Application for the Reassessment of a Hazardous Substance under ...

•ATSDR (1997): http://www.atsdr.cdc.gov/toxprofiles/tp88.html•WHO (1993): http://www.inchem.org/documents/jmpr/jmpmono/v93pr05.htm•CCRIS (2008): http://toxnet.nlm.nih.gov/cgi-bin/sis/search - dichlorvosContact genotoxicity of dichlorvosA. Tungul, A.M. Bonin, S. He1 and R.S.U. Baker2Mutagenesis vol. 6 no. 5 pp. 405-408, 1991“Micronuclei induction by dichlorvos in the mouse skin”Toxicology Unit, National Institute of Occupational Health and Safety GPO Box 58,Sydney, New South Wales 2001, Australia 1 Guangxi Medical College Nanning,Guangxi, People's Republic of ChinaMicronucleus (MN) induction in cultured keratinocytes was investigated following skinpainting of HRA/Skh mice with the pesticide, dichlorvos. Whole skin and partiallypurifiedepidermal cells from 5–6 week old male animals were cultured for 4 days invitro after single topical applications of various concentrations of dichlorvos in vivo.Appropriate doses, allowing optimum survival of keratinocytes, were selected followingan initial range-finding experiment. To evaluate MN induction in dividing cells, thecytokinesis-block method was employed. Results showed statistically significant MN atall dose levels in partially-purified epidermal cells and a positive trend with respect todose from 51 to 1033 nmol dichlorvos. A significant increase in MN was also detectablein cultured cells from whole skin, dissociated within as little as 1 h after application ofdichlorvos. Although a number of technical difficulties are associated with the skinmicronucleus method, it has been used successfully in this laboratory to detect severalskin carcinogens of both high and low potency. Since dichlorvos is rapidly absorbedthrough the skin, and can induce MN in skin cells of treated mice, this compound maytherefore be considered to pose a contact hazard for exposed humans.Pletsa V, Steenwinkel MJ, van Delft JH, Baan RA, Kyrtopoulos SA.Cancer Lett. 1999 Nov 15;146(2):155-60―Induction of somatic mutations but not methylated DNA adducts in lambdalacZtransgenic mice by dichlorvos.‖Laboratory of Chemical Carcinogenesis, Institute of Biological Research andBiotechnology, National Hellenic Research Foundation, Athens, Greece.In order to examine the in vivo genotoxic activity of dichlorvos, lambdalacZ transgenicmice (Muta Mouse) were treated i.p. with single (4.4 or 11 mg/kg [b.w.]) or multiple (5x 11 mg/kg [b.w.]) doses of this agent and sacrificed 4 h or 14 days post-treatment forDNA adduct measurement or mutant frequency analysis, respectively. Neithermethylated DNA adducts nor an increase in mutant frequency were detected in the bonemarrow, white blood cells, liver, spleen, lung, brain and sperm cells after the singledoses. However, following multiple dosing a statistically significant 3-fold increase inmutant frequency was observed in the liver, while a non-statistically significant increasewas observed in the bone marrow. In contrast, dimethylsulphate, a model methylatingagent, gave rise to detectable DNA adducts but no increase in mutant frequencyDichlorvos reassessment – application Page 193 of 436