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Description of key information

No kinetic data are available on the absorption of thioglycolic acid and its salts by inhalation or oral exposure. However, the physico-chemical properties of thioglycolates, small ionisable water-soluble molecules with a very low log Kow, as well as, the acute oral and inhalation toxicity data suggest that thioglycolic 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.
Short description of key information on absorption rate:
Under testing conditions that take into account realistic use conditions for cosmetic formulations (30-min exposure and rinsing), the dermal absorption of ammonium thioglycolate (pH between 6 and 9) seems very limited, about 1% of a dose of 133 mg/kg bw (as thioglycolic acid) was absorbed within 72h in rats and 0.77% of a dose of 2.1 mg thioglycolic 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 rat of 1% is assumed for ammonium thioglycolate.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - dermal (%):
1

Additional information

No data are available on the absorption of thioglycolic acid and its salts by inhalation or oral exposure. However, the physico-chemical properties of the thioglycolates, small ionisable water-soluble molecules with a very low logKowas well as the acute oral and inhalation toxicity data suggest that thioglycolic acid and/or its salts are significantly absorbed by the inhalative and oral routes.

Regarding dermal absorption, it seems that the dermal penetration of thioglycolate is pH-dependent, the more acidic the pH, the fewer molecules are ionized and the more it is absorbed. A former study, performed under exaggerated exposure conditions (no rinsing) 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 thioglycolic acid) excreted in the urine within 5 hours in the form of neutral sulphate (Freeman, 1956). However, under testing conditions that take into account realistic use conditions for cosmetic formulations (30-min exposure and rinsing), the dermal absorption of ammonium thioglycolate (pH between 6 and 9) seems very limited, about 1% of a dose of 133 mg/kg bw (as thioglycolic acid) was absorbed within 72h in rats (Reindl, 1993). In an in vitro dermal absorption/penetration assay with excised skin of pigs performed according to OECD Guideline 428, the amount of ammonium thioglycolate systemically available (epidermis/dermis plus receptor fluid) was found to be 19.83 µg/cm², corresponding to 0.77% of a dose of 2.63 mg ammonium thioglycolate/cm² (Toner, 2007).

After i. v. injection,35S-thioglycolate is mainly distributed in the kidneys, lungs, and spleen of a female monkey (Freeman 1956), in the small intestine and kidneys of a rat (Bakshy and Gershbein, 1972). Residual 35S blood concentrations at 0.5 to 7 h post-injection did not exceed 5.3% in rats (Bakshy and Gershbein, 1972). Significant concentrations of dithiodiglycolate were detected in the urine of rabbits 24 h after thioglycolic acid was injected i. p. negligible concentrations of thioglycolic acid were detected (Bakshy and Gershbein, 1972).

 

Absorption and excretion

The pulmonary excretion of sodium thioglycolate 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 thioglycolate. 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; reliability 2).

The urinary excretion of sodium thioglycolate was evaluated using rabbits (weights and strain not stated). Four animals were injected i. v. with a 5% solution of sodium35S-thioglycolate (doses of 70, 80, 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 thioglycolatecaused 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 urineindicatedthat 63-83% of the compound was excreted in the first 24 hours after its administration(Freeman et al. 1956a; reliability 2).

The urinary excretion of sodium thioglycolate 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 sodium35S-thioglycolate. 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; reliability 2).

35S-thioglycolic 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 administered35S 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; reliability 2).

Two male New Zealand rabbits (weights not stated) were injected i. p. with35S-thioglycolic 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; reliability 2).

Distribution

The distribution of radioactivity was determined two hour after i. v. injection of 50 mg/kg35S-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. The greatest content of35S, 0.66% of the total administered, was detected in the feces. This observation may have been due to contamination of the feces with urine missed during the rinsing of urine residue from the cage after collection (Bakshy and Gershbein, 1972; reliability 2).

The distribution of35S thioglycolic 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; reliability 2).

The distribution of35S-thioglycolic acid in the blood was further investigated in the New Zealand rabbit after i. v. injection of35S-thioglycolic acid (adjusted to pH 7.2-7.4 with NaOH), with emphasis on binding to the following serum protein fractions:α1,α2,β, andγ-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; reliability 2).

A female monkey given 300 mg35S-labelled sodium thioglycolate/kg body weight by i. v. injection, excreted labeled 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; reliability 2).

Metabolism

Unlabeled 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; reliability 2).

Discussion on absorption rate:

Studies performed with ammonium thioglycolate based cosmetic formulations are available

In vitro study

The dermal absorption/percutaneous penetration of [14C]-radiolabelled ammonium thioglycolate 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 thioglycolate was approximately 2.63 mg/cm² skin (equivalent to 2.1 mg thioglycolic 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 thioglycolate 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 thioglycolic acid (Toner, 2007).

In vivo study

Three groups of rats (5/sex; ~200 g) received on the clipped dorsal skin approximately 300 mg of ammonium14C-thioglycolate (radiochemical purity 97.6%) as an 11% solution (equivalent to 165 mg a. i./kg bw or 133 mg/kg bw as thioglycolic 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 ammonium14C-thioglycolate 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, feces, adsorption at the application site and carcass14C recovery.

Most of the14C was removed from the rat skin during washing of the test material and neutralization solution (mean 96.1 - 96.8%). The mean14C recovered in urine and feces in the pH 6, pH 7, and pH 8 exposure groups was 0.139%, 0.119%, and 0.137%, respectively. The mean14C-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% Ammonium14C-thioglycolate at pH 6, pH 7, and pH 8 was 1.09%, 0.81%, and 0.86%, respectively. Cutaneous absorption and14C 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 urinary excretion of an ammonium thioglycolate 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 of35S 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 anin vivomicronucleus test (Haddouk, 2006)) showed that pH can significantly affect the systemic toxicity of thioglycolic acid after a dermal application to mice. No mortality and no clinical signs were observed at 1491 mg thioglycolate/kg/day at pH 7 for 2 days. In contrast, 2 out of 3 males died after the first treatment with 1500 mg thioglycolate/kg/day at pH 4. Thus, it seems that the dermal penetration of thioglycolic acid is pH-dependent, the more the pH is acidic, the less the molecule is ionized and more it is absorbed.