Trimethyl borate

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

ADME Information on the hydrolysis products is displayed below. Both substances are readily absorbed via the oral and inhalation route, methanol via the dermal route as well. Neither substance as a tendency to bioaccumulate, both are rapidly excreted.

BORIC ACID:

Absorption of borates via the oral route is nearly 100%. For the inhalation route also 100% absorption is assumed as worst case scenario. Dermal absorption through intact skin is very low. For risk assessment of borates a dermal absorption of 0.5% is used as a realistic worst case approach. In the blood, boric acid is the main species present. Boric acid is not further metabolised. Borates are distributed rapidly and evenly through the body, with concentrations in bone 2 -3 times higher than in other tissues. Boron is excreted rapidly, 60 with elimination half-lives of 1h in the mouse, 3h in the rat and <27.8 h in humans, and has low potential for accumulation. Boric acid is mainly excreted in the urine.

METHANOL:

Methanol is readily absorbed after inhalation, ingestion and dermal contact and distributes rapidly throughout the body. Metabolism in humans, rodents, and monkeys contributes up to 98 percent of the clearance, with more than 90 percent of the administered dose exhaled as carbon dioxide. Renal and pulmonary excretion contributes only about 2 – 3 percent. The metabolism and toxicokinetics of methanol varies by species and dose. In humans, the half-life time is approximately 2.5 – 3 hours at doses lower than 100 mg/kg bw. At higher doses, the half life can be 24 hours or more (IPCS/WHO, 1977; Kavet and Nauss, 1990).

The mammalian metabolism of methanol occurs mainly in the liver, where methanol is initially converted to formaldehyde, which is in turn converted to formate. Formate is converted to carbon dioxide and water. In humans and monkeys, the conversion to formaldehyde is mediated by alcohol dehydrogenases and basically limited to the capacity of those enzymes. In rodents, the oxidation to formaldehyde predominantly employes the catalase-peroxidase pathway which is of less capacity and rate-limiting. Upon saturation at high doses, methanol accumulates in the blood of rodents and primates. Formaldehyde is further oxidized to formic acid and, finally, formic acid to carbon dioxide (CO2). In primates, the last reaction step, conversion of formate to carbon dioxide by the formyl-tetrahydrofolate synthetase, is of comparably low capacity which may lead to a disproportionate increase of formate in the blood and in sensitive target tissues (such as CNS and the retina) (DFG 1999; IPCS/WHO, 1997; Dorman et al., 1994; Medinsky et al., 1997, Medinsky and Dorman, 1995; Mc Martin et al., 1977).

In humans, when exposed via inhalation up to an air concentration of 0.065 mg/L, no increase of blood methanol is expected. Up to 0.26 mg/L (single or repeated exposure), the methanol blood level is likely to increase 2 to 4- fold above the endogenous methanol concentration in humans, but still remains significantly below 10 mg/L (Lee et al., 1992; NTP, 2003). Air concentrations up to 1.6 mg/L resulted in similar blood methanol levels among rats, monkeys, and humans. However, above 1.6 mg/L, a steep exponential increase occurs in rats, a smaller exponential increase occurs in monkeys, whereas humans exhibit a linear relationship between air concentrations and blood methanol levels. Baseline levels of formate in blood are about 3 to 19 mg/L (0.07 – 0.4 mM) in humans. Toxic blood formate concentrations are reported to be 220 mg/L and higher (> 5 mM formate). Inhalation of about 1.20 mg methanol/L for 2.5 hours contributed only insignificantly to the internal formate pool in monkeys (in the μM-range). This also held true for folate-deficient conditions. After repeated inhalation of 2.6 mg/L for 6 hours/day, 5 days/week, for 1 or 2 weeks, monkeys showed no discernible increase in formate concentration in blood (estimated body burden 200 to 300 mg/kg bw/d). Formate accumulation, however, has been observed in primates upon bolus administration of more than 500 mg Methanol/kg bw (Horton et al., 1992; Medinsky and Dorman, 1995). The critical methanol dose that saturates the folate pathway in humans is estimated to be ≥ 200 mg/kg bw. Based on data produced in monkeys, metabolic saturation in humans is also less likely to happen during inhalation where the dose is distributed over several hours (DFG 1999; IPCS/WHO, 1997; Burbacher et al., 1999).