title: Oxime silanes: structure/toxicity relationships.
abstract: Acute and repeated oral and dermal rat toxicology studies of standard designs were conducted on four methyl ethyl ketoxime (MEKO) silanes and four methyl isobutyl ketoxime (MIBKO) silanes. Each compound contained either MEKO or MIBKO groups (but not both) and either a single methyl, vinyl, or phenyl group (trifunctional oxime silane), two methyl groups or a methyl and vinyl group (difunctional oxime silane), or no nonoxime group (tetrafunctional oxime silane) attached to the central silicon atom. All compounds caused transient narcosis and anemia, with oral exposure associated with the hydrolyzed oxime groups. Difunctional oxime silanes, containing both a methyl and a vinyl group, caused degeneration of the seminiferous tubules of the testes following oral administration. Serial testicular histopathology indicated the effect originated at the level of the spermatocyte, resulting in a wave of cellular depletion of later maturation stages of spermatogenesis. Spermatogenesis gradually recovered but function was not evaluated. Tetrafunctional oxime silanes, trifunctional oxime silanes, including those containing a single methyl or vinyl group, or difunctional oxime silane containing two methyl groups did not affect the testes, indicating that both a methyl and vinyl group needs to be present on the oxime silane molecule for testicular toxicity. The testicular toxicity appears to be associated with the methyl/vinyl silane portion and not the oxime portion of the oxime silane molecule. With the exception of the methyl/vinyl difunctional oxime silanes, the silane portion of oxime silanes does not appear to contribute any significant toxicity to these compounds.
authors.affiliation: Adolor Corporation, Exton, Pennsylvania, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Derelanko
authors.forename: George M
authors.initials: GM
authors.lastname: Rusch
mesh_terms: D000279:Administration, Cutaneous; D000284:Administration, Oral; D000740:Anemia / Q000097:blood / Q000139:chemically induced*; D000818:Animals; D002074:Butanones / Q000633:toxicity; D003432:Cross-Linking Reagents / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004906:Erythrocyte Count; D005260:Female; D007928:Lethal Dose 50; D008297:Male; D015394:Molecular Structure; D010091:Oximes / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D012821:Silanes / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D013091:Spermatogenesis / Q000187:drug effects; D013329:Structure-Activity Relationship; D053608:Stupor / Q000139:chemically induced*; D013737:Testis / Q000187:drug effects* / Q000473:pathology
chemical_list: D002074:Butanones; D003432:Cross-Linking Reagents; D010091:Oximes; D012821:Silanes; C104767:2-butanone oxime