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Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Remarks:
Although the study was not conducted according to the recommended guidelines, it provides scientific valid information to assess the elimination pattern of the substance.
Objective of study:
excretion
Principles of method if other than guideline:
Adult white rats (5 to 9 months old) of an inbred Oregon State Wistar strain were used. The aqueous solutions of sodium acetate were administered to the rats by means of a stomach tube. After the acetate-C14 was administered, the rat was placed in a Delmar metabolism cage and the CO2 was trapped by sodium hydroxide solution. The sodium hydroxide solution from the CO2 trap was changed periodically and was analyzed for radioactivity after conversion of CO2 to BaCO3. The BaCO3 was filtered onto a glass fiber disk, washed and dried and the radioactivity counted. The urine samples were collected and clarified by centrifugation at low speed. The radioactivity in the faeces was obtained by extracting the faeces with a sufficient volume of 50% ethanol. The solid materials were centrifuge out and an aliquot of the supernatant was analysed for radioactivity.
GLP compliance:
no
Radiolabelling:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Route of administration:
oral: gavage
Vehicle:
water
Duration and frequency of treatment / exposure:
Single dose
Details on excretion:
From 79 to 95% of orally administered acetate-14C was recovered in the form of 14CO2. Only a small amount of the radioactivity was found in the urine and faeces. The radioactivity recovered from excreta during the first 24-h period was considerably less from the males than from the females. Male rats apparently tend to fix more of the radioactivity in the body tissues, and the acetate carbons were not turned over as rapidly as in the females.

There are two separate rates for the elimination of 14CO2. The initial rate of elimination (1 to 8 hours postmedication) is very rapid and has a biological half-life of 4 to 6 hours, followed by a much slower rate of elimination (half-life of about 25 hours). The appearance of two separate rates of 14CO2elimination represents two routes of metabolism of the acetate carbons. The initial rate of elimination is probably due to the direct reaction of acetate with CoA-SH to form acetyl-CoA, which subsequently is oxidised to CO2through the TCA cycle. In the intact animal, the CO2would be present in the form of blood bicarbonate and as the blood bicarbonate is turned over, there is a subsequent release of CO2from the lungs. The slower, secondary rate of elimination is probably derived from acetate carbons which are incorporate into other metabolites, such as fatty acids and amino acids and are subsequently catabolised to CO2.

Conclusions:
From 79 to 95% of orally administered acetate-14C was recovered in the form of 14CO2. Only a small amount of the radioactivity was found in the urine and faeces. The radioactivity recovered from excreta during the first 24-h period was considerably less from the males than from the females. Male rats apparently tend to fix more of the radioactivity in the body tissues, and the acetate carbons were not turned over as rapidly as in the females.
Executive summary:

Adult white rats (5 to 9 months old) of an inbred Oregon State Wistar strain were used. The aqueous solutions of sodium acetate were administered to the rats by means of a stomach tube. After the acetate-C14was administered, the rat was placed in a Delmar metabolism cage and the CO2was trapped by sodium hydroxide solution. The sodium hydroxide solution from the CO2trap was changed periodically and was analyzed for radioactivity after conversion of CO2to BaCO3. The BaCO3was filtered onto a glass fiber disk, washed and dried and the radioactivity counted. The urine samples were collected and clarified by centrifugation at low speed. The radioactivity in the faeces was obtained by extracting the faeces with a sufficient volume of 50% ethanol. The solid materials were centrifuge out and an aliquot of the supernatant was analysed for radioactivity.

From 79 to 95% of orally administered acetate-14C was recovered in the form of 14CO2. Only a small amount of the radioactivity was found in the urine and faeces. The radioactivity recovered from excreta during the first 24-h period was considerably less from the males than from the females. Male rats apparently tend to fix more of the radioactivity in the body tissues, and the acetate carbons were not turned over as rapidly as in the females.

There are two separate rates for the elimination of 14CO2. The initial rate of elimination (1 to 8 hours postmedication) is very rapid and has a biological half-life of 4 to 6 hours, followed by a much slower rate of elimination (half-life of about 25 hours). The appearance of two separate rates of 14CO2elimination represents two routes of metabolism of the acetate carbons. The initial rate of elimination is probably due to the direct reaction of acetate with CoA-SH to form acetyl-CoA, which subsequently is oxidised to CO2through the TCA cycle. In the intact animal, the CO2would be present in the form of blood bicarbonate and as the blood bicarbonate is turned over, there is a subsequent release of CO2from the lungs. The slower, secondary rate of elimination is probably derived from acetate carbons which are incorporate into other metabolites, such as fatty acids and amino acids and are subsequently catabolised to CO2.

Endpoint:
basic toxicokinetics in vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH
Triacetoxyvinylsilane undergoes rapid hydrolysis in aqueous to acetic acid and the corresponding trisilanol. Trisilanols undergo continuous condensation reactions to produce higher molecular weight siloxanes which are biologically unavailable. Therefore, the toxicity of triacetoxyvinylsilane is due to the hydrolysis product acetic acid and hence, its toxicokinetics is essential in the triacetoxyvinylsilane systemic exposure. Acetic acid and sodium acetate are grouped together because of their close structural relationship (US EPA officially recognises acetic acid and acetates as a subcategory), and thus, sodium acetate has comparable properties with acetic acid.
See attached the reporting format.
Reason / purpose for cross-reference:
read-across source
Details on excretion:
Based on the experimental results obtained with the supporting substance sodium acetate in male and female rats, the read-across approach was applied and similar results on excretion were expected with triacetoxyvinylsilane hydrolysis product acetic acid:
Most of orally administered acetic acid-14C is expected to be recovered in the form of 14CO2. Only a small amount of the radioactivity would be found in the urine and faeces. The radioactivity recovered from excreta during the first 24-h period is expected to be considerably less from the males than from the females. Male rats apparently tend to fix more of the radioactivity in the body tissues, and the acetate carbons were not turned over as rapidly as in the females.

Based on the experimental results obtained with the supporting substance sodium acetate in male and female rats, the read-across approach was applied and similar results on excretion were expected with triacetoxyvinylsilane hydrolysis product acetic acid:

There are two separate rates for the elimination of14CO2. The initial rate of elimination is very rapid and comes followed by a much slower rate of elimination. The appearance of two separate rates of14CO2elimination could represent two routes of metabolism of the acetate carbons. The initial rate of elimination is probably due to the direct reaction of acetate with CoA-SH to form acetyl-CoA, which subsequently is oxidised to CO2through the TCA cycle. In the intact animal, the CO2would be present in the form of blood bicarbonate and as the blood bicarbonate is turned over, there is a subsequent release of CO2from the lungs. The slower, secondary rate of elimination is probably derived from acetate carbons which are incorporate into other metabolites, such as fatty acids and amino acids and are subsequently catabolised to CO2.

Conclusions:
Based on the experimental results obtained with the supporting substance sodium acetate in male and female rats, the read-across approach was applied and similar results on excretion were expected with triacetoxyvinylsilane hydrolysis product acetic acid:
Most of orally administered acetic acid-14C is expected to be recovered in the form of 14CO2. Only a small amount of the radioactivity would be found in the urine and faeces. The radioactivity recovered from excreta during the first 24-h period is expected to be considerably less from the males than from the females. Male rats apparently tend to fix more of the radioactivity in the body tissues, and the acetate carbons were not turned over as rapidly as in the females.
Executive summary:

Based on the experimental results obtained with the supporting substance sodium acetate in male and female rats, the read-across approach was applied and similar results on excretion were expected with triacetoxyvinylsilane hydrolysis product acetic acid:

Most of orally administered acetic acid-14C is expected to be recovered in the form of14CO2. Only a small amount of the radioactivity would be found in the urine and faeces. The radioactivity recovered from excreta during the first 24-h period is expected to be considerably less from the males than from the females. Male rats apparently tend to fix more of the radioactivity in the body tissues, and the acetate carbons were not turned over as rapidly as in the females.

There are two separate rates for the elimination of14CO2. The initial rate of elimination is very rapid and comes followed by a much slower rate of elimination. The appearance of two separate rates of14CO2elimination could represent two routes of metabolism of the acetate carbons. The initial rate of elimination is probably due to the direct reaction of acetate with CoA-SH to form acetyl-CoA, which subsequently is oxidised to CO2through the TCA cycle. In the intact animal, the CO2would be present in the form of blood bicarbonate and as the blood bicarbonate is turned over, there is a subsequent release of CO2from the lungs. The slower, secondary rate of elimination is probably derived from acetate carbons which are incorporate into other metabolites, such as fatty acids and amino acids and are subsequently catabolised to CO2.

Description of key information

Short description of key information on bioaccumulation potential result:

Based on the experimental results obtained with the supporting substance sodium acetate in male and female rats, the read-across approach was applied and similar results on excretion were expected with triacetoxyvinylsilane hydrolysis product acetic acid:

Most of orally administered acetic acid-14C is expected to be recovered in the form of14CO2. Only a small amount of the radioactivity would be found in the urine and faeces. The radioactivity recovered from excreta during the first 24-h period is expected to be considerably less from the males than from the females. Male rats apparently tend to fix more of the radioactivity in the body tissues, and the acetate carbons were not turned over as rapidly as in the females.

Key value for chemical safety assessment

Additional information

It is well known that triacetoxisilane undergoes rapid hydrolysis in aqueous or moist environments to acetic acid and trisilanol.

The confirm that hydrolysis of acetoxysilanes is fast, the test of hydrolysis of propyl triacetoxysilane in water was performed. It was measured, that the process was very fast. The half-life at different pH of propyltriacetoxysilane was determined to be < 37.5 seconds since the test item was completely hydrolysed at 150 seconds after the initial contact with water.

As it is stated in different publications, silanols hydrolyse well in water and the carbon- bounded substituents can have profound effects on the rate of hydrolysis. (Arkles B., Chemtech 1977; Pluddemann E.P., Plenum Press NY, 1982; Kay, B.D. and Assink R.A, J. Non-Cryst. Solids, 1988).

The rates of hydrolysis of the alkoxy groups are generally related to their steric bulk: CH3O>C2H5O> t-C4H9O and a methoxysilane hydrolyzes at 6-10 times rate of an ethoxysilane. Smith (Smith K. J. Org. Chem 1986) proved that increased organic substitution enhances the hydrolysis rate Me3SiOMe> Me2Si(OMe)2> MeSi(OMe)3.

During the performed hydrolysis test, the condensation and polimerysation of the molecules formed in hydrolysis were observed too. It was observed as the phase separation. Unfortunately, this phase separation caused the technical difficulties of the determination of the molecular weight of larger condensation products. It was possible to determined MW of smaller condensates which still are in solutions. Their average MW were between 604-695.

This phase separation as a result of condensation was described by Arkles. The hydrolysis of propyltrimetoxysilane showed that oligomers are formed and branched structures presages phase separation (Arkles B. et al, Silanes and Coupling Agents, 1992).

Taking in account both, the hydrolysis and condensation, it is expected that the observed in the hydrolysis test phase changed product contains large chain polymers with MW>1000.

Authors showed that molecules of MW>1000 cannot be biologically available (Van Gestel et a, Reg. Toxicol. and Pharmacol., 1985, 5, 422-31 and Zitko V, Handbook of Environmental Chemistry, v. 2 221-29).

A stated before, triacetoxysilane is not stable when exposed to water or moisture and undergo rapid hydrolysis. The hydrolysis produces 3 moles of acetic acid and the silanetriol which condensate to higher weight siloxanes. The polymerization products are considered biologically unavailable and the toxicity is driven by acetate anion.

The toxicity of triacetoxyvinylsilane should be evaluated as the toxicity of acetic acid.

Supporting study:

Read-across from experimental results with sodium acetate:

In the study by Philleo et. al., 1967 (reliability 2) male and female rats were used for an excretion study with sodium acetate-C14oral administration. CO2was trapped by sodium hydroxide solution. The trapped CO2was periodically analyzed for radioactivity after conversion of CO2to BaCO3(urine and faeces samples).

Based on the experimental results obtained with the supporting substance sodium acetate in male and female rats, the read-across approach was applied and similar results on excretion were expected with triacetoxyvinylsilane hydrolysis product acetic acid:

Most of orally administered acetic acid-14C is expected to be recovered in the form of14CO2. Only a small amount of the radioactivity would be found in the urine and faeces. The radioactivity recovered from excreta during the first 24-h period is expected to be considerably less from the males than from the females. Male rats apparently tend to fix more of the radioactivity in the body tissues, and the acetate carbons were not turned over as rapidly as in the females.

There are two separate rates for the elimination of14CO2. The initial rate of elimination is very rapid and comes followed by a much slower rate of elimination. The appearance of two separate rates of14CO2elimination could represent two routes of metabolism of the acetate carbons. The initial rate of elimination is probably due to the direct reaction of acetate with CoA-SH to form acetyl-CoA, which subsequently is oxidised to CO2through the TCA cycle. In the intact animal, the CO2would be present in the form of blood bicarbonate and as the blood bicarbonate is turned over, there is a subsequent release of CO2from the lungs. The slower, secondary rate of elimination is probably derived from acetate carbons which are incorporate into other metabolites, such as fatty acids and amino acids and are subsequently catabolised to CO2.