From EPA Toxicolgical Review of Dichloroacetic acid:
The potential developmental toxicity of DCA was studied in vitro using a rat whole embryo culture system (Saillenfait et al., 1995). Groups of 10 to 20 explanted embryos from Sprague-Dawley rats were cultured for 46 hours in 0, 1.0, 2.5, 3.5, 5.0, 7.5, or 10 mM DCA. A significant, dose-dependent decrease in crown rump length was seen at 3.5 mM and above, while significant, dose-related decreases in yolk sac diameter, head length, somite (embryonic segment) number, protein content, and DNA content were seen at 2.5 mM and above. In addition, several defects which were nonexistent in the 0 and 1.0 mM groups were present to a substantial degree in the higher dose groups. At 2.5 mM, 30% of the embryos had brain defects, 45% had eye defects, and 10% had reduced embryonic axis. At 3.5 mM, 95% had brain defects, 75% had eye defects, 80% had reduced embryonic axis, 15% had reduced first branchial arch, 40% had otic system defects, and 15% had defective flexion. The results indicated a teratogenic effect from DCA in this system.
Developmental Pharmacology and Toxicology
Developmental toxicity of dichloroacetate in the rat
Dr. M. K. Smith 1 *, J. L. Randall 2, E. J. Read 3, J. A. Stober 1
1Environmental Monitoring Systems Laboratory, U.S. Environmental Protection Agency, Cincinnati, Ohio 45268
2Pathology Associates, Inc., Cincinnati, Ohio 45069
3Computer Sciences Corporation, Cincinnati, Ohio 45268
*Correspondence to M. K. Smith, U.S. Environmental Protection Agency, 26 W. Martin Luther King Drive, Cincinnati, OH 45268
Dichloroacetic acid (DCA) is a principal by-product of the chlorine disinfection of water containing humic and fulvic acids, and is also a drug of interest in the therapeutic management of metabolic disorders. The developmental effects of DCA were evaluated in the pregnant Long-Evans rat. In two separate studies, animals were dosed by oral intubation on gestation days 6-15 (plug = 0) with 0, 900, 1,400 1,900 or 2,400 mg/kg/day and 0, 14, 140, or 400 mg/kg/day. The vehicle control was distilled water. Maternal observations included clinical signs, weight change, and gross evaluation of organ weights and uterine contents at necropsy (day 20). Corpora lutea were counted and uteri stained for implantation sites. Live fetuses were examined for external, skeletal, and soft tissue malformations. Seven dams died during treatment (1,400 mg 1/19, 1,900 mg 2/19, 2,400 mg 4/21), and maternal weight gain was reduced at all except the lowest treatment levels. Liver, spleen, and kidney weights increased in a dose-related manner. The mean percentage of resorbed implants per litter was significantly elevated at 900 mg/kg/day. Live fetuses showed dose-dependent reductions in weight and length at doses above 140 mg/kg. Statistically significant frequencies of soft tissue malformations ranged from 2.6% (140 mg/kg) to 73% (2,400 mg/kg). These were principally in the cardiovascular system and predominantly comprised defects between the ascending aorta and the right ventricle. Skeletal malformations were not observed in significant numbers in any dose group. We conclude that the no observed adverse effect level (NOAEL) for the developmental toxicity of DCA in the rat was 14 mg/kg/day, a dose level that produced obvious treatment-related maternal effects. © 1992 Wiley-Liss, Inc.
Received: 22 July 1991; Accepted: 12 February 1992