The developmental toxicity of bromochloroacetonitrile in pregnant long‐evans rats

Abstract

Bromochloroacetonitrile (BCAN) is a by-product of the chlorine disinfection of water containing natural organic material. Adverse effects of BCAN in an in vivo teratology screen (i.e. neonatal survival assay) gave reason for further investigation into the developmental toxicity of this compound. BCAN was administered orally to pregnant Long-Evans rats on gestation days 6-18 (vaginal plug = day 0). Four groups of approximately 20 females received BCAN at 5, 25, 45 or 65 mg/kg/day in a tricaprylin vehicle. Endpoints assessed at necropsy (day 20) included maternal organ weights, number of corpora lutea and uterine contents (number of implants and fetuses); live fetuses were weighed, measured and subsequently examined for external, skeletal and soft tissue malformations. Gestational maternal weight gain was reduced at 45 and 65 mg kg -1 . Maternal toxicity, manifested as increased organ weights and deaths, occurred at 65 mg kg -1 . Postimplantation loss was elevated at 45 mg kg -1 while total litter loss was observed at both 45 and 65 mg kg -1 . Fetal crown-rump lengths were shorter for all BCAN doses tested and fetal weights were reduced at all but the lowest dose level. The frequency of cardiovascular malformations was increased for all levels of BCAN tested; urogenital and skeletal malformations were observed only at the higher dose levels. This pattern of developmental effects is similar to that seen with trichloro-and dichloroacetonitrile (TCAN and DCAN), closely related compounds examined previously in our laboratory.

Identification of developmentally toxic drinking water disinfection byproducts and evaluation of data relevant to mode of action

“…Accumulation in embryos was higher with tricaprylin vehicle than corn oil vehicle (Gordon et al, 1991). Bromochloro-acetonitrile LE rat, G-tricap ascending aortaright ventricle defect, also interventricular septal defect and levocardia (Christ et al, 1995) ---Metabolism to cyanide does not appear to account for developmental toxicity (Christ et al, 1995;Smith et al, 1988).…”

“…LE rat, G-tricap, screen one dose, with replicate, GD7-15, also maternal and fetal toxicity (Smith et al, 1987) -Metabolism to cyanide does not appear to account for developmental toxicity (Christ et al, 1995;Smith et al, 1988) LE rat, G-tricap, also maternal mortality (nonsignificant), fetal toxicity and malformations (Smith et al, 1989b) Suggestive data: LE rat, G-tricap, screen one dose, GD7-15, 45% of sperm-positive rats not pregnant (possibly due to late preimplantation loss or very early resorptions) in 1 of 2 replicate dose groups (Smith et al, 1987) Trichloroacetonitrile (TCAN) LE rat, G-tricap, also with maternal and fetal toxicity and malformations at higher doses (Smith et al, 1988) -Metabolism to cyanide does not appear to account for developmental toxicity (Christ et al, 1995;Smith et al, 1988) LE rat, G-corn oil (Christ et al, 1996) LE rat, G, accumulation of radioactivity in maternal liver and in fetus from two to three daily doses of 14 C-TCAN was higher for the trichloromethyl carbon (C2) than the cyano carbon. Accumulation in embryos was higher with tricaprylin vehicle than corn oil vehicle (Gordon et al, 1991) LE rat, G-tricap, screen one dose, GD7-15 (Smith et al, 1987) Suggestive data: LE rat, G-tricap, replicate screen one dose, GD7-15, 45% of sperm positive rats not pregnant (possibly due to late preimplantation loss or very early resorption) (Smith et al, 1987) Bromochloro-acetonitrile LE rat, G-tricap, also maternal mortality and fetal toxicity and malformations (Christ et al, 1995) LE rat, G-tricap, screen one dose, GD7-15 (Smith et al, 1987) Metabolism to cyanide does not appear to account for developmental toxicity (Christ et al, 1995;Smith et al, 1988) Dibromoacetonitrile -LE rat, G-tricap, screen one dose, GD7-15 (Smith et al, 1987) Metabolism to cyanide does not appear to account for developmental toxicity (Christ et al, 1995;Smith et al, 1988) SD rat, DW (NTP, National Toxicology Program, 1997) Chloroacetonitrile -LE rat, G-tricap, screen one dose, GD7-15 (Smith et al, 1987) Metabolism to cyanide does not appear to account for developmental toxicity (Christ et al, 1995;Smith et al, 1988) 1,1,3,3,-Tetrachloropropanone -CF-1 mouse, rabbit, G-corn oil, fertility not affected…”

“…With bromodichloromethane, the effect appeared to be an all-or-nothing phenomenon: litters were either fully resorbed or survived with no effects (i.e., no increase in resorptions per surviving litter and no fetal effects) (Bielmeier et al, 2001(Bielmeier et al, , 2004Narotsky et al, 1992Narotsky et al, , 1997a. When the haloacetic acids and haloacetonitriles (trichloroacetic acid, dichloroacetonitrile, trichloroacetonitrile, bromochloroacetonitrile) were tested in Long-Evans rats, they caused full-litter resorption with a dose-related progression of increased (per litter) resorption, malformations, and fetal weight depression in surviving litters (Christ et al, 1995(Christ et al, , 1996Smith et al, 1987Smith et al, , 1988Smith et al, , 1989a. These findings suggest that the partial and full-litter resorptions from these chemicals may be due to direct effects on the embryo or fetus rather than disruption of hormonal maintenance of pregnancy in (Hwang et al, 2002) Human, DW, epi (Cedergren et al, 2002) ---Human, DW, epi (Kallen and Robert, 2000) Human, DW, epi (Magnus et al, 1999)…”

“…Trichloroacetic acid (TCA) SD rat, DW, ventricular and atrial septal defects (Johnson et al, 1998) SD rat, G-water (Fisher et al, 2001) CD-1 mouse, day 8 (3-6 somites), also neural tube, b pharyngeal arch and eye defects (Hunter et al, 1996) SD rat, day 10 (4-7 somites), hypoplasia of prosencephalon, eye defects, decreased yolk sac diameter (Saillenfait et al, 1995) LE rat, G, antagonistic interaction with DCA on resorption (Smith et al, 1991(Smith et al, , 1992b LE rat, G-water, primarily levocardia, also IV septal (Smith et al, 1989a) Has similar potency to its metabolites in mouse embryo culture (Hunter and Rogers, 1999) Dibromochloroacetic acid -SD rat, DW, MTD not achieved (NTP, National Toxicology Program, 2000) CD-1 mouse, day 8 (3-6 somites), yolk sac defects at same concentration as heart defects; also pharyngeal arch, eye; and neural tube defects (Hunter et al, 2006a) --Bromodichloroacetic acid --CD-1 mouse, day 8 (3-6 somites), yolk sac defects at same concentration as heart defects; also pharyngeal arch and eye defects; neural tube defects but NS (Hunter et al, 2006a) --Dichloroacetonitrile LE Rat, G-tricap, primarily levocardia, also interventricular septal defects, also eye defects (Smith et al, 1989b) ---Metabolism to cyanide does not appear to account for developmental toxicity (Christ et al, 1995;Smith et al, 1988) Trichloroacetonitrile (TCAN) LE rat, G-tricap, mainly levocardia, interventricular septal defect and common carotid trunk (Smith et al, 1988) LE rat, G-corn oil, increased but not significant, primarily levocardia, also eye defects (Christ et al, 1996) --Metabolism to cyanide does not appear to account for developmental toxicity (Christ et al, 1995;Smith et al, 1988).…”

Approaching DBP toxicity as a mixtures problem

“…Health effects data can be divided into three study categories: individual DBPs, defined mixtures of a small number of DBPs, and complex mixtures of either concentrated water (extracts) or finished drinking water. Numerous studies of relatively high dose levels of individual DBPs have been performed in experimental animals and have shown toxicologic evidence of carcinogenicity, reproductive effects, developmental effects, and other toxic effects (e.g., George et al, 2000; DeAngelo et al, 1998; Christ et al, 1995; Bull & Kopfler, 1991; NTP, 1989; NTP, 1987; NTP, 1985). A relatively small number of toxicologic studies are available on defined mixtures of DBPs for a variety of effects, including mutagenicity, carcinogenicity, hepatotoxicity, nephrotoxicity, developmental toxicity, neurological effects, and changes in pharmacokinetic behavior (Simmons et al, 2001).…”