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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

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Link to relevant study record(s)

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Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Objective of study:
toxicokinetics
Qualifier:
no guideline followed
GLP compliance:
not specified
Species:
rabbit
Strain:
New Zealand White
Sex:
male
Details on test animals or test system and environmental conditions:
Animals:
New Zealand rabbits (male, adult, weight unstated, n=3) 
Diet: Purina chow (rats) and Staley pellets(rabbits) ad libitum
Water: ad libitum
Housing: in a circular metabolism cage.
Route of administration:
other: i.p. and i.v.
Vehicle:
water
Details on exposure:
The solutions were injected by the i.v. or i p routes and blood removed  by cardiac puncture under restraint. The urine samples were collected 24  hr after injection, the residues being rinsed from the cage and funnel with water and combined with the initial portions. Dilution in volumetric  flasks followed. Toluene was employed throughout as urinary preservative. For urinary sulphur partition, aliquots were analyzed for total,  inorganic and inorganic + ethereal sulphate contents. Prior to the  precipitation of the barium sulphate, an aqueous solution of sodium  sulphate was introduced in amount equivalent to infinite layer thickness.  Each precipitate was collected in a stainless steel filter apparatus,  washed with cold water and dried for 16 hr at 100°. The product was  transferred to cupped nickel-plated planchettes and counted in an SC-16  windowless counter with an attached Super scalar SC-18A from Tracerlabs,  Incorporated, Boston, also the source of the filter apparatus and  planchettes. In all cases, infinite layer thickness was achieved by 25 mg  barium sulfate. For following S35. partition among blood proteins, serum was separated  from the clot and subjected to paper electrophoresis according to the  method of Kunkel and Tiselius.
Details on distribution in tissues:
The distribution of radioactivity in serum proteins was studied in one  rabbit after i.v. injection of 75 mg thioglycolic acid/kg bw. Albumin  contained more of the label than the globulins. However the extend of  this uptake amounted to 0.14% 20 min after i.v. injection diminished to  0.016% after 3 h. The small amount of radioactivity detected in albumin  might have been due to isotopic exchange.
Details on excretion:
Three rabbits given 100 or 200 mg thioglycolic acid/kg bw by the i.p.  route excreted over 80% of the label in the urine during the first 24  hours. The greatest activity (ca. 50%) was contained in the neutral  sulphate portion.
Metabolites identified:
no
Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Objective of study:
toxicokinetics
Qualifier:
no guideline followed
GLP compliance:
no
Radiolabelling:
yes
Species:
rat
Strain:
other: Holtzman
Sex:
male
Details on test animals or test system and environmental conditions:
Animals:Holtzman rats (male, 200-250 g, n=12) 
Diet: Purina chow (rats),  ad libitum
Water: ad libitum
Housing: in a circular metabolism cage.
Route of administration:
other: i.p. and i.v.
Vehicle:
water
Duration and frequency of treatment / exposure:
The solutions were injected by the i.v. or i p routes and blood removed  from the tail vein of rats.
Remarks:
Doses / Concentrations:
100 mg/kg bw
No. of animals per sex per dose / concentration:
12
Control animals:
no
Details on dosing and sampling:
The urine samples were collected 24 hr after  injection, the residues being rinsed from the cage and funnel with water  and combined with the initial portions. Dilution in volumetric flasks  followed. Toluene was employed throughout as urinary preservative.For  urinary sulphur partition, aliquots were analyzed for total, inorganic  and inorganic + ethereal sulphate contents. Prior to the precipitation of  the barium sulphate, an aqueous solution of sodium sulphate was  introduced in amount equivalent to infinite layer thickness. Each  precipitate was collected in a stainless steel filter apparatus, washed  with cold water and dried for 16 hr at 100°. The product was transferred  to cupped nickel-plated planchettes and counted in an SC-16 windowless  counter with an attached Super scalar SC-18A from Tracerlabs,  Incorporated, Boston, also the source of the filter apparatus and  planchettes. In all cases, infinite layer thickness was achieved by 25 mg  barium sulfate.In the tissue studies, the animal was sacrificed by  decapitation, incised, the tissues removed, drained and weighed. Each of  the organs in its entirety was allowed to disintegrate in concentrated  nitric acid for 16 hr and then digested with 60% perchloric acid until a  clear solution resulted; several additions of both acids were required  and the duration of the digestion was 2-4 hr. Weighed amounts of muscle  (gastrocnemius), bone and unclipped skin in addition to blood and faeces  were also submitted to such treatment prior to further processing and  precipitation of barium sulphate. The disulphure content of urine  collected over a 24-h period following thioglycolate administration to  rats was determined by reduction of an aliquot with amalgamated zinc and  titration with 0.04 N iodine solution.
Details on distribution in tissues:
Tissue distribution was evaluated in 1 rat, 2 hours after an i.v.  injection of 50 mg thioglycolic acid/kg bw. 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. 

Five rats were given an i.v. injection of 100 mg thioglycolic acid/kg bw in an examination of the rate of disappearance from the blood. 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.
Details on excretion:
Two groups of 12 rats given about 100 mg sodium thioglycolic acid/kg bw by the intravenous or intraperitoneal routes (2 rats of the i.p.  series received 75 mg/kg bw) excreted 82.3 (+/- 1.6)% and 90.6 (+/-1.8)%  of the label in the urine during the first 24 hours, respectively. The  greatest activity was contained in the neutral sulphate portion (>50%).

Significant levels of dithioglycolate (equivalent to 28% of the  administered dose) were recovered from the urine of 6 rats treated with  about 100 or 150 mg thioglycolic acid/kg bw by i.p. injection after 24  hours. Only negligible levels of thioglycolate were detected in the urine  samples.
Metabolites identified:
yes
Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Objective of study:
excretion
Qualifier:
no guideline followed
GLP compliance:
no
Radiolabelling:
yes
Species:
rat
Strain:
not specified
Sex:
not specified
Details on test animals or test system and environmental conditions:
no data
Route of administration:
intraperitoneal
Vehicle:
water
Control animals:
yes, concurrent no treatment
Details on study design:
In studies using 6 rats, 24-hour urine collections were made following  intraperitoneal administration of 2.5% aqueous labelled sodium  thioglycolate (12.5-75 mg/kg body weight)
Details on excretion:
Of the total sulphur administered, significant levels were excreted as  inorganic sulphate (23-72%); 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. No  hydrogen sulphide was detected in exhaled air during any of three 10-hour  tests on 1 rat (weight and strain not stated) treated intraperitoneally  with 150 mg sodium thioglycolate/kg bodyweight.
Metabolites identified:
no
Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
Executive summary:

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 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.

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Objective of study:
distribution
Qualifier:
no guideline followed
GLP compliance:
no
Species:
monkey
Strain:
not specified
Sex:
female
Details on test animals or test system and environmental conditions:
Animals: female, 6 kg, further details not presented.
Route of administration:
intravenous
Details on exposure:
A female monkey was given 300 mg 35S-labelled sodium thioglycolate/kg body  weight by i.v. injection.
Details on distribution in tissues:
Tissue samples from 10 organs  showed the largest amounts of label in the kidney, lungs and spleen.
Details on excretion:
Labelled sulphur was excreted in the urine (for up  to 10 hours) entirely as neutral "sulphur".
Metabolites identified:
no
Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
Executive summary:

A female monkey given 300 mg35S-labelled sodium thioglycolate/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.

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Objective of study:
excretion
Qualifier:
no guideline followed
GLP compliance:
no
Radiolabelling:
yes
Species:
rabbit
Strain:
not specified
Sex:
not specified
Details on test animals or test system and environmental conditions:
no data
Route of administration:
intravenous
Vehicle:
water
Control animals:
yes, concurrent no treatment
Details on study design:
Rabbits were given single intravenous injections of 35S-labelled sodium  thioglycolate (5% aqueous); 70, 80, 80, 123 mg/kg body weight, followed  by 24 hours urine collection. Six rabbits were fasted for 24 hours, The  bladder was emptied by catheterization and a water rince. Two rabbits  served as controls and four were injected intravenously with labelled  sodium thioglycolate in 5 per cent solution. Each animal was placed in a  stainless steel metabolism cage. Urine was collected into a container  with a few drops liquid petrolatum to prevent oxidation by air of  possible sulphydryl compound excreted. Catheterisation was repeated at  the end of the 24-hour period to assure a total 24-hour urine samples.  The urine from each animal as well as the solution injected were analysed  for the content of sulphydryl, radiosulphur, inorganic radiosulphate and  total radiosulphate. The neutral radiosulphur was calculated.
Details on excretion:
Table 2 shows that the thioglycolate caused a considerable increase in  excretion of iodine reducing material, more than enough to account for  the compound admistrated, indicating the breakdown of body constituent.  
Radioactive sulphur fractions excreted are shown in table 3. The total  radioactivity excreted as sulphur was similar for each dose suggesting  that maximal oxidation of sulphur occurred. The rabbit excreted more as  neutral sulphur and organic sulphate than inorganic sulphate. The  radioactivityin the urine indicated that actually less than 100 per cent  of the compound was excreted in this first 24-hour period after its  administration. Because all of the radioactivity injected could not be accounted for in  one 24-hour urine sample, samples were collected for longer periods from  a few  animals. Each 24-hour sample were analyzed for total radioactive  sulphur. The results are shown in table 5.
Metabolites identified:
no
Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
Executive summary:

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.

Endpoint:
basic toxicokinetics in vivo
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Justification for type of information:
The read-across is a category approach based on the hypothesis that compounds in this category are transformed to a common compound. This approach serves to use existing data on genotoxicity, repeated-dose toxicity, and reproductive toxicity endpoints for substances in this category.
There are no relevant variations in properties among source substances and the same potency is predicted for all target substances. This is Scenario 5 of the RAAF . Substances ATG, MEATG, KTG, CaTG, and NaTG are different inorganic salts of a common acid, thioglycolic acid (TGA; synonym: 2- mercaptoacetic acid). They dissociate rapidly in aqueous media, e.g., the test organism, to the common thioglycolate anion and to their different counter ions. The water solubility of all category members is high, except for CaTG which is only moderately soluble in water.
In the repeated-dose toxicity studies with NaTG, specific toxicity is exerted via the well-investigated inhibition of mitochondrial fatty acid beta-oxidation by the thioglycolate (2-mercaptoacetate) anion 2,3,4. Inhibition of beta-oxidation leads to increased triglycerides and decreased acetyl-CoA in liver, and subsequently reduced gluconeogenesis. The latter presents as hypoglycaemia in NaTGtreated rats, which is aggravated by fasting (Grosdidier, 2011; Report No. 37043 TSR). This mode of action (MoA) is thought to mediate the acute oral toxicity in fasted rats observed with all category members.
It can be predicted with high confidence that the target substances will display the same MoA and lead to the same effects seen with NaTG.
Reason / purpose for cross-reference:
read-across: supporting information
Details on absorption:
Study A: 0.27% of the applied dose
Study B: 0.24% of the applied dose
Study C: 0.26% of the applied dose
Details on excretion:
Urine: 76.5 - 80.3% of the eliminated 14C
Faeces: 19.7 - 23.5% of the eliminated 14C
Metabolites identified:
not measured
Conclusions:
Based on the data for ATG, NaTG is assumed to show low dermal absorption and no potential for bioaccumulation.
Endpoint:
dermal absorption in vivo
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Justification for type of information:
REPORTING FORMAT FOR THE CATEGORY APPROACH

1. HYPOTHESIS FOR THE CATEGORY APPROACH
This scenario covers the category approach for which the hypothesis is based on transformation to a common compound. For the REACH information requirement under consideration, the effects obtained in studies conducted with different source substances are used to predict the effects that would be observed in a study with the target substance if it were to be conducted. The same type of effect is observed for the different source substances; this may include absence of effects for every member of the category. No relevant differences in strengths of effect are observed for several source substances.
There are no relevant variations in properties among source substances and the same potency is predicted for all target substances. This corresponds to Scenario 5 of the RAAF (ECHA, 2017). The substances ATG, MEATG, KTG, CaTG, and NaTG are different inorganic salts of a common acid, thioglycolic acid (TGA; synonym: 2-mercaptoacetic acid). They dissociate rapidly in aqueous media to the common thioglycolate anion and to their different counter ions. The water solubility of all category members is high.
This approach serves to use existing data on aquatic toxicity endpoints for substances in this category.
It can be predicted with high confidence that the target substances will display the same mode of action and lead to the same type and strength of effects as observed with the source substances.


2. CATEGORY APPROACH JUSTIFICATION
For details, refer to Justification for read-across attached to Iuclid section 13
Reason / purpose for cross-reference:
read-across: supporting information
GLP compliance:
yes
Key result
Time point:
30 min
Dose:
165 mg/kg bw
Parameter:
percentage
Absorption:
ca. 1 %
Remarks on result:
other: rinsing after 30 min
Conclusions:
Based on data for ATG, the cutaneous absorption of aqueous NaTG solutions is expected to be ca. 1%.
Endpoint:
dermal absorption in vitro / ex vivo
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Justification for type of information:
The read-across is a category approach based on the hypothesis that compounds in this category are transformed to a common compound. This approach serves to use existing data on genotoxicity, repeated-dose toxicity, and reproductive toxicity endpoints for substances in this category.
There are no relevant variations in properties among source substances and the same potency is predicted for all target substances. This is Scenario 5 of the RAAF11 . Substances ATG, MEATG, KTG, CaTG, and NaTG are different inorganic salts of a common acid, thioglycolic acid (TGA; synonym: 2- mercaptoacetic acid). They dissociate rapidly in aqueous media, e.g., the test organism, to the common thioglycolate anion and to their different counter ions (Figure 1). The water solubility of all category members is high, except for CaTG which is only moderately soluble in water.
In the repeated-dose toxicity studies with NaTG, specific toxicity is exerted via the well-investigated inhibition of mitochondrial fatty acid beta-oxidation by the thioglycolate (2-mercaptoacetate) anion 2,3,4. Inhibition of beta-oxidation leads to increased triglycerides and decreased acetyl-CoA in liver, and subsequently reduced gluconeogenesis. The latter presents as hypoglycaemia in NaTGtreated rats, which is aggravated by fasting (Grosdidier, 2011; Report No. 37043 TSR). This mode of action (MoA) is thought to mediate the acute oral toxicity in fasted rats observed with all category members (see Table 2).
It can be predicted with high confidence that the target substances will display the same MoA and lead to the same effects seen with NaTG.
Reason / purpose for cross-reference:
read-across: supporting information
Details on test animals or test system and environmental conditions:
le).

Test Preparation

ATG in Permanent Hair Waving Formulation

CaTG in Depilatory Formulation

MEATG in Hair Straightening Formulation

Test Item Concentration (w/w)

13

10

18

Mean Application Rate of Formulation (mg/cm2)

20.28

20.11

20.12

Mean Application Rate of Test Item (µg equiv./cm2)

2636.13

2010.74

3621.78

Dislodgeable Dose at 30, 15, 45 min, respectively (% Applied Dose)

98.69

104.70

98.14

Total Dislodgeable Dose* (% Applied Dose)

98.98

105.07

98.36

Unabsorbed Dose** (% Applied Dose)

99.04

105.08

98.41

Dermal Adsorption (% Applied Dose)

0.17

0.07

0.09

Percutaneous Penetration (% Applied Dose)

0.22

0.02

0.17

Dermal Bioavailability (% Applied Dose)

0.77

0.20

0.38

Mass Balance (% Applied Dose)

99.97

105.36

98.87

Dislodgeable Dose at 30, 15, 45 min, respectively (µg equiv./cm2)

2601.66

2105.30

3554.39

Total Dislodgeable Dose* (µg equiv./cm2)

2609.26

2112.73

3562.29

Unabsorbed Dose** (µg equiv./cm2)

2610.93

2112.94

3564.05

Dermal Adsorption (µg equiv./cm2)

4.58

1.48

3.15

Percutaneous Penetration (µg equiv./cm2)

5.23

0.41

5.83

Dermal Bioavailability (µg equiv./cm2)

19.83

4.09

13.64

Mass Balance (µg equiv./cm2)

2635.34

2118.52

3580.85

* Total dislodgeable dose = skin washes + tissue swabs + pipette tips + donor chamber wash

** Unabsorbed dose = total dislogeable Dose + unexposed skin

Conclusions:
Based on data for CaTG, the cutaneous absorption of aqueous NaTG solutions is expected to be less than 1%..
Executive summary:

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:

Test Preparation

ATG in Permanent Hair Waving Formulation

CaTG in Depilatory Formulation

MEATG in Hair Straightening Formulation

Test Item Concentration (w/w)

13

10

18

Mean Application Rate of Formulation (mg/cm2)

20.28

20.11

20.12

Mean Application Rate of Test Item (µg equiv./cm2)

2636.13

2010.74

3621.78

Dislodgeable Dose at 30, 15, 45 min, respectively (% Applied Dose)

98.69

104.70

98.14

Total Dislodgeable Dose* (% Applied Dose)

98.98

105.07

98.36

Unabsorbed Dose** (% Applied Dose)

99.04

105.08

98.41

Dermal Adsorption (% Applied Dose)

0.17

0.07

0.09

Percutaneous Penetration (% Applied Dose)

0.22

0.02

0.17

Dermal Bioavailability (% Applied Dose)

0.77

0.20

0.38

Mass Balance (% Applied Dose)

99.97

105.36

98.87

Dislodgeable Dose at 30, 15, 45 min, respectively (µg equiv./cm2)

2601.66

2105.30

3554.39

Total Dislodgeable Dose* (µg equiv./cm2)

2609.26

2112.73

3562.29

Unabsorbed Dose** (µg equiv./cm2)

2610.93

2112.94

3564.05

Dermal Adsorption (µg equiv./cm2)

4.58

1.48

3.15

Percutaneous Penetration (µg equiv./cm2)

5.23

0.41

5.83

Dermal Bioavailability (µg equiv./cm2)

19.83

4.09

13.64

Mass Balance (µg equiv./cm2)

2635.34

2118.52

3580.85

* 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 (Dermal Adsorption) 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.

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 sodium thioglycolate.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
100
Absorption rate - dermal (%):
1
Absorption rate - inhalation (%):
100

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, and γ-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 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-thioglycolate 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 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 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 total 35S 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 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.