The following abstract presents results of a study conducted by a contract laboratory for the National Toxicology Program (NTP). The findings have not been peer reviewed and were not evaluated in accordance with the levels of evidence criteria established by the NTP on March 2009 (see http://ntp.niehs.nih.gov/ntp/htdocs/levels/09-3566%20NTP-ITOX-R1.pdf). The findings and conclusions for this study should not be construed to represent the views of the NTP or the US Government.
Isophorone diisocyanate, which is resistant to light discoloration and chemical attack, is used as an intermediate for polyurethanes and as a raw material in paints, varnishes, and elastomers. It was selected for evaluation as a sensitizing agent for contact hypersensitivity in mice.
Isophorone diisocyanate (< 99% purity) was obtained from the Aldrich Chemical Corp., Milwaukee, WI (Lot #02217JT) and was prepared in acetone/olive oil (4:1), which also served as the vehicle. Primary irritancy studies indicated that 1.0% isophorone diisocyanate was the minimum irritating concentration and treatment with 3.0% isophorone diisocyanate resulted in an irritation response nearly twice as great as 1.0%. Female B6C3F1 mice were sensitized dermally to either 0, 0.1%, 0.3%, or 1.0% solutions of isophorone diisocyanate daily for 5 consecutive days and challenged 7 days later with a 3.0% solution. A 0.5% solution of 1-fluoro-2,4-dinitrobenzene (DNFB, Sigma Chem. Corp.; Lot No. 88F-3833; > 99.0% pure as determined by HPLC), was used as a positive control. Site preparation included dermabrasion as well as intradermal injection of Freund's complete adjuvant in some mice. Mice were divided into 10 treatment groups of 8 mice/group as shown in Table 1. The irritancy response was determined by monitoring the extravasation of 125I-bovine serum albumin into the treated area. The contact hypersensitivity response was determined by monitoring the infiltration of 125I-iododeoxyuridine labeled cells into the challenge site.
Study Design: Contact Hypersensitivity Study with Isophorone Diisocyanate
|2 (8)||Baseline Control||+||Vehicle||3.0% IPDI|
|3 (8)||Experimental||+||0.1% IPDI||3.0% IPDI|
|4 (8)||Experimental||+||0.3% IPDI||3.0% IPDI|
|5 (8)||Experimental||+||1.0% IPDI||3.0% IPDI|
|6 (8)||DNFB Positive Control||-||0.5% DNFB||0.5% DNFB|
|7 (8)||DNFB Negative Control||-||Vehicle||0.5% DNFB|
|8 (8)||Baseline Control||-||Vehicle||3.0% IPDI|
|9 (8)||Experimental||-||0.3% IPDI||3.0% IPDI|
|10 (8)||Experimental||-||1.0% IPDI||3.0% IPDI|
note: IPDI = Isophorone diisocyanate; FCA = Freund's complete adjuvant; DNFB = 1-fluoro-2,4-dinitrobenzene
There were no treatment-related effects on survival or body weights. Hypersensitivity responses as determined using the radioisotope procedure. A statistically significant hypersensitivity response was elicited in mice using a sensitizing concentration of 1.0% and a challenge concentration of 3.0%, with or without pretreatment with Freund's complete adjuvant (Groups 5 and 10). The positive control group (6) produced a statistically significant contact hypersensitivity response at a sensitizing and challenge concentration of 0.5% DNFB.
Under these experimental conditions, a contact hypersensitivity response to isophorone diisocyanate was observed in mice whether or not the site of sensitization was prepared using Freund's complete adjuvant.