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EC number: 204-815-4
CAS number: 126-97-6
The three [C]-radiolabelled test items (Ammonium thioglycolic acid (ATG), Calcium thioglycolic acid (CaTG) and Monoethanolamine thioglycolic acid (MeaTG)) are used in basic formulations (test preparations). The formulations are typical for a permanent hair waving formulation, a depilatory formulation and a hair straightening formulation.
As part of a safety evaluation of each test item, this study was required to assess their extent of dermal bioavailability, following topical application of ATG in a permanent hair waving formulation (13%, w/w), CaTG in a depilatory formulation (10%, w/w) and MeaTG in a hair straightening formulation (18%, w/w) to excised pig skin. The skin surface was washed at 30, 15 and 45 min, respectively, for each formulation to reflect the in use conditions. The skin was again washed at 24 h post dose for all groups as a final wash off before test run termination.
Previously frozen dermatomed pig skin was mounted into static diffusion cells containing receptor fluid (phosphate buffered saline, ca 10 mL) in the receptor chamber. The skin surface temperature was maintained at ca 32°C throughout the experiment. An electrical resistance barrier integrity test was performed and any pig skin sample exhibiting a resistance <4 kΩ was excluded from subsequent dermal bioavailability measurements.
The permanent hair waving formulation, depilatory formulation and hair straightening formulation containing [14C]-ATG, [14C]-CaTG and [14C]-MEATG, respectively, were applied, at an application volume of ca 20 mg/cm2 , to dermatomed pig skin mounted into static diffusion cells in vitro.
Dermal Bioavailability was assessed by collecting receptor fluid aliquots (250 µL) at 0.5, 1, 2, 4, 6 and 24 h post dose. At 30, 15 and 45 min post dose, respectively, for ATG in a permanent hair waving formulation, CaTG in a depilatory formulation and MEATG in a hair straightening formulation, exposure was terminated by washing the skin surface with a dilute shampoo solution and drying the skin surface with tissue paper (tissue swabs). At 24 h post dose, the washing procedure was repeated. The skin was then removed from the static diffusion cells, dried and the stratum corneum was removed with 20 successive tape strips.
The remaining skin was divided into exposed and unexposed skin and solubilised with Solvable® tissue solubiliser. The receptor fluid in the receptor chamber was removed and split into fractions for analysis. All samples were analysed by liquid scintillation counting.
A summary of the mean results are provided in the tables overleaf:
ATG in Permanent Hair Waving Formulation
CaTG in Depilatory Formulation
MeaTG in Hair Straightening Formulation
Test Item Concentration (w/w)
Mean Application Rate of Formulation (mg/cm2)
Mean Application Rate of Test Item (µg equiv./cm2)
Dislodgeable Dose at 30, 15, 45 min, respectively (% Applied Dose)
Total Dislodgeable Dose* (% Applied Dose)
Unabsorbed Dose** (% Applied Dose)
Dermal Adsorption (% Applied Dose)
Percutaneous Penetration (% Applied Dose)
Dermal Bioavailability (% Applied Dose)
Mass Balance (% Applied Dose)
Dislodgeable Dose at 30, 15, 45 min, respectively (µg equiv./cm2)
Total Dislodgeable Dose* (µg equiv./cm2)
Unabsorbed Dose** (µg equiv./cm2)
Dermal Adsorption (µg equiv./cm2)
Percutaneous Penetration (µg equiv./cm2)
Dermal Bioavailability (µg equiv./cm2)
Mass Balance (µg equiv./cm2)
* Total dislodgeable dose = skin washes + tissue swabs + pipette tips + donor chamber wash
** Unabsorbed dose = total dislogeable Dose + unexposed skin
For [14C]-ATG in permanent hair waving formulation (13%, w/w) applied to dermatomed pig skin in vitro, most of the applied dose (98.69%) was removed by washing at 30 min post dose. At 24 h post dose, the total dislodgeable dose was 98.98% of the applied dose. The total unabsorbed dose was 99.04% of the applied dose. The stratum corneum (Dermal Adsorption) retained 0.17% of the applied dose. The percutaneous penetration and dermal bioavailability were 0.22% (5.23 µg equiv./cm2) and 0.77% (19.83 µg equiv./cm2) of the applied dose, respectively. The mass balance was complete with 99.97% of the applied dose recovered.
For [14C]-CaTG in depilatory formulation (10%, w/w) applied to dermatomed pig skin in vitro, most of the applied dose (104.70%) was removed by washing at 15 min post dose. At 24 h post dose, the total dislodgeable dose was 105.07% of the applied dose. The total unabsorbed dose was 105.08% of the applied dose. The stratum corneum retained 0.07% of the applied dose. The percutaneous penetration and dermal bioavailability were 0.02% (0.41 µg equiv./cm2 ) and 0.20% (4.09 µg equiv./cm2 ) of the applied dose, respectively. The mass balance was complete with 105.36% of the applied dose recovered.
For [14C]-MEATG in a permanent hair waving formulation (18%, w/w) applied to dermatomed pig skin in vitro, most of the applied dose (98.14%) was removed by washing at 45 min post dose. At 24 h post dose, the total dislodgeable dose was 98.36% of the applied dose. The total unabsorbed dose was 98.41% of the applied dose. The stratum corneum (Dermal Adsorption) retained 0.09% of the applied dose. The percutaneous penetration and dermal bioavailability were 0.17% (5.83 µg equiv./cm2 ) and 0.38% (13.64 µg equiv./cm2) of the applied dose, respectively. The mass balance was complete with 98.87% of the applied dose recovered.
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 MeaTG.
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 log Kow as 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 excretionThe 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). DistributionThe 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. 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).MetabolismUnlabeled 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 availableIn vitro studyThe 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 studyThree 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
14C-activity in % of applied dose,mean (SD)
Urine (0-72 h)
Faeces (0-72 h)
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