National Toxicology Program

National Toxicology Program
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Abstract from Report IMM20603 on 1,5-Naphthalene-Diisocyanate

ABSTRACT

Report on the Assessment of Contact Hypersensitivity of 1,5-Naphthalene-Diisocyanate in Female BALB/c Mice (CAS No. 3173-72-6)

Report Date: April 2011

The following abstract presents results of a study conducted by a contract laboratory for the National Toxicology Program. The findings have not been peer reviewed and were not evaluated in accordance with the levels of evidence criteria established by NTP in March 2009. The findings and conclusions for this study should not be construed to represent the views of the NTP or the U.S. Government.


Abstract

1,5-Naphthalene-diisocyanate is an aromatic diisocyanate used in the automotive industry to produce high-quality polyurethane elastomers, resin, and synthetic rubber for plastic tires (Baur et al., 2001). It has been reported that inhalation of NDI vapors or mists can induce airway disorders such as asthma and other respiratory symptoms (Harries et al., 1979; Alexanderson et al., 1986; Fuortes et al., 1995; Tee et al., 1998). Respiratory sensitizers may also produce hypersensitivity responses in the skin (De Jong et al., 2009); thus, these studies were conducted to determine the sensitizing potential of NDI when applied dermally to female BALB/c mice. The Local Lymph Node Assay was performed to measure the sensitization potential of NDI at 0.025% to 10% (w/v) using methyl ethyl ketone as the vehicle. When compared to the vehicle control, NDI treatment at all concentrations tested (0.025% - 10%) produced statistically significant increases in the draining lymph node cell proliferation. In addition, these increases were all above the level of 3-fold enhancement over the vehicle control, with the exception of the 0.025% NDI treatment group in Study 2. The irritancy potential of NDI was examined using the irritancy assay. NDI at concentrations of 0.1% - 10% produced increases in percent ear swelling at 24 hr following the last exposure when compared to the vehicle control, with statistical significance being consistently observed at concentrations of 0.5% and above.

To clarify whether the positive response observed in the LLNA assay was due to irritancy or if NDI was a contact sensitizer, the Mouse Ear Swelling Test was performed. When sensitized with 0.025% to 0.5% NDI and subsequently challenged with 0.1% NDI, no significant effects on percent ear swelling were observed. However, when NDI at 1% was applied during the challenge phase, sensitization with NDI at 0.1% - 5% produced significant increases in the percent ear swelling at both 24 hr and 48 hr post-challenge when compared to the vehicle irritancy control.

Overall, the results from these studies in BALB/c mice have demonstrated that NDI at 0.05% - 10% produced increases in lymph node cell proliferation that were above the level of 3-fold enhancement over the vehicle control in the LLNA. Furthermore, NDI challenge at 1% induced a significant increase in percent ear swelling when the mice were sensitized with NDI at 0.1% - 5% as evaluated using MEST. In addition, NDI induced significant increases in the IRR assay at 0.5% and above.

References

Baur X., Chen Z., & Marczynski B. Respiratory diseases caused by occupational exposure to 1,5-Naphthalene-Diisocyanate: results of workplace-related challenge tests and antibody analyses. American Journal of Industrial Medicine. 2001. 39: 369-372.

Harries M.G., Burge P.S., Samson M., Newman Taylor A.J., & Pepys J. Isocyanate asthma: respiratory symptoms due to 1,5-nathalene diisocyanate. Thorax. 1979. 34: 762-766.

Alexanderson R., Gustafsson P., Hedenstierna G., & Rosen G. Exposure to naphthalene-diisocyanate in a rubber plant: symptoms and lung function. Arch Environ Health. 1986. 41:85-89.

Fuortes L.J., Kiken S., & Makowsky M. An outbreak of naphthalene diisocyanate-induced asthma in a plastics factory. Arch Environ Health. 1995. 50:337-340.

Tee R.D., Cullinan P., Welch J., Burge P.S., & Newman Taylor A.J. Specific IgE to isocyanates: A useful diagnostic role in occupational asthma. J Allergy Clin Immunol. 1998. 101:709-715.

De Jong W.H., Arts J.H., De Klerk A., Schijf M.A., Ezendam J., Kuper C.F., & Van Loveren H. Contact and respiratory sensitizers can be identified by cytokine profiles following inhalation exposure. Toxicology. 2009 Jul 10;261(3):103-11.


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