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Administrative data

Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

The weight of evidence suggests that NaTG is not genotoxic.

Link to relevant study records

Referenceopen allclose all

Endpoint:
in vitro gene mutation study in bacteria
Remarks:
Type of genotoxicity: gene mutation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods with acceptable restrictions
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 471 (Bacterial Reverse Mutation Assay)
Deviations:
not specified
GLP compliance:
not specified
Type of assay:
bacterial reverse mutation assay
Target gene:
Histidine reversion
Species / strain / cell type:
S. typhimurium, other: Strains: TA98, TA100, TA1535 and TA1537
Metabolic activation:
with and without
Metabolic activation system:
Rat and hamster liver S9 induced with aroclor 1254
Test concentrations with justification for top dose:
0, 10, 33, 100, 333 and 1000 µg/plate
Vehicle / solvent:
no data
Untreated negative controls:
no
Negative solvent / vehicle controls:
yes
True negative controls:
no
Positive controls:
yes
Positive control substance:
other: Without activation : sodium azide (TA1535 and TA 100),  9-aminoacridine (TA 97), 4-nitro-o-phenylenediamine (TA98).   With activation : 2-aminoanthracene (all strains).
Details on test system and experimental conditions:
In the Salmonella assay, a test tube containing a suspension of one  strain of Salmonella typhimurium plus S9 mix or plain buffer without S9,  is incubated for 20 minutes at 37º C with the test chemical. Control  cultures, with all the same ingredients except the test chemical, are  also incubated. In addition, positive control cultures are also prepared;  these contain the particular bacterial tester strain under investigation,  the various culture ingredients, and a known potent mutagen. After 20  minutes, agar is added to the cultures and the contents of the tubes are  thoroughly mixed and poured onto the surface of Petri dishes containing  standard bacterial culture medium. The plates are incubated for 48 hours  and then counted. The substance was tested initially in a toxicity assay to determine the  appropriate dose range. 
The toxicity assay was performed by using TA 100.  Toxic concentrations were those at which a decrease in the number of his+  colonies was seen or at which there was a clearing in the density of the  background lawn.

- Test Design   . Number of replicates : 3
- Description of follow up repeat study : same conditions than the initial experiment performed 1 week later
Evaluation criteria:
The positive control plates are counted, and the number of mutant  colonies appearing on them must be significantly increased over the  spontaneous control number for the test to be considered valid.  If no increase in mutant colonies is seen after testing several strains  under several different culture conditions, the test chemical is  considered to be non mutagenic in the Salmonella test.
Statistics:
None
Species / strain:
S. typhimurium, other: Strains: TA98, TA100, TA1535 and TA1537
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
cytotoxicity
Remarks:
> 1000 µg/plate
Vehicle controls validity:
valid
Untreated negative controls validity:
not examined
Positive controls validity:
valid
Remarks on result:
other: all strains/cell types tested
Remarks:
Migrated from field 'Test system'.

Chemical Name:

Sodium thioglycolate

CAS Number:

367-51-1

Study Type:

Salmonella

Study ID:

471613

Study Result:

Negative

Year Completed:

1979

Vehicle Control:

Water

Protocol:

Preincubation

Individual strain data is presented as mean ± standard error.

Abbreviations are noted at bottom of page.

Trial summary calls are shown in parentheses.

Strain: TA1535

Dose

No Activation

No Activation

10% HLI

10% HLI

10% RLI

(Negative)

(Negative)

(Negative)

(Negative)

(Negative)

ug/Plate

Mean

± SEM

Mean

± SEM

Mean

± SEM

Mean

± SEM

Mean

± SEM

0     

7

0.7

7

0.6

6

0.9

7

2.6

7

0.7

10     

6

1

6

0.9

5

0.9

6

2

8

1.2

33     

5

1.5

6

0.9

7

1.5

9

1.2

6

1.3

100     

8

3.5

9

1.3

7

0.6

9

0.7

6

0.9

333     

6

0.6

6

0.9

5

1.2

7

1.5

8

1.2

1000     

5

1.2

8

2

5

0.3

8

1.2

8

0.9

Positive Control

288

32.3

251

40.8

106

16

43

4.1

135

9.7

Strain: TA100

Dose

No Activation

No Activation

10% HLI

10% HLI

10% RLI

10% RLI

(Negative)

(Negative)

(Negative)

(Equivocal)

(Negative)

(Negative)

ug/Plate

Mean

± SEM

Mean

± SEM

Mean

± SEM

Mean

± SEM

Mean

± SEM

Mean

± SEM

0     

100

5

110

5.8

185

26.5

179

11.7

175

27.8

189

8.7

10     

95

5

126

11.4

160

18

164

6.2

140

30.4

204

37.7

33     

105

31.2

129

7.5

195

30

174

7.6

170

40.9

189

3.5

100     

115

10

121

3.8

220

18

221

4.2

145

18

175

9

333     

125

13.2

122

8.5

160

5

173

10.1

135

8.7

221

8.1

1000     

120

30

124

8.8

215

13.2

202

4.3

155

35

181

18.1

Positive Control

430

27.8

599

36.4

558

5.9

836

172.5

300

11.1

430

70.3

Conclusions:
Under these experimental conditions, sodium thioglycolate is considered as non-genotoxic
Executive summary:

In a study performed according to the US NTP protocol, four S. typhimurium strains (TA 98, TA 100, TA 1535 and TA 1537) were exposed to sodium thioglycolate in a preincubation assay. Based on a preliminary toxicity assay, concentrations up to 1000 µg/plate were used with or without metabolic activation (rat and hamster S9) in all four strains. Sodium thioglycolate did not induce mutations in these studies. Positive and solvent controls gave the expected results.

Endpoint:
in vitro gene mutation study in mammalian cells
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
Key result
Species / strain:
mouse lymphoma L5178Y cells
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
other: 4-h experiment (+/-S9): > 1600 µg/ml / 24-h experiment (-S9): >= 800 µg/ml
Vehicle controls validity:
valid
Untreated negative controls validity:
not examined
Positive controls validity:
valid
Remarks on result:
other: all strains/cell types tested
Remarks:
Migrated from field 'Test system'.
Conclusions:
By analogy to ATG, NaTG is considered negative for gene mutations in mammalian cells.
Endpoint:
in vitro cytogenicity / chromosome aberration study in mammalian cells
Remarks:
Type of genotoxicity: chromosome aberration
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
Key result
Species / strain:
lymphocytes: human
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
other: With S9 : 1000 µg/ml. Without S9 : 300 µg/ml
Vehicle controls validity:
valid
Untreated negative controls validity:
not examined
Positive controls validity:
valid
Remarks on result:
other: strain/cell type: Human lymphocytes
Remarks:
Migrated from field 'Test system'.
Conclusions:
By analogy to TGA, NaTG is considered negative for chromosomal aberrations in vitro.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (negative)

Genetic toxicity in vivo

Description of key information

The weight of evidence suggests that NaTG is not genotoxic.

Link to relevant study records
Reference
Endpoint:
in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus
Remarks:
Type of genotoxicity: chromosome aberration
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
GLP compliance:
yes
Type of assay:
other: Micronucleus assay on mouse bone marrow
Species:
mouse
Strain:
NMRI
Sex:
male/female
Details on test animals or test system and environmental conditions:
- Animals . 
. Source: Harlan Winkelmann GmbH D-33178 Borchen
. Number of Animals: 72 (36 males/36 females), 6 males and 6 females per  group
. Initial Age at Start of Acclimatisation: 8-10 weeks
. Acclimatisation: minimum 5 days
. Initial Body Weight at Start of Treatment: males mean value 37.1 g (SD  ± 2.9 g) females mean value 31.5 g (SD ± 1.9 g)

- Environmental conditions
. Housing: single Cage Type: Makrolon Type I, with wire mesh top (EHRET  GmbH, D-79302 Emmendingen)
. Bedding: granulated soft wood bedding (Harlan Winkelmann GmbH, D-33178  Borchen)
. Temperature 22 ± 3 °C
. Relative humidity 30 - 70 %
. Artificial light 6.00 a.m. - 6.00 p.m.

- Food and water
. Feed: pelleted standard diet, ad libitum (Harlan Winkelmann GmbH,  D-33178 Borchen)
. Water: tap water, ad libitum, (Gemeindewerke, D-64380 Roßdorf)
Route of administration:
oral: gavage
Vehicle:
Name: deionised water         
Route and Frequency of Administration: orally, once         
Volume Administered: 10 mL/kg b.w.
Duration of treatment / exposure:
single administration
Frequency of treatment:
single
Post exposure period:
24 and 48 hours
Remarks:
Doses / Concentrations:
0, 62.5, 125 and 250 mg/kg bw
Basis:
actual ingested
No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle
Positive control(s):
Name: CPA; Cyclophosphamide         
Dissolved in: deionised water         
Dosing: 40 mg/kg b.w.         
Route and frequency of administration: orally, once         
Volume administered: 10 mL/kg b.w.
Tissues and cell types examined:
Bonne marrow
Details of tissue and slide preparation:
- Preparation of the bone marrow smears
Ten animals (5 males, 5 females) per test group (all groups after 24  hours and only the high dose group after 48 hours) were killed by CO2  inhalation, following by bleeding. The femurs of the animals were removed  and the bone marrow was flushed out using foetal calf serum. After  centrifugation, the supernatant was removed and the cells in the sediment  were resuspended by shaking. A drop of this cell suspension was placed  and spread on a slide. The slides were air dried and stained with  May-Grünwald. The slides were coded so that the scorer is unaware of the  treatment group of the slide under evaluation ("blind" scoring).

- Microscopic examination of the slides
For each animal, the number of the micronucleated polychromatic  erythrocytes (MPE) was counted in 2000 polychromatic erythrocytes; the  polychromatic (PE) and normochromatic (NE) erythrocyte ratio was  established by scoring a total of 1000 erythrocytes (PE + NE). 
Evaluation criteria:
The study was considered valid as the following criteria are met:
- the negative controls are in the range of our historical control data.
- the positive controls are in the range of our historical control data.
- at least 4 animals per group and sex can be evaluated
- PCE to erythrocyte ratio should not be less than 20 % of the negative  control.

A test item is classified as mutagenic if it induces either a  dose-related increase or a clear increase in the number of micronucleated  polychromatic erythrocytes in a single dose group. 
Statistics:
Statistical methods (nonparametric Mann-Whitney test (8)) will be used  as an aid in evaluating the results. However, the primary point of  consideration is the biological relevance of the results. A test item that fails to produce a biological relevant increase in the  number of micronucleated polychromatic erythrocytes is considered  non-mutagenic in this system.
Sex:
male/female
Genotoxicity:
negative
Toxicity:
yes
Remarks:
clinical signs
Vehicle controls validity:
valid
Negative controls validity:
not examined
Positive controls validity:
valid
Additional information on results:
As estimated by a pre-experiment 250 mg Sodium Thioglycolate 98%, Pure  per kg b.w. was suitable.
The mean number of polychromatic erythrocytes was not decreased after  treatment with the test item as compared to the mean value of PCEs of the  vehicle control indicating that Sodium Thioglycolate 98%, Pure had no  cytotoxic properties in the bone marrow. In comparison to the corresponding vehicle controls there was no  statistically significant or biologically relevant enhancement in the  frequency of the detected micronuclei at any preparation interval and  dose level after administration of the test item. 
The mean values of micronuclei observed after treatment with Sodium Thioglycolate 98%,  Pure were below or near to the value of the vehicle control group.
40 mg/kg b.w. cyclophosphamide administered orally was used as positive  control which showed a statistically significant increase of induced  micronucleus frequency.

Summary of Micronucleus Test Results

test group

dose (mg/kg b.w)

sampling time (h)

PCEs with micronuclei (%)

range

PCE per 2000 erythocytes

vehicle

0

24

0.050

0 - 2

1098

test item

62.5

24

0.060

0 - 2

1124

test item

125

24

0.025

0 - 1

1123

test item

250

24

0.055

0 - 3

1100

Positive control

40

24

1.500

10 -43

1099

test item

250

48

0.095

0 - 6

1123

Historical Controls (1999 – 2004)

Vehicle Controls

Positive Controls (CPA)

Males

Females

Total

Males

Females

Total

Mean*±SD

0.078±0.04

0.058±0.033

0.069±0.028

1.867±0.57

1.368±0.497

1.632±0.468

Range**

0.01 - 0.23

0.0 - 0.19

0.01 - 0.15

0.70 -3.46

0.49 -3.55

0.77 - 3.48

No. of Experiments

229

217

230

228

217

229

*: mean value (percent micronucleated cells)

**: range of the mean group values (percent micronucleated cells)

Conclusions:
Interpretation of results (migrated information): negative
Sodium Thioglycolate 98%, Pure is considered to be non-mutagenic in this micronucleus assay.
Executive summary:

The clastogenic potential of sodium thioglycolate was evaluated in a micronucleus assay on mouse bone marrow performed according to the OECD guideline # 474.Sodium thioglycolate was administered by single gavage to three groups of five male and five female NMRI mice at dose-levels of 0, 62.5, 125 and 250 mg/kg bw. The positive control was the cyclophosphamide administered orally. The polychromatic erythrocytes/normochromatic erythrocytesratios (PE/NE) in the treated groups were equivalent to those of the control groups. However, systemic exposure was confirmed by the clinical signs observed in males and females receiving 250 mg/kg bw of sodium thioglycolate. No increase of the frequency of the micronucleated polychromatic erythrocytes was observed in the bone marrow harvested 24 or 48 hours after the treatment. Positive and vehicle controls gave the expected results.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (negative)

Additional information

Additional information from genetic toxicity in vivo:

Several in vitro and in vivo genotoxicity studies were performed with thioglycolic acid and its salts. The conducted genotoxicity studies on thioglycolic acid or its salts described in this chapter can be bridged to each other, because in aquous solutions only the organic thioglycolate anion may have the potential to cause genotoxic effects in vitro or in vivo. All genotoxicity studies conducted to date have either negative results or are of doubtful significance. Therefore, the weight of evidence suggests that thioglycolic acid and its salts are non-genotoxic.

Justification for classification or non-classification

Conclusive, but not sufficient for classification.