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Assessment of the toxicokinetik behaviour of test substance (CAS 108 -59 -8):

The test substance (molecular weight of 132.12 g/mol) is a liquid (Ciba-Geigy, 1980) with a log Pow of -0.05 (Gestis, 2011), a water solubility of 99 g/L (OECD SIDS, 2006), and a vapor pressure of 0.15 hPa (Gestis, 2011).

Absorption

From the physico-chemical properties of dimethyl malonate (DMM) it can be assumed that it is readily absorbed via mucous membranes. In a combined repeated dose toxicity study/reproduction and developmental screening test, rats were administered 100, 300, and 1000 mg/kg bw test substance by gavage, respectively. No mortality was reported. Histopathology revealed an increased incidence of hepatocellular hypertrophy in the rats at the 1000 mg/kg bw dose group; therefore bioavailability of the test substance after oral administration is indicated (Degussa Ag, 2003, see chapter “repeated dose toxicity”).

In a Buehler Test, which was performed to detect skin sensitizing properties in guinea pigs, no indications of systemic availability after dermal application was detected (Huels AG, 1992). Although the physical state and molecular weight would favor a dermal uptake, the low log Pow (-0,086) and the high water solubility would prevent the test substance to cross the lipid rich environment of the stratum corneum. Dermal uptake for these substances will be low (ECHA GD 7c, 2008).

The test substance itself has a low vapor pressure of 0.15 hPa at 25°C. Moderate log Pow values (between -1 and 4) are favourable for absorption directly across the respiratory tract epithelium by passive diffusion. Due to the high water solubility of DMM it would be effectively removed from the air in the upper respiratory tract. Therefore, a low potential of toxicity of the substance vapor via the inhalative route is considered.

Metabolism

DMM is likely to be metabolized by unspecific (serine-) esterases of different tissues, in particular in the liver to the mono ester and finally to malonic acid and the corresponding alcohol methanol. This is corroborated by the findings of the abiotic hydrolysis, in particular at alkaline pH that can be regarded as qualitatively similar to the hydrolysis catalyzed by unspecific esterases. The hydrolysis products are likely to be metabolized via physiological pathways as the tricarboxylic acid cycle because they are part of the normal intermediate metabolism.

The mammalian metabolism of methanol, a metabolite of DMM, occurs mainly in the liver, where methanol is converted to formaldehyde, which is in turn converted to formate. Formate is then finally converted to carbon dioxide and water. In humans, the conversion to formaldehyde is mediated by alcohol dehydrogenase. In rodents, the reaction occurs mainly via a catalase-peroxide pathway. In rodents, the first step is rate limiting and methanol in turn accumulates in the blood. In primates, the conversion of formate to carbon dioxide is rate-limiting, leading to a disproportionate increase of formate in the blood and sensitive target tissues (OECD, 2004, ICCA HPV dossier on methanol). Methanol exhibits potential hazardous properties for human health (neurological effects, CNS depression, ocular effects, reproductive and developmental effects, and other organ toxicity). The effects of methanol on the CNS and retina in humans only occur at doses at which formate accumulates due to a rate-limiting conversion to carbon dioxide. In primates, formate accumulatian was observed at methanol doses greater than 500 mg/kg bw. Such high methanol exposures could only be produced from DMM doses of more than 1000 mg/kg bw. As there were no indications of a methanol associated toxicity from a well performed repeated dose toxicity study with DMM in rodents (which are, however, known to be less sensitive to methanol toxicity than humans), and because methanol toxicity would not be expected up to doses as high as 1000 mg DMM/kg bw/day, it was concluded that methanol does not make a relevant contribution to the toxicity profile of DMM. Studies on genotoxicity (Ames-Test, chromosome aberration in-vitro) gave no indications of a reactivity of test substance or its metabolites under the test conditions (i.e. no increased mutagenicity or cytotoxicity in treatments with metabolic activation).

Excretion

The methyl moiety of DMM is converted to carbon dioxide and water, which will be excreted by the lung or urine, respectively. Malonic acid is further metabolized via physiological pathways as the tricarboxylic acid cycle.

References

Institut für Arbeitsschutz der Deutschen Gesetzlichen Unfallversicherung (IFA), GESTIS-Stoffdatenbank,Gefahrstoffinformationssystem der Deutschen Gesetzlichen Unfallversicherung (19.04.2011)