Carbamic acid, N-[(dimethoxymethylsilyl)methyl]-, methyl ester

Endpoint summary

Description of key information

No studies are available. Based on molecular structure, molecular weight, water solubility, vapour pressure and octanol-water partition coefficient it can be expected that the submission substance is likely to be absorbed via the dermal and oral route. Hydrolysis is expected to occur rapidly, and based on the physico-chemical parameters of the silanol containing degradation product, absorption via the gastrointestinal tract, dermal or inhalation routes are expected. Due to the high water solubility, the hydrolysis product is expected to be widely distributed in the body. Excretion via the renal route is considered favoured, and test material deposited in the stratum corneum is expected to be sloughed off with the skin cells. Thus, bioaccumulation is expected to be low.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Additional information

There are no studies available in which the toxicokinetic properties of methyl-N-{[dimethoxy(methyl)silyl]methyl}carbamate have been investigated. Therefore, the toxicokinetic behaviour assessment of the substance and its hydrolysis product was assessed from its physico-chemical properties and from the available toxicology studies.

Methyl-N-{[dimethoxy(methyl)silyl]methyl}carbamate hydrolyses in contact with water (half-life is 1.9 h at pH 7 and 20-25°C), generating methanol and methyl-N-{[dihydroxy(methyl)silyl]methyl}carbamate. Acid environments are known to catalyse this abiotic and enzyme-independent reaction and enhance the reaction rate, which is further increased by the body temperature of approximately 37°C present in mammals. Thus, the predicted half-lives at pH 4, 5, and 9 are 0.2, 0.2, and 0.2 h at 20-25°C. At pH 2 at 37.5°C, which is the condition found in the stomach, methyl-N-{[dimethoxy(methyl)silyl]methyl}carbamate is predicted to hydrolyse within 5 s. This suggests that systemic exposure to both the parent, methyl-N-{[dimethoxy(methyl)silyl]methyl}carbamate, and to the hydrolysis product, methyl-N-{[dihydroxy(methyl)silyl]methyl}carbamate, is possible. Hence, this toxicokinetic behaviour assessment will try to predict the behaviour of both these substances. The toxicokinetics of methanol is discussed elsewhere and is not included in this summary.

The molecular weight and the predicted water solubility of methyl-N-{[dimethoxy(methyl)silyl]methyl}carbamate are 193 g/mol and 4.9E+04 mg/L, respectively. In contrast, the molecular weight and predicted water solubility of the hydrolysis product, methyl-N-{[dihydroxy(methyl)silyl]methyl}carbamate, are 165 g/mol and 1E+06 mg/L, respectively. This shows that the hydrolysis product is smaller in size and is more water soluble and, thereby, suggests that it will have greater potential to be absorbed through biological membranes than the parent substance. However, the predicted log Kow values of 1.1 for the parent substance and -1.9 for the hydrolysis product indicate that the hydrolysis product, unlike the parent, is not lipophilic enough to efficiently pass through biological membranes by passive diffusion.

Absorption

Oral

The predicted water solubility of the parent (4.9E+04 mg/L) and the hydrolysis product (1E+06 mg/L) suggests that both substances will readily dissolve in the gastrointestinal fluids. Furthermore, the molecular weight (≤ 193 g/mol) of the substances suggest they may have the potential to pass though aqueous pores or be carried through the epithelial barrier by the bulk passage of water. However, the predicted moderate log Kow values of 1.1 of the parent substance compared to -1.9 of the hydrolysis product indicate that the hydrolysis product, unlike the parent, is not lipophilic enough to efficiently pass through biological membranes by passive diffusion. This suggests that the registered substance does have the potential to be absorbed by the oral route.

An acute oral toxicity study with methyl-N-{[dimethoxy(methyl)silyl]methyl}carbamate is available (BSL Bioservice, 2002). In this acute toxic class method three fasted Wistar rats of each sex were administered one dose of 200 or 2000 mg/kg bw of the test substance (CAS 23432-65-7) in a stepwise procedure via oral gavage. The animals were observed for 14 days after administration. The acute oral LD50 value for males/females was calculated to be greater than 2000 mg/kg bw. No signs of clinical toxicity and no mortalities occurred during the observation period. All animals showed the expected body weight gains over the study period. No treatment related gross necropsy findings were observed.

Furthermore, a sub-acute repeated dose toxicity study by the oral route is available for methyl-N-{[dimethoxy(methyl)silyl]methyl}carbamate. Based decreased organ weights of the adrenals and thymus as well as histopathological evaluated lesions in the spleen, thymus, thyroid, testes and epididymides which are considered treatment related findings and effects of toxicological relevance, the NOAEL for males/females is considered to be 150 mg/kg bw/day. This suggests as well that the registered substance is absorbed by the oral route.

Dermal

An acute dermal toxicity studies is available for methyl-N-{[dimethoxy(methyl)silyl]methyl}carbamate (CAS 23432-65-7) (BSL, 2003). In this study undiluted test material was occlusively administered to rats for 24 h. The LD50 was determined to be > 2000 mg/kg bw. No mortality was observed and no clinical signs of toxicity were observed throughout the observation period in either study. Weight gain of all animals was normal. Beside acute injection of blood vessels in the abdominal region, which is due to the euthanasia injection, no special gross pathological changes were found in any animal. No changes of the skin at the application site were observed. This shows that the registered substance is of low acute toxicity and/or has a low potential to be absorbed by the dermal route.

Further indications can be derived by QSAR based dermal permeability prediction (DERMWIN V2.00.2009) using molecular weight, log Kow and water solubility. A dermal penetration rate of 0.0343 mg/cm²/h and 0.0105 mg/cm²/h were calculated for methyl-N-{[dimethoxy(methyl)silyl]methyl}carbamate and for the hydrolysis product, methyl-N-[3‑(dihydroxy(methyl)silyl)methyl]carbamate, respectively. These values are considered as indicator for a dermal absorption of 80% (high).

Inhalation

The predicted vapour pressure of the parent substance (0.011 hPa at 25°C) and the boiling point (211.2°C) indicates that inhalation of the registered substance as a vapour is unlikely. 

Metabolism

No data are available describing the metabolism of methyl-N-{[dimethoxy(methyl)silyl]methyl}carbamate. However, metabolism of the target substance is considered negligible, since abiotic and enzyme independent hydrolysis is the prominent degradation reaction, leading to the highly water soluble products methanol and methyl-N-{[dihydroxy(methyl)silyl]methyl}carbamate.

Distribution

For blood: tissue partitioning a QSPR algorithm has been developed by De Jongh et al. (1997) in which the distribution of compound between blood and human body tissues as a function of water and lipid content of tissues and the n-octanol: water partition coefficient (K_ow) is described. Using this value for methyl-N-{[dimethoxy(methyl)silyl]methyl}carbamate predicts that it will distribute into the main body compartments as follows: fat >> liver > brain > muscle > kidney with tissue: blood partition coefficients of 11.8 for fat and 1.2 to 0.9 for the remaining tissues. For the hydrolysis product, distribution would be approximately equal to liver, muscle, brain and kidney and negligible to fat. In comparison to the parent product, distribution would be approximately 100 fold lower to fat.

Table 1: Tissue: blood partition coefficients

	Log Kow	Kow	Liver	Muscle	Fat	Brain	Kidney
methyl-N-{[dimethoxy(methyl)silyl]methyl}carbamate	1.1	12.59	0.9	1.0	11.8	1.2	1.0
methyl-N-{[dihydroxy(methyl)silyl]methyl}carbamate	-1.9	0.01	0.5	0.7	-0.1	0.7	0.8

Any absorbed test substance is likely to be in the form of the hydrolysis product, methyl-N-{[dihydroxy(methyl)silyl]methyl}carbamate. The molecular weight (165 g/mol) and high water solubility (1E+06 mg/L) of the hydrolysis product suggest it will diffuse through aqueous channels, pores and will be widely distributed in the body. However, the log Kow of -1.9 indicates the hydrolysis product is not lipophilic enough to distribute into cells and the extracellular concentration may be higher than the intracellular concentration. Accumulation in the body is not favourable for the substance.

Excretion

Methyl-N-{[dimethoxy(methyl)silyl]methyl}carbamate is known to undergo hydrolysis rapidly within the body. The hydrolysis product named above is highly water soluble and has a molecular weight lower than 500 g/mol. Therefore, the hydrolysis product is expected to be excreted predominantly via the renal route.