Simulated gastric hydrolysis and developmental toxicity of dibutyltin bis(2‐ethylhexyl thioglycolate) in rats

Abstract

Previously, dibutyltin dichloride (DBTC) was the putative toxophore for dibutyltin bis‐alkyl and bis‐thio esters. Recent chemical and toxicological data on dioctyltin bis(2‐ethylhexyl thioglycolate) suggest the thioglycolate esters of alkyltins do not generate the dichloride toxophore. Our results, using 119Sn‐nuclear magnetic resonance (NMR) spectroscopy, demonstrated that dibutyltin bis(2‐ethylhexyl thioglycolate) (DBTE) is hydrolyzed to dibutyltin chloro‐(2‐ethylhexyl thioglycolate) (DBTEC) under simulated gastric conditions. No DBTC was detected. DBTE was administered orally to presumed‐pregnant Sprague–Dawley rats in a corn oil vehicle at 2.5, 8.5, and 25.0 mg/kg/day (Gestation Day 5 [GD5] through GD19). There were no maternal deaths, no treatment‐related statistically significant reductions in feed consumption, maternal body weight or weight gain, or adverse gestational outcomes. Maternal thymus weight was significantly reduced in rats at 25 mg/kg. There were no effects on fetal growth, no dose‐dependent pattern of external, visceral, or skeletal malformations, and no increase in anatomical variations. Based on the obtained experimental data, it is concluded here that DBTE forms DBTEC, not DBTC, in the stomach, and DBTE was not teratogenic nor fetotoxic in rats, a species sensitive to DBTC. The maternal no‐observed‐adverse‐effect level (NOAEL) was 8.5 mg/kg/day, and the developmental NOAEL was 25 mg/kg/day, the high dose. The maternal LOAEL was 25 mg/kg/day based on reduced maternal thymus weight.

Simulated gastric hydrolysis and developmental toxicity of dimethyltin bis(2-ethylhexylthioglycolate) in rats

“…Toxicological read-across from DMTC to DMTE, based on their structural similarity was supported solely by analytical data from the simulated gastric hydrolysis study proven now to have methodological artifacts. The experimental results presented here show the simulated gastric metabolism of DMTE, in failing to hydrolyze in vitro to DMTC, is entirely consistent with results from similar studies with DOTE (Nasshan, 2015b;Costlow et al, 2017) and DBTE (Nasshan, 2015a;Costlow et al, 2021). Results of the developmental toxicity study with DMTE further challenge the applicability of the dialkyltin dichloride to dialkyltin bisthioglycolate read-across in the DMTE case.…”

“…More specifically, Costlow et al, 2017, detected no toxophore DOTC formation following gastric stimulation conditions of DOTE with no developmental toxicity observed in exposed rabbits (Costlow et al, 2017). Additionally, for DBTE, no dibutyl dichloride toxophore was detected following gastric simulation and orally administered DBTE produced no maternal deaths, no treatment-related statistically significant reductions in feed consumption or maternal body weight and no adverse gestational outcomes in rats (Costlow et al, 2021). Therefore, such experimental investigation was also warranted for the organotin compound dimethyltin bis(2-ethylhexyl thioglycolate) (DMTE) to verify its suitable hazard classification based on empirical data on the substance.…”