Tel.: +49 6322 5740. E-mail address: H.D.Hoffmann@web.de (H.D. Hoffmann). 1 Deceased. but with very limited possibilities of exposure for the consumer. As diisocyanates cause both irritation and sensitization on skin and in the respiratory tract (including asthma), workplace expo- sure limits have been established to reduce possible inhalation and dermal exposure. Vapors or splashes of isocyanates are irritant to the eyes (Henschler et al., 1962). Therefore clear recommendations are provided for the use of protective equipment against dermal, inhalative and eye exposure when using or handling these sub- stances (Allport et al., 2003b, 2003e). The chemical reactivity of MDI and TDI required for the technical performance and value of these materials is in the main also responsible for the toxicological effects. When isocyanate groups come into contact with water they are hydrolysed resulting in the formation of amines which imme- 0378-4274/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.toxlet.2010.09.021