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Link to relevant study record(s)

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 substance is likely to be absorbed via the inhalation, 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 and to a lesser extend via the dermal and inhalation route 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

Toxicokinetic behaviour assessment – CAS 23432-62-4

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 substance is likely to be absorbed via the dermal, inhalation and oral route. Hydrolysis is expected to occur rapidly, and based on the physico-chemical parameters of the silanol containing degradation product, absorption of the hydrolysis product via the gastrointestinal tract, and to a lesser extend via the dermal or inhalation route 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.

 

Discussion

There are no studies available in which the toxicokinetic properties of methyl-N-[3-(trimethoxysilyl)propyl]carbamate (CAS 23432-62-4) 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 including toxicological data on the read-across substances, methyl-N-[(trimethoxysilyl)methyl]carbamate (CAS 23432-64-6) and methyl-N-{[dimethoxy(methyl)silyl]methyl}carbamate (CAS 23432-65-7).

Methyl-N-[3 (trimethoxysilyl)propyl]carbamate hydrolyses in contact with water (half-life is 3.0 h at pH 7 and 20-25°C), generating methanol and methyl-N-[3-(trihydroxysilyl)propyl]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, 0.3, and 0.1 h at 20-25 °C, and at pH 2 at 37.5 °C, which is the condition found in the stomach, methyl-N-[3 (trimethoxysilyl)propyl]carbamate is predicted to hydrolyse within 5 s. The ultimate hydrolysis product is (3-aminopropyl)silanetriol. As the predicted half-life at pH 7 and 25 °C for this type of carbamates was calculated to be in the range of many years, this theoretical ultimate hydrolysis product is not taken into account in this assessment. This suggests that systemic exposure to both the parent, methyl-N-[3-(trimethoxysilyl)propyl]carbamate, and to the first hydrolysis product, methyl-N-[3-(trihydroxysilyl)propyl]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-[3-(trimethoxysilyl)propyl]carbamate are 237 g/mol and 4.39E+04 mg/l, respectively. In contrast, the molecular weight and predicted water solubility of the hydrolysis product, methyl-N-[3‑(trihydroxysilyl)propyl]carbamate, are 195 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 0.8 for the parent substance and -2.3 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

An acute oral toxicity study with methyl-N-[3-(trimethoxysilyl)propyl]carbamate is available (BSL Bioservice, 2002). In this study three male and female Wistar rats were treated with 200 or 2000 mg/kg bw by oral gavage using a stepwise procedure. The test substance was applied in cotton seed oil (total application volume 5 ml/kg). No mortality was observed in the 200 and 2000 mg/kg bw dose groups in any sex. There were no changes or differences observed in body weight gains. No clinical signs of toxicity were observed in any animal at any dose level. 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. In conclusion a LD50 >2000 mg/kg bw was derived for male and female rats. Furthermore, a sub-acute repeated dose toxicity study by the oral route is available for the structural analogue substance methyl-N-{[dimethoxy(methyl)silyl]methyl}carbamate (CAS 23432-65-7). In this study altered organ weights of the adrenals and thymus as well as histopathological evaluated lesions in the spleen, thymus, thyroid, testes and epididymides were noted are considered treatment related findings and effects of toxicological relevance. Therefore, the NOAEL for males/females is considered to be 150 mg/kg bw/day and the LOAEL is 500 mg/kg bw/day.This suggests that the registered substance has the potential to be absorbed by the oral route,

The predicted water solubility of the parent (4.39E+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 (≤ 237 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 0.8 of the parent substance compared to -2.3 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.

Dermal

QSAR based dermal permeability prediction (DERMWIN V2.01.2010) using molecular weight, log Kow and water solubility, calculated a dermal penetration rate of 45.5 µg/cm2/h for methyl-N-[3-(trimethoxysilyl)propyl]carbamate and 11.8 µg/cm2/h for the hydrolysis product, methyl-N-[3-(trihydroxysilyl)propyl]carbamate. These values are considered as indicator for a dermal absorption of >80% (high).

Acute dermal toxicity studies are available (BSL, 2003a and BSL, 2003b) for the structural analogue substances, methyl-N-[(trimethoxysilyl)methyl]carbamate (CAS 23432-64-6) and methyl-N-{[dimethoxy(methyl)silyl]methyl}carbamate (CAS 23432-65-7) respectively. In both studies the undiluted test material was occlusively administered to rats for 24 h. The LD50 was determined to be > 2000 mg/kg bw for both substances. 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. With regard to the calculated high dermal absorption potential within this analogue group this shows both substances to be of low toxicity via the dermal route. Therefore low acute dermal toxicity is expected for methyl-N-[3-(trimethoxysilyl)propyl]carbamate.

Inhalation

The vapour pressure of the parent substance (0.06 Pa at 25 °C) and the boiling point (258 °C) indicate that inhalation of the registered substance as a vapour is unlikely. 

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 (Kow) is described. Using this value for methyl-N-[3-(trimethoxysilyl)propyl]carbamate predicts that it will distribute into the main body compartments as follows: fat >> brain > muscle ≈ kidney > liver with tissue: blood partition coefficients of 6.0 for fat and 1.1 to 0.7 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 60 fold lower to fat and comparable for the remaining tissues.

Table 1 Tissue:blood partition coefficients

 

Log Kow

Kow

Liver

Muscle

Fat

Brain

Kidney

Methyl-N-[3 (trimethoxysilyl)propyl]carbamate

0.8

6.31

0.7

0.9

6.0

1.1

0.9

Methyl-N-[3‑(trihydroxysilyl)propyl]carbamate

-2.3

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-[3-(trihydroxysilyl)propyl]carbamate. The molecular weight (195 g/mol) and high water solubility (1E+06mg/l) of the hydrolysis product suggests it will diffuse through aqueous channels, pores and will be widely distributed in the body. However, the log Kow of -2.3 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.

Metabolism

No data are available describing the metabolism of methyl-N-[3-(trimethoxysilyl)propyl]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-[3-(trihydroxysilyl)propyl]carbamate.

Excretion

Methyl-N-[3-(trimethoxysilyl)propyl]carbamate is known to undergo hydrolysis rapidly. The hydrolysis product named above is far more water soluble than the parent chemical and has a molecular weight lower than 500 g/mol. Therefore, the hydrolysis product is expected to be excreted predominantly via the renal route.

Summary

Oral absorption – methyl-N-[3-(trimethoxysilyl)propyl]carbamate ≈ methyl-N-[3 -(trihydroxysilyl)propyl]carbamate
Dermal absorption - methyl-N-[3-(trimethoxysilyl)propyl]carbamate ≈ methyl-N-[3-(trihydroxysilyl)propyl]carbamate
Inhaled absorption – not expected for methyl-N-[3-(trimethoxysilyl)propyl]carbamate

Distribution – methyl-N-[3-(trimethoxysilyl)propyl]carbamate: fat >> brain > muscle ≈ kidney > liver
Distribution – methyl-N-[3-(trihydroxysilyl)propyl]carbamate: kidney ≈ muscle ≈ brain ≈ liver > fat

Metabolism – no data

Excretion via urine – minimal for methyl-N-[3-(trimethoxysilyl)propyl]carbamate, significant for methyl-N-[3-(trihydroxysilyl)propyl]carbamate