Developmental Toxicity of Hydroxylamine: An Example of a Maternally Mediated Effect

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Abstract
Hydroxylamine (HA) is an important reducing agent that is used in several industries. HA is a moderate irritant and a powerful inducer of methemoglobinemia. HA has been shown to react readily with DNA in vitro. Several chemical derivatives of HA are potent developmental toxicants, whereas HA has been reported to cause no develop-mentally toxic effects. Since HA and its developmentally toxic derivatives share the presence of a terminal hydroxylamine functional group (−NHOH), and since that functional group has been proposed to be the biologically active portion of the molecule, it was deemed appropriate to re-examine the possible developmental toxicity of HA. Subcutaneous or intravenous injection of pregnant rabbits with 50–650 mg HA·HCl/kg on gestational day 12 caused the death or sacrifice of all rabbits within 30 hours. All maternally injected rabbits exhibited severe cyanosis, presumably due to methemoglobinemia. Histological examination of embryos revealed alterations of the cardiovascular system at 5 hours, but an absence of cell death in limb buds. At 8 hours, all embryos were dead. These effects appear to be secondary to the observed cyanosis in the maternal animals. In order to circumvent the powerful methemoglobinemia-inducing properties of HA, in-tracoelomic injections of 25–200 μg HA·HCl in 5–40 μl of saline were made directly into the chorionic cavity of developing rabbit embryos, thereby bypassing the maternal system. Controls received similar volumes of saline. At doses of ≥ 75 μg, HA·HCl killed 91 percent of injected embryos; among survivors, all exhibited reduced birth weights and 215 exhibited malformations in the craniofacial region and sternum. At doses of 25–50 μg, HA·HCl caused increased resorptions compared with controls; however, surviving fetuses displayed neither malformations nor reduced birth weights. Histological analysis at 4 hours after injection revealed cellular debris in the limb buds; when the antioxidant propyl gallate was co-administered with HA, cellular debris was absent at 4 hours. It is concluded that although HA is a directly acting developmental toxicant if it reaches the embryo, the observed embryolethality seen after subcutaneous injection of pregnant animals is a consequence of the powerful maternal toxicity of HA.