Biodisposition of dibromoacetic acid (DBA) and bromodichloromethane (BDCM) administered to rats and rabbits in drinking water during range-finding reproduction and developmental toxicity studies.
Dibromoacetic acid (DBA) and bromodichloromethane (BDCM), by-products of chlorine disinfection of water, were provided in drinking water in range-finding reproductive/developmental toxicity studies (rats) and a developmental toxicity study (BDCM) in rabbits. Studies included absorption and biodisposition of DBA and BDCM, including passage into placentas, amniotic fluid, fetuses (rats and rabbits), or milk (rats). The DBA and BDCM range-finding reproductive/developmental toxicity studies each included 50 Sprague-Dawley rats/sex/group. DBA (0, 125, 250, 500, or 1000 ppm) or BDCM (0, 50, 150, 450, or 1350 ppm) was provided in drinking water 14 days premating through gestation and lactation (63 to 70 days). The developmental toxicity range-finding study included 25 time-mated New Zealand white rabbits/group given 0, 50, 150, 450, or 1350 ppm BDCM in drinking water on gestation days (GDs) 6 through 29. Satellite groups (6 male, 17 female rats/group/study and 4 rabbits/group) were used for bioanalytical sampling. Rats and rabbits had exposure-related reduced water consumption caused by apparent taste aversion to DBA or BDCM, especially in the parental animals at the two highest exposure levels (500 and 1000 ppm DBA; 450 and 1350 ppm BDCM). Female rats consumed slightly higher mg/kg/day doses of DBA than male rats, especially during gestation and lactation; weanling rats consumed the highest mg/kg/day doses. DBA produced detectable and quantifiable concentrations in plasma, placentas, amniotic fluid, and milk. Plasma samples confirmed that rats drink predominately during the dark; this drinking pattern, not accumulation, produced detectable plasma concentrations for 18 to 24 hours/day. No quantifiable concentrations of BDCM occurred in plasma, placentas, amniotic fluid, or milk, suggesting that BDCM is rapidly degraded or metabolized in vivo. DBA (500 and 1000 ppm, rats) and BDCM (450 and 1350 ppm, rats and rabbits) produced secondary toxicity in the parental generation by reducing water consumption, which caused severe exposure-related apparent dehydration, reduced feed intake and weight gain. Reproductive and developmental parameters were essentially unaffected (mating possibly reduced [DBA at 1000 ppm]; exposure-related decreases in body weights of pups secondary to reduced water and feed consumption [DBA at 250, 500, and 1000 ppm; BDCM at 150, 450, and 1350 ppm]). No effects on development of rabbit fetuses occurred at BDCM concentrations as high as 1350 ppm. Results from these preliminary studies, in which DBA and BDCM were provided in the drinking water at concentrations thousands of times higher than those to which humans are exposed, suggest that neither DBA nor BDCM are reproductive/developmental risks for humans.
Christian
M S
MS
Argus Research Laboratories, Inc., Horsham, Pennsylvania 19044, USA.
York
R G
RG
Hoberman
A M
AM
Diener
R M
RM
Fisher
L C
LC
Gates
G A
GA
D000085:Acetates / Q000493:pharmacokinetics* / Q000633:toxicity*; D000818:Animals; D004326:Drinking; D005314:Embryonic and Fetal Development / Q000187:drug effects*; D005260:Female; D005328:Fetal Viability / Q000187:drug effects; D005865:Gestational Age; D008297:Male; D011247:Pregnancy; D011817:Rabbits; D051381:Rats; D012098:Reproduction / Q000187:drug effects*; D012727:Sex Characteristics; D013723:Teratogens / Q000633:toxicity*; D014018:Tissue Distribution; D022882:Trihalomethanes / Q000493:pharmacokinetics* / Q000633:toxicity*; D014881:Water Supply
D000085:Acetates; D013723:Teratogens; D022882:Trihalomethanes; C032707:chlorodibromomethane; C088674:dibromoacetic acid