Ethylene di(S-thioacetate)

Endpoint summary

Description of key information

Based on the read-across approach, GDMA is expected to show similar effects compard to NaTG. After correction for molecular weight differences the NOEAL of GDMA for repeated dose toxicity is predicted to be 37 mg/kg bw/d (13 wk repeated dose toxicity study, oral, rat, NaTG)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Justification for type of information:

This scenario covers the analogue approach for which the read-across hypothesis is based on (bio) transformation to common compound(s). For the REACH information requirement under consideration, the effects obtained in a study conducted with one source substance 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(s) or absence of effect is predicted. The predicted strength of the effects may be similar or based on a worst-case approach
The hypothesis corresponds to Scenario 1 of the RAAF. The source substance NaTG will be used to read-across two endpoints, e.g. repeated dose toxicity and toxicity to reproduction, of the target substance GDMA. Source and target substance are expected to share common metabolites. GDMA is rapidly hydrolysed after absorption into TGA and ethylene glycol, while NaTG will dissociate into TGA and sodium ion. By now, no experimental toxicokinetic data is available for GDMA. Therefore, simulated gastric acid hydrolysis as well as in vitro metabolic studies are planned to strengthen the hypothesis.
For detailed information, please refer to section 13.2.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across: supporting information

Dose descriptor:

LOAEL

Effect level:

37 mg/kg bw/day (actual dose received)

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

clinical biochemistry

histopathology: non-neoplastic

mortality

Remarks on result:

other: corrected for molecular weight differences

Key result

Dose descriptor:

NOAEL

Effect level:

37 mg/kg bw/day (actual dose received)

Sex:

male/female

Basis for effect level:

histopathology: non-neoplastic

serum/plasma biochemistry

Remarks on result:

other: corrected for molecular weight differences.

Dose descriptor:

NOEL

Effect level:

12 mg/kg bw/day (actual dose received)

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

other:

Remarks on result:

other: corrected for molecular weight differences

Critical effects observed:

not specified

Conclusions:

Based on the read-across hypothesis, GDMA is expected to show similar effects in an sub chronic oral toxicity study. Therefore, after correction for molecular weight differences, the NOAEL for GDMA was determined to be 37 mg/kg bw/day.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

37 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

The available key studies are reliable or reliable with restrictions (Klimisch 1 – 2) and were conducted according to or similar to guidelines.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

For NaTG, a 90-day repeated dose toxicity study according to OECD 408 is available.

Sodium thioglycolate was administered by daily oral administration (gavage) to Sprague-Dawley rats at dose‑levels of 7, 20 or 60 mg a.i./kg/day (a.i. = active ingredient) for 13 weeks. On completion of the treatment period, designated animals were held for a 4-week treatment-free period in order to evaluate the reversibility of any findings.

At 60 mg a.i./kg/day, one female was prematurely sacrificed for humane reasons on day 14and one male was found dead on day 90.Changes, which were also noted in the animals sacrificed on schedule, were found in the kidneys of the female sacrificed for humane reasons, and the liver and thymus of both these animals. The vacuolation/microvacuolation of kidney and liver was considered to be related to treatment with sodium thioglycolate. The demise and death of these animals were attributed to treatment with sodium thioglycolate.In surviving animals, hypersalivation, piloerection and/or areas of thinned hair were transiently observed in some animals.At laboratory investigations, marked panleucopenia was noted in both sexes (all the white blood cell subtypes were affected). High mean red blood cell count, hemoglobin concentration, packed cell volume and mean prothrombin time were observed in males and females. However, the bone marrow cellularity and number of megakaryocytes were similar to the control values. Hypoglycemia was noted in males and females, associated with high urea (males and females) and creatinine (males only) levels and low chloride levels (male and female). High fat acid level was observed in males and females. High aspartate aminotransferase (males only) and alanine aminotransferase (males and females) activities were noted. Low mean ß‑hydroxybutyrate levels, associated with high lactate concentrations, were reported in males and females.

Sodium thioglycolate-related changes were noted in the liver of males and females and the kidneys of females. In both organs, there were microvacuolar changes that were considered not to be adverse since theywere observed with low incidence and severity. Microvacuolation in the liver was Oil Red O positive, indicating the presence of neutral lipids and a microvesicular lipidosis (syn. steatosis) change. A minimal increase in incidence and severity of extramedullary hematopoiesis was noted in the liver of females. All these changes were not observed at the end of the treatment-free period.

At 20 mg a.i./kg/day, non-adverse minimal periportal microvacuolation corresponding to minimally increased severity of lipidosis (syn. steatosis) was noted in two males. In females, low glucose and ß‑hydroxybutyrate levels were noted, associated with high urea and fatty acid concentrations. High mean prothrombin time was also noted in females. At this dose level, no signs of adverse toxic effects were noted.

At 7 mg a.i./kg/day, no changes or signs of toxicity were noted.

Consequently, under the experimental conditions of this study, based on the adverse effects observed at 60 mg a.i./kg/day, particularly mortality, haematological and significant blood chemistry changes associated with liver microscopic changes and the limited blood chemistry effects without microscopic changes in the liver observed at 20 mg a.i./kg/day, the No Observed Adverse Effect Level (NOAEL) of sodium thioglycolate was 20 mg a.i./kg/day, and the No Observed Effect Level (NOEL) was 7 mg a.i./kg/day given by daily oral administration (gavage) to rats for 13 weeks.

 

No experimental data is available for GDMA. Based on the read-across hypothesis, similar effects as for NaTG would be expected for GDMA:

 

Table 6: Repeated dose toxicity of non-common compounds

	CAS	NOAELs
Ethylene glycol	107-21-1	90 d NOEL = 150 mg/kg bw/day (Cruzan et al., 2004) 28 d NOAEL = 200 mg/kg bw/day (rats) (Schladt et al. 1998)

 

As demonstrated in Table 6 and in section AE 2.5, the non-common compounds do not contribute to a relevant extent to the overall acute toxicity of the substances. The main driver for toxicity of the substances seems to be the TGA moiety.

A data gap for repeated dose toxicity was identified for GDMA. Based on the considerations concerning bioavailability, there is reason to believe that NaTG could be the worst-case for GDMA. Data obtained with NaTG was applied to GDMA and corrected for molecular weight differences. The estimated sub chronic NOAEL was determined to be 37 mg/kg bw/day.