API Publ 4743:2005 pdf download

API Publ 4743:2005 pdf download.Hazard Narrative for Tertiary-Butyl Alcohol (TBA).
THA did not form aldehydes or kelones by dehydrogcnation and was not a substrate for alcohol dchydrogcnase (Arslanian et al. 1971; Videla et al. 1982) as it lacks thc carbonyl hydrogen required for alcohol dehydrogenase activity (Baker et aL 1982). Further oxidation of 2-methyl.1,2-propancdioi can result in the formation of 2.hydroxyisobutyratc. which can also be further metabolized to form acetone. In both the liemauner ci al. (1998) and the Baker et al. (1982) studies, the doses of TBA were very high (250 to 2000 mg/kg) and the resulting production of acetone in urine was very small. No differences in blood acetone levels were seen in TBA-treatcd male or fcmalc rats (300 mg/kg) compared to controls (Poet et al. 1997). Baker et al. (1982) could not conclude that TBA was the sole source of acetone in rat urine.
In in vitro studies, TBA served usa substrate for rat mixed function oxidases (MFOs) and was dernethylated to yield small amounts of formaldehyde apparently involving the interaction of TBA with hydroxy radicals generated from hydrogen peroxide (Cederbaum and Cohen 1980:
1983). Formaldehyde was not found in the urine of rats or humans following administration of TBA (I3emauer et at. 1998).
Human data regarding the movement of TBA in the body are limited to results obtained from a single volunteer who ingested a gelatin capsule resulting in a dose of 5 mg TIIA/kg (Bernauer ci al. 1998). The major TBA metabolite in the urine of that individual was 2. hydroxyisobutyrate. with smaller amounts 2-methyl-i ,2-propanediol and TI3A glucuronide. In contrast to rats, only trace amounts of TBA sulfate were recovered likely due to species differences in sulfotransferase(s) (Bemauer et al. 1998). No mention was made of the presence of acetone in the urine.
Elimination half-lives ranged from 3.8 hours at doses less than 300 mgkg and were increased to 4.3 and 5 hours in the high-dose female and male rats, respectively. Poet et al. (1997) stated that the elimination of TBA appeared to saturate at higher doses. Other studies have estimated the elimination half-life to be 8 to 9 hours following oral (Thurman ci al. 1980) or intrapcritoneal injection (Bakeret al. 1982). The doses were much higher in these studies than the doses administered by Poet et al. (1997). According to Poet et at., these doses were likely greater than metabolismielimination saturation levels. Saturable has been reported in mice administered TBi by intraperitoneal injection at doses ranging from 5 to 20 mmoles/kg (approximately 360 to 1550 mg/kg) (Faulkner and llussain 1989).
2.3.2 Animal Toxicity Studies
2.3.2.1 Acute and Subacute
The acute toxicity of TBA is low. An oral LDc0 of 3,500 mg/kg in rats (NTP 1995, 1997) and an oral LDc0 of 3,600 mg/kg in rabbits (NTP 1995. 1997) have been reported. Following an intraperitoneal injection, a LD50 of 441 mg/kg was reported in mice (NTP 1995. 1997).
The accumulation of triacyiglycerols (TAGs) in the liver of rats was evaluated to determine if the effects of certain alcohols on hepatic liver metabolism in the rat were related to oxidative metabolism by alcohol dehydrogenase (ADII). Ethanol, n-propanol. and isobutanol are all metabolized through the ADH pathway and induced a fatty liver. TBA, which is not metabolized by ADH. was used to determine if the fatty liver effects were due to oxidation of these alcohols by ADH. Female Wistar rats were administered a single dose of TBA at 25 mmol!kg (1850 mg/kg) via a gastric tube (Beaugc et al. I 981). At 2, 5, and 20 hours following exposure, there were significant increases in blood glucose, blood free fatty acids (FFA), liver TAGs, and liver wet weight. Significant decreases were noted in blood TAGs, blood phospholipids and liver phospholipids. The results indicated that TBA administration induced fatty liver without impairing hepatic fatty acid oxidation.
Male Sprague Dawley rats were exposed to THA at concentrations of 2000 ppm for 3 days or 500 ppm for 5 days (6 hour/day exposures) via inhalation in order to evaluate the changes in the cytochrome P.450 enzyme system in the liver, kidney, and lung (Aarstad et al. 1985). Cytochrome P-450 levels were significantly increased in the kidney but not the liver following inhalation of 500 ppm TBA for 5 days: or in the liver but not the kidney following inhalation of 2000 ppm for 3 days. No significant changes were noted in the cytochrome P-450 levels in the lung following either exposure duration.