Reproductive toxicity gases

The data base for GA consists of intraperitoneal and subcutaneous subchronic studies in rats, teratology studies in rats and rabbits, and delayed neuropathy studies in rats and chickens. Deficiencies in the data base include the lack of a multi-generation reproductive toxicity study, a standard toxicity study in a second species, and adequate toxicity studies by the oral exposure route. Although well-designed and well-conducted, the principal study involved a non-oral (intraperitoneal) exposure route. Consequently, overall confidence in the RfD is low. 

Ba, Al, [Ga], Sc, Y, Eu, Ti, [V]) generally distinguished by extreme c or x values nor can pronounced toxicides of heavy metals like Cd be attributed in this way except for abnormally high c values. The generally positive sign of the latter value (c, except for Etf+) renders a link between reproduction toxicity and metal ion addition to nucleic acids unlikely. 

Wickramaratne GA, Foster JR, Ellis MK, and Tomenson JA (1998) Molinate Rodent reproductive toxicity and its relevance to humans - A review. Regulatory Toxicology and Pharmacology 27 112-118. 

No review of subacute, subchronic, or chronic toxicity of chemical warfare nerve agents would be complete without discussion of the significant paper by Munro et al. that reviewed both animal and human studies of the nerve agents tabun (GA), sarin (GB), and VX. These studies included subacute, subchronic, and chronic toxicity studies in animals. Special attention was paid to the phenomenon of Organophosphorus-Induced Delayed Neuropathy (OPIDN). Reproductive toxicity and carcinogenicity tests were reviewed as well as in vitro studies of mutagenicity. Munro et al. s findings can be summarized as follows ... 

Saad, B., N.H. Hanif, M.I. Saleh, N.H. Hasim, A. Abu, and N. Ali. 2004. Determination of o-phenylphenol, diphenyl and diphenylamine in apples and oranges using HPLC with fluorescence detection. Food Chem. 84(2) 313-317. Schmidt, T.C., M. Less, R. Haas, E. von Low, K. Steinbach, and G. Stork. 1998. Gas chromatographic determination of aromatic amines in water solid-phase extraction and derivatization with iodine. 7. Chromatogr. A 810 161-72. Thysen, B., S. K. Varma, and E. Bloch. 1985a. Reproductive toxicity of 2,4-toluenediamine in the rat. 1. Effect on male fertility. 7. Toxicol. Environ. Health 16 6) 753-61. 

Agent GA (Tabun). RfDe = 4 x 10 mg kg d" . A NOAEL was identified in a 90-d study in rats. A total uncertainty factor of 3000 was applied to account for protection of sensitive subpopulations (10), animal-to-human extrapolation (10), extrapolation from a subchronic to chronic exposure (3), and incomplete data base (3). An uncertainty factor of 3 was used to extrapolate from a subchronic to chronic exposure because of the unlikelihood that the LOAEL would have been substantially lower if the exposure had been chronic. A LOAEL-to-NOAEL uncertainty factor was not needed because a NOAEL was used in the derivation. The data base for GA lacks a multigeneration reproductive toxicity study, but because the available evidence indicates that organophosphate cholinesterase inhibitors such as GA are not likely to be reproductive toxins, the missing study was not considered critical. Therefore, a UFd of 3, not the default value of 10, was applied. A Modifying Factor of 3 was applied because the key study involved a nonoral exposure route (intraperitoneal injections). 

DOT CLASSIFICATION 2.2 Label Nonflammable Gas SAFETY PROFILE MUdly toxic by inhalation. Experimental reproductive effects. Mutation data reported. An asphyxiant in high concentrations. At elevated pressures, 50% mixtures with air are combustible although ignition is difficult. When heated to decomposition it emits toxic fumes of F" and CT. See also CHLORINATED HYDROCARBONS, ALIPHATIC and FLUORIDES. 

Human systemic effects by ingestion nausea, hypermotility, diarrhea, agranulocytosis, thrombocytopenia. Human reproductive effects by ingestion menstrual changes. Mutation data reported. A skin irritant. Used as a poison gas. When heated to decomposition it emits toxic fumes of CT and NOx. 

High doses of fluorine gas and hydrogen fluoride in animal studies have resulted in testicular degeneration. The available animal and human data strongly suggest that the reproductive system is a target of fluoride toxicity at high exposure levels. 

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