Mercaptoacetic acid, monoester with propane-1,2,3-triol

Endpoint summary

Description of key information

A bioaccumulation potential of GMT is not expected.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

No data are available on the toxikokinetics, metabolism and distribution of glyceryl thioglycolate (GMT) by dermal, oral or inhalative exposure. Ester hydrolysis is the first step of GMT metabolism in the body, resulting in the metabolites glycerol and thioglycolate. Depending on the energy situation glycerol will be fed into common metabolic pathways namely either gluconeogenesis or triglyceride synthesis. Glycerol is an intrinsic precursor for gluconeogenesis, triglyceride or phospholipid synthesis and therefore does not represent any hazard.

For the toxicological relevant metabolite thioglycolate extensive research has been conducted to identify the mode of action. The overall assessment is therefore based on relevant existing information and experimental studies of both GMT and thioglycolate, respectively one of its salt sodium thioglycolate.

Absorption and excretion

Judging from the ratio of oral to dermal LD50 values (177 vs >2000 mg/kg bw), the dermal absorption of GMT is predicted to be low. When repeatedly administered by the oral route according to OECD 422 GMT led to mortality at concentrations > 50 mg/kg bw. It was evident that females were more prone to develop signs of toxicity. The mode of action of thioglycolate involves disruption of katabolic pathways leading to low blood glucose and ketone body levels and in the long run liver steatosis. Dams are in need of a well regulated energy metabolism. The observed signs of toxicity therefore indicate that GMT displays the same mode of action most probably via its metabolite thioglycolate. The repeated dose toxicity of sodium thioglycolate (NaTG) was evaluated in a 90-day toxicity study (OECD 408). Supporting information is provided by a 2-generation reproductive toxicity study (OECD 416). Both studies identify a NOAEL for NaTG of 20 mg/kg bw/day. Taking into account the level of esterification of GMT and the molecular weight of both substances this would represent a NAEL for GMT of 36.4 mg/kg bw/day (8/10 x 20 x 166.2/114.1).

In rats NaTG was exhaled as hydrogen sulphide after i.p. injection with 150 mg/kg of NaTG (Freeman et al. 1956). In rabbits injected i.v. with a 5% solution of ³⁵S-NaTG (doses of 70, 80, 80, and 123 mg/kg, respectively) NaTG caused a considerable increase in urinary excretion of iodine reducing material, indicating the breakdown of body constituent. 63-83% of the compound was excreted in the first 24 hours p.a. as inorganic sulphate and neutral sulphur (Freeman et al. 1956).

When rats were injected i.p. with ³⁵S-NaTG (12.5 to 75.0 mg/kg bw/d) the total labelled sulphur excreted during the first 24 hours was 59-96% of the dose. Two of the rats excreted 9% or 11% on the second day and 2% or 6% on the third day respectively (Freeman et al. 1956). Comparison of the urinary excretion of ³⁵S-thioglycolic acid (100 mg/kg adjusted to pH 7.2-7.4 with NaOH) after i.v. and i.p. injection was made using Holtzman rats. The mean urine sulphate content for i.v. dosed rats was 82.3 ± 1.6% and for i.p. dosed rats was 90.6 ± 1.8%. Most of the radioactivity was excreted in the form of neutral sulphate (Bakshy and Gershbein, 1972). Male New Zealand rabbits were injected i.p. with ³⁵S-thioglycolic acid (100 or 200 mg/kg adjusted to pH 7.2-7.4 with NaOH).The mean urine sulphur detected within 24 h was 88% excreted mostly in the form of neutral sulphate (Bakshy and Gershbein, 1972).

Distribution

The distribution of radioactivity was determined two hour after i.v. injection of 50 mg/kg ³⁵S-thioglycolic acid (adjusted to pH 7.2-7.4 with NaOH) to one Holtzman rat. The small intestine, kidney, liver and stomach exhibited the greatest activity, respectively 0.07, 0.03, 0.02 and 0.02 % of the dose. It is possibly consistent with the generally rapid elimination of thioglycolate in the urine and bile. (Bakshy and Gershbein, 1972). The distribution of ³⁵S-thioglycolic acid (adjusted to pH 7.2-7.4 with NaOH) in whole blood was evaluated in Holtzman rats and New Zealand rabbits. Five Holtzman rats were injected i.v. with 100 mg/kg of the test substance and bled during periods of up to 7 h. At 4-7 hours after the injection, only 0.1% activity or less remained (Bakshy and Gershbein, 1972). Emphasis on the binding to the serum protein fractions:α1,α2,β, andγ-globulins and albumin were made when evaluating the blood of the rabbit (75mg/kg. i.v.). Most of the radioactivity was bound to albumin. The extent of this uptake amounted to 0.14% at 20 min post-injection and had diminished to 0.016% at 3 h. (Bakshy and Gershbein, 1972). A female monkey (300 mg ³⁵S-NaTG /kg i.v.) excreted labelled sulphur in the urine (for up to 10 hours) entirely as neutral sulphur. Tissue samples from 10 organs showed the largest amounts of label in the kidney, lungs and spleen (Freeman et al. 1956).

Metabolism

Unlabelled thioglycolic acid (100 or150 mg/kg) was administered to a group of seven rats via i.p. injection. Significant concentrations of dithioglycolate (average concentration 28%) were detected in the urine at 24 h post-injection. Only negligible concentrations of thioglycolate were detected (Bakshy and Gershbein 1972).

Discussion on bioaccumulation potential result:

GMT is rapidly eliminated from the gut. It is expected that upon hydrolysis of the ester bonds GMT will yield glycerol and thioglycolate. Glycerol is a precursor for gluconeogenesis, triglyceride or phospholipid synthesis and therefore does not represent any bioaccumulation hazard. After i.p. or i.v. injection with the toxicological relevant metabolite ³⁵S-thioglycolic acid (adjusted to pH 7.2-7.4 with NaOH) rabbit, rat and monkey display a rapid and nearly complete urinary excretion of radiolabelled sulphur. Only negligible amounts of radiolabelled sulphur where detected in blood or body tissues. Taken together these results a bioaccumulation potential of GMT is not expected.