Mercaptoacetic acid

Endpoint summary

Description of key information

No data is available on the absorption of mercaptoacetic acid and/or its salts by inhalation or oral exposure. However, the physico-chemical properties of mercaptoacetates, small ionisable water-soluble molecules with a very low log Kow, as well as, the acute oral and inhalation toxicity data suggest that mercaptoacetic acid and its salts are significantly absorbed by the inhalation and oral routes. The available information are provided from former studies performed by parenteral administration.

 

The dermal penetration of mercaptoacetic acid is pH-dependent, more the pH is acidic, less the molecule is ionized and more it is absorbed. A former study, performed under exaggerated exposure conditions (no rincing) and at an unknown pH, suggests an extensive dermal absorption of the sodium salt in the rabbits, with at least 30-40% of the dose (up to 660 mg/kg bw as mercaptoacetic acid) excreted in the urine within 5 hours in the form of neutral sulphate. However, under testing conditions that take into account realistic use conditions for cosmetic formulations (30-min exposure and rinsing), the dermal absorption of ammonium mercaptoacetate (pH between 6 and 9) seems very limited, about 1% of a dose of 133 mg/kg bw (as mercaptoacetic acid) was absorbed within 72h in rats and 0.77% of a dose of 2.1 mg mercaptoacetic acid/cm² was systemically available in an in vitro dermal absorption/penetration assay with excised skin of pigs.

Overall, for the purpose of risk assessment, a dermal absorption rate of 10% is assumed for mercaptoacetic acid.

 

Absorption and excretion

The pulmonary excretion of sodium mercaptoacetate as hydrogen sulphide was investigated in the rat (weight and strain not stated). The animal was injected i.p. with 150 mg/kg of sodium mercaptoacetate. Expired air from the animal was analyzed for hydrogen sulphide over a period of 10 h. Hydrogen sulphide was not detected in expired air at any time during the study (Freeman et al. 1956a).

 

The urinary excretion of sodium mercaptoacetate was evaluated using rabbits (weights and strain not stated). Four animals were injected i.v. with a 5% solution of sodium35S-mercaptoacetate (doses of 70, 80, and 123 mg/kg, respectively). Two animals served as controls. Urine was then collected over a period of 24 h. A few drops of liquid petrolatum were placed in each container to prevent air oxidation of possible sulfhydryl compounds. Quantities of organic sulphate, inorganic sulphate, and neutral sulphur in each urine sample were expressed as the percentage of administered radioactivity. Sodium mercaptoacetate caused a considerable increase in excretion of iodine reducing material, more than enough to account for the compound administered indicating the breakdown of body constituent and was excreted mostly as inorganic sulphate and neutral sulphur. The radioactivity in the urine indicated that 63-83% of the compound was excreted in the first 24 hours after its administration (Freeman et al. 1956a).

 

The urinary excretion of sodium mercaptoacetate was also evaluated in rats (weight and strain not stated) injected i.p. with 12.5 to 75.0 mg/kg of a 2.5% solution of sodium 35S-mercaptoacetate. Urine was collected over a period of 24 h. Quantities of inorganic sulphate excreted, expressed as % of administered radioactivity, ranged from 23 to 72%. The total labeled 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. 1956a).

 

35S-mercaptoacetic acid (100 mg/kg adjusted to pH 7.2-7.4 with NaOH) was administered to Holtzman rats (weight = 200-250 g), 12 rats were injected i.v. and to 10 i.p.. Also, 2 rats were each given 75 mg/kg via i.p. injection. Animals injected i.v. (12 rats) comprised one group, and those injected intraperitoneally (12 rats) comprised the other. Urine samples were collected 24 h after injection, after which the administered 35S was excreted, and excretion percentages were determined. 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).

 

Two male New Zealand rabbits (weights not stated) were injected i.p. with35S-mercaptoacetic acid (100 mg/kg adjusted to pH 7.2-7.4 with NaOH) and one rabbit was injected i.p. with 200 mg/kg. Urine samples were collected 24 h after injection. The mean urine sulphur content of the 3 rabbits was 88% of the administered dose. Most of the radioactivity was excreted 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/kg35S-mercaptoacetic 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 mercaptoacetate in the urine and bile. The greatest content of35S, 0.66% of the total administered, was detected in the faeces. This observation may have been due to contamination of the faeces with urine missed during the rinsing of urine residue from the cage after collection (Bakshy and Gershbein, 1972).

 

The distribution of35S mercaptoacetic acid (adjusted to pH 7.2-7.4 with NaOH) in whole blood was evaluated in five Holtzman rats injected i.v. with 100 mg/kg of the test substance and bled during periods of up to 7 h. Four of the 5 had less than 3% residual activity at 1 hour, while one had 5.3% residual activity. At 4-7 hours after the injection, only 0.1% activity or less remained (Bakshy and Gershbein, 1972).

 

The distribution of35S-mercaptoacetic acid in the blood was further investigated in the New Zealand rabbit after i.v. injection of35S-mercaptoacetic acid (adjusted to pH 7.2-7.4 with NaOH), with emphasis on binding to the following serum protein fractions: a1, a2, ß, and ¿-globulins and albumin. The test substance (75 mg/kg) was injected 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. The small amount of radioactivity detected in albumin might have been due to isotopic exchange (Bakshy and Gershbein, 1972).

 

A female monkey given 300 mg35S-labelled sodium mercaptoacetate/kg body weight by i.v. injection, 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. 1956a).

 

Metabolism

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

 

Dermal absorption

Regarding dermal absorption, no data is available on mercaptoacetic acid. Concerning the sodium or ammonium salts, former studies on the pure substances and recent studies performed with ammonium mercaptoacetate based cosmetic formulations are available

In vitro study

The dermal absorption/percutaneous penetration of [14C]-radiolabelled ammonium mercaptoacetate out of a representative permanent hair waiving formulation (13% in the formulation, pH 9.5) was studied on the clipped excised skin of four Landrace large white cross pigs. The pig skin, dermatomed to a mean thickness of 0.80 mm, was used because it shares essential penetration characteristics with human skin. The dermal absorption/percutaneous penetration of the test substance was investigated for the open application of about 20 mg formulation per cm² pig skin. Therefore the resulting dose of ammonium mercaptoacetate was approximately 2.63 mg/cm² skin (equivalent to 2.1 mg mercaptoacetic acid/cm²). Skin discs of about 3.14 cm² were exposed to the formulations for 30 min., terminated by gently rinsing with a commercial shampoo solution diluted with water. The amount of ammonium mercaptoacetate systemically available (epidermis/dermis plus receptor fluid) was found to be 19.83 µg/cm² (0.77%), corresponding to 16.74 µg/cm² when calculated for mercaptoacetic acid (Toner, 2007).

 

In vivo study

Three groups of rats (5/sex; ~200 g) received on the clipped dorsal skin approximately 300 mg of ammonium 14C-mercaptoacetate (radiochemical purity 97.6%) as an 11% solution (equivalent to 165 mg a.i./kg bw or 133 mg/kg bw as mercaptoacetic acid) at pH 6, pH 7, and pH 8 for 30 minutes followed by a washing of the site. The test site was then neutralized with 0.3 ml of a “natural styling solution” containing 2.1% hydrogen peroxide for 10 minutes followed by a washing of the site. These applications were to mimic human exposure to hair waving products. After the second wash, the test sites were covered with four layers of gauze and the rats were placed into metabolism cages for 72 hours. Following the observation period, the animals were sacrificed. The test sites and surrounding skin were excised and dissolved in Soluene-350 for radioactivity analysis. The radioactivity of the waste wash water, urine, and feces as well as the carcasses was also measured. The results of the radioactivity count are presented in the following Table.

 

Recovery of the radioactivity after dermal administration of ammonium 14C-mercaptoacetate to rats

Analysed sample	14C-activity in % of applied dose, mean (SD)
	pH 6	pH 7	pH 8
Rinsings	96.8 (1.2)	96.7 (2.1)	96.1 (1.4)
Adsorption (application site)	0.82 (0.43)	0.57 (0.24)	0.60 (0.34)
Urine (0-72 h)	0.11 (0.12)	0.091 (0.073)	0.11 (0.11)
Faeces (0-72 h)	0.029 (0.032)	0.028 (0.025)	0.027 (0.025)
Carcass	0.126 (0.087)	0.116 (0.076)	0.121 (0.089)
Total recovery	97.9 (1.1)	97.5 (2.1)	97.0 (1.5)
Cutaneous absorption[1]	1.09	0.81	0.86

[1]total of urine, faeces, adsorption at the application site and carcass14C recovery.

 

Most of the 14C was removed from the rat skin during washing of the test material and neutralization solution (mean 96.1 - 96.8%). The mean1 4C recovered in urine and faeces in the pH 6, pH 7, and pH 8 exposure groups was 0.139%, 0.119%, and 0.137%, respectively. The mean 14C-content of the skin at the application site for the pH 6, pH 7, and pH 8 exposure groups was 0.82%, 0.57%, and 0.60%, respectively. The mean cutaneous absorption for 11% Ammonium 14C-mercaptoacetate at pH 6, pH 7, and pH 8 was 1.09%, 0.81%, and 0.86%, respectively. Cutaneous absorption and 14C concentrations in urine, feces, and carcasses were higher in males than females, but it was determined that this was not statistically significant (Reindl, 1993).

 

The absorption of sodium 35S-mercaptoacetate (radiochemical activity 0.66 mCi/mM) was investigated using male rabbits (2-3 kg, strain not stated). Five animals were fed during a period of approximately 24 h and then fasted for 24 h. A 25.0% solution of sodium 35S-mercaptoacetate (330 mg/kg bw as mercaptoacetic acid, pH unknown) was then applied to clipped skin of the back via inunction (apparently without rincing and occlusion). After at the end of one, two, three, four, and five hours, they were catheterized to collect urine samples, which were then analyzed for total sulphur and radioactive sulphur. At the end of 1 h, 5 to 8% of the dose of sodium 35S-mercaptoacetate applied had been excreted in the urine. The amount excreted at 5 h varied from 30% to 40%. The increased excretion of total sulphur (cold and 35S) per unit time may not have been attributable directly to percutaneous mercaptoacetate absorption because sodium mercaptoacetate may have altered the metabolism of other sources of sulphur in the body as demonstrated in rabbits after i.v. injection (see below). No further increase in the absorption and excretion of mercaptoacetate per unit time was observed when a larger dose of the test solution (660 mg/kg bw as mercaptoacetic acid, pH unknown) was applied to three additional rabbits (same procedure). However, the animals given 660 mg/kg died within 24 hours, while those given 330 mg/kg did not. The authors concluded that the total amount absorbed over an extended period of time probably was related to the amount applied (Freemanet al. 1956a).

 

The urinary excretion of an ammonium mercaptoacetate solution (0.6 N, pH 9.3) was evaluated in rabbits (2.3-3.0 kg, strain not stated). A single application (1.0 ml/kg, equivalent to 65.5 mg/kg bw) of the solution containing 0.10 to 0.20 µCi of 35S was made via a syringe to a clipped area (15% of body surface) on an animal’s right side (apparently without occlusion and rinsing). At 24 hours, 16.22 ± 0.55 % of the labeled sulphur had been excreted in the urine, while in the following 48 hours 6.46% was excreted. When the same volume was applied on 4 successive days, approximately 35-40% of the total35S had been excreted in the urine within this time (Gershbein, 1979).

 

The range finding study of an in vivo micronucleus test (Haddouk, 2006)) showed that pH can significantly affects the systemic toxicity of mercaptoacetic acid after a dermal application to mice. No mortality and no clinical signs were observed at 1491 mg mercaptoacetate/kg/day at pH 7 for 2 days. In contrast, 2 out of 3 males died after the first treatment with 1500 mg mercaptoacetate/kg/day at pH 4. Thus, it seems that the dermal penetration of mercaptoacetic acid is pH-dependent, more the pH is acidic, less the molecule is ionized and more it is absorbed.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100