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Administrative data

Description of key information

Based on read across from 2-EHTG, the oral LD50 for GDMA is predicted to be 312 mg/kg bw.

In a 1-h inhalation study with a liquid aerosol (mist) of GDMA, the LD50 was >2.25 mg/L. Using Haber's Law, the predicted 4-h LC50 is >0.563 mg/L.

Based on read across from 2-EHTG, the dermal LD50 for GDMA is predicted to be >2000 mg/kg bw.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
see category report attached as "full study report"
Reason / purpose:
read-across source
Principles of method if other than guideline:
read across using the OECD QSAR Toolbox 4.2
Species:
rat
Route of administration:
oral: gavage
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
312 mg/kg bw
Based on:
act. ingr.
Remarks:
read across from 2-EHTG
Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
Based on read across from 2-EHTG, GDMA should be classified as Acute Tox 4 - H302: Harmful if swallowed.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
312 mg/kg bw
Quality of whole database:
Read across from analogue substance

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1979
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
no guideline followed
Principles of method if other than guideline:
1-h inhalation study with GDMA mist
GLP compliance:
no
Remarks:
GLP was not mandatory at the time of study
Test type:
traditional method
Limit test:
yes
Specific details on test material used for the study:
not specified
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
not specified
Route of administration:
inhalation: mist
Type of inhalation exposure:
whole body
Vehicle:
air
Remark on MMAD/GSD:
not reported
Details on inhalation exposure:
Total weight of compound used: 2.7 g
Air flow rate: 20 L/min
Duration: 60 min
Total air: 1200 L
Nominal conc.: 2.25 mg/L
Avg. chamber temperature: 20 °C
Analytical verification of test atmosphere concentrations:
not specified
Duration of exposure:
1 h
No. of animals per sex per dose:
5
Control animals:
no
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 2.25 mg/L air (nominal)
Based on:
test mat.
Exp. duration:
1 h
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 0.563 mg/L air (nominal)
Based on:
test mat.
Exp. duration:
4 h
Remarks on result:
other: calculated using Haber's law
Mortality:
none
Clinical signs:
other: decreased activity, laboured breathing, lacrimation, nasal discharge
Body weight:
no effect
Gross pathology:
9/10 lungs showed few scattered red or grey foci
Interpretation of results:
other: H335: May cause respiratory irritation.
Conclusions:
With an estimated 4-h LC50 of >0.563 mg/L, GDMA may be classified as Acute Tox 3, H331: Toxic if inhaled. As no animal died in the study, the classification as toxic would not be appropriate. Because the animals showed symptoms of irritation of the lungs, H335: May cause respiratory irritation was used instead of H331: Toxic if inhaled.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
Value:
563 mg/m³
Quality of whole database:
As no animal died in the study, the classification as toxic would not be appropriate. Because the animals showed symptoms of irritation of the lungs, H335: May cause respiratory irritation was used instead of H331: Toxic if inhaled.

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Remarks:
One-to-one read-across
Adequacy of study:
key study
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH
A brief overview of the read-across study is reported below. Detailed information on the read-across justification is included in the read-across study report available in the "Attached justification" field. Please also refer to this report for the list of tools used in the assessment.

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The present read-across study falls within the RAAF scenario 2, i.e. one-to-one analogue approach based on the hypothesis that different compounds are supposed to cause the same type of effects as a result of structural similarity.
In the case of GDMA, the hypothesis to apply the read-across approach is based on the structural similarity of the target compound GDMA with respect to the source compound EHTG. Supporting information to further justify the analogue approach is provided by comparing the source and target compounds in terms of mechanistic similarity, physico-chemical properties and ADME profile.
Additional details can be found in the attached read-across study report.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Please refer to section 1.2 (general information/composition) of both target and source's IUCLID dossiers, and to the attached read-across study report.

3. ANALOGUE APPROACH JUSTIFICATION
Structural similarity: The main structural difference among the target GDMA and the source EHTG consists in the following: the target GDMA possesses two sulfanyl acetate fragments esterified by the ethylene glycol, while the source EHTG possesses only one sulfanyl acetate group esterified by a 2-ethylhexanol. These differences are reflected in minimal differences in molecular structure data (e.g., no. of atoms and bonds), while no significant structural differences in terms of functional groups, structural fragments and chemical class were identified. In particular, two functional groups, i.e. Carboxylic acid ester and Thiol, and two ECOSAR chemical classes, i.e. Esters and Thiols, were identified in both target and source compounds. In addition, the source EHTG possesses an additional functional group, i.e. Alkane branched with tertiary carbon (which correspond to the US EPA fragment “Tertiary carbon”).
Concluding, target and source compounds exhibited moderate structural similarity. Uncertainty associated with structural similarity was assessed to be low.


Mechanistic similarity: The target and the source compounds show a similar mechanistic profile with respect to protein binding potential, where the same alert was identified by the OASIS profiler ("Thiols and disulfide compounds") and the OECD profiler (“Thiols”) in both target and source (as illustrated in Figure 5.1). For this structural alert, it has been suggested an SN2 type mechanism with thiol groups in biological macromolecules resulting in the formation of disulfide bridges. The identified structural alert and the mechanism related to it, could explain the skin sensitising potential identified for the source compound EHTG. It is highlighted that the identified structural difference between the target and the source in the form of 2-ethylhexanol was not profiled as relevant i.e. not related to any specific structural alert. Finally, the ACD/Acute Toxicity Hazards profiler did not identify any hazardous fragments that might be responsible for the acute toxicity of the compounds in rodents.

Concluding, target and source compounds exhibited high mechanistic similarity. However, the uncertainty associated with mechanistic similarity was assessed as medium, due to limitations associated with the endpoint type, further explained in the following text.


Physico-chemical similarity:From the analysis and comparison of experimental and in silico predicted physico-chemical data, it was noted that the target GDMA and source EHTG exhibit minor differences in their physico-chemical profile.
In particular, the target GDMA is less hydrophobic and more water soluble than the source EHTG indicating slightly more favourable properties for dermal uptake. Both compounds are characterized by low volatility (VP <0.5 kPa). Concerning dissociation, the target and source compounds show similar pKa values close to 8, which refer to thiol groups that are very weak acids. It is expected that both compounds will exist in the non-dissociated form at physiologically pHs, i.e. pH of 1.7 (stomach) and 5 (skin), thus with a positive impact on dermal absorption, and will be partially ionised at pH-s 7.4 (blood) and 8.0 (colon).
The estimated surface tension values of the target (GDMA) and the source (EHTG) were noted to be above 10 mN/m (i.e., 46.21 and 32.23 mN/m respectively), indicating an unlikely positive effect on dermal uptake. The possibility of forming more hydrogen bods (4) to the skin components is less favorable for dermal uptake in the case of the target (GDMA). The liquid physical state of both chemicals highlights a readily uptake from the skin.
Based on the above considerations, the target GDMA and the source EHTG are expected to have similar dermal uptake, however for GDMA moderate to high water solubility and lower lipophilicity was determined.
Both experimental and predicted data used in the present assessment were characterized by good reliability. In addition, a good consistency between experimental and predicted data was observed (except for water solubility prediction generated for the target GDMA).
Concluding, the target and source compounds exhibit moderate similarity in terms of their physico-chemical profile. The uncertainty associated with PC similarity was assessed as medium.

ADME similarity: the ADME property similarity was assessed based on predicted data by ACD/Percepta for absorption, bioavailability, distribution, and metabolism. A moderate similarity in terms of the predicted ADME profile was demonstrated for the target and the source.
The target and the source compounds were both predicted to be well orally absorbed in the organism, with a predicted passive absorption across intestinal epithelium equal to 100%. For the source EHTG, this prediction is supported by the available toxicokinetics data. The prediction for the target, GDMA, is supported by physicochemical data, i.e. the molecular weight (below 500) and logKow value (between 1 and 4), which are favorable for absorption by passive diffusion .
Both compounds were found to be characterized by high oral bioavailability (F equal to 99.9% for GDMA and 97.2% for EHTG, based on a standard administration dose equal to 50 mg). However, it should be acknowledged that a significant first-pass metabolism was predicted for both compounds (63% and 59% of the absorbed fraction for target and source, respectively), meaning that there is a high probability that both substances will be metabolically transformed by enzymes in liver and intestine. In the experimental study available for the source EHTG, the intact substance was not identified neither in organs neither in excrements, which confirms the predicted significant metabolism for the source. EHTG is expected to be partially hydrolyzed in the stomach before to be absorbed. EHTG is further hydrolyzed in several tissues by carboxylesterases to thioglycolic acid and the corresponding alcohol (2-ethylhexanol).
Following extensive metabolism, the actual oral bioavailability is predicted to decline to 37% and 39.9% for target and source, respectively.
The predicted volumes of distribution (1.2 and 8.9 L/Kg for target and source, respectively) are above the volume of total body water (0.7 L/kg), and this indicates that both compounds have affinity to extravascular tissue. A comparison based on plasma protein binding potential was not possible since the PPB% prediction generated for the source EHTG was not reliable. Following, based on the experimental data for the source it was further confirmed that the substance is distributed to organs but no major site of accumulation (regarding concentration per g tissue) was defined.
Lipophilicity of the target (GDMA) compound is in the range (1-4) that favours dermal absorption but in combination with high water solubility. In contrast, the lipophilicity of the source compound (EHTG) is on the upper range value and water solubility is low. Molecular weights of the target and the source are similar and range from 210.27 Da to 204.33 Da, respectively. Furthermore, generally, both dissociate at pHs greater than 7.6. From the physico-chemical data analysis, a similar dermal uptake is expected for the target GDMA if compared to the dermal uptake expected for the source EHGT. Concluding, the target and source compounds exhibit moderate similarity in terms of the predicted ADME profile and the uncertainty associated with ADME similarity was assessed to be medium, due to limitations associated to the following issue: ADME properties for the target were only predicted and did not cover rate and extent of metabolism and elimination.


Potential metabolic products: The major metabolites and biotransformation pathways of target and source compounds were generated with the ChemTunes Liver BioPath tool and the OECD QSAR Toolbox Skin metabolism simulator.

From each parent compound, two metabolites are derived from the hydrolysis of the carboxylic acid esters (primary phase I reaction):
a) sulfanylacetic acid acid (common phase I metabolite for the target GDMA and source EHTG);
b) 2-hydroxyethyl sulfanylacetate (phase I metabolite for the target GDMA)
c) 2-ethylhexan-1-ol (phase I metabolite for the source EHTG).
Conjugation via methylation of the thiol group is expected to occur as phase II metabolism for each of the three compounds.
The predicted metabolites from the OECD QSAR Toolbox skin metabolism analysis were the same as the phase I metabolites as provided by ChemTunes liver BioPath. A further metabolite (i.e., methanol) was predicted for MMP by the OECD QSAR Toolbox.
Finally, the predicted metabolites of target and source compounds were profiled with the OECD QSAR toolbox (structural- and mechanistic-based profilers). The assessment of their structural and mechanistic similarity was performed in order to possibly understand whether some metabolites of the target might have an influence on the prediction of repeated dose toxicity. The results of this profiling are reported in the report in Appendix A of the report, and are following summarised:
- The common hydrolysis metabolite of target GDMA and source EHTG, i.e. sulfanylacetic acid, possesses the thiol functional group, for which a protein binding potential is predicted.
- Due to the main structural difference between target GDMA and source EHTG chemicals (i.e. two sulfanyl acetate fragments esterified by the ethylene glycol and only one sulfanyl acetate group esterified by a 2-ethylhexanol, respectively), a difference in functional groups was identified for Phase I and II metabolites of the target and the source. The “Thiol” group is absent in the source EHTG metabolites as well as carboxylic acid ester is not present in one EHTG metabolite. Whereas the other metabolites of the target GDMA lack the “Alkane, branched with tertiary carbon” group of the source EHTG.
-The major mechanistic differences were identified among the target GDMA and the source EHTG metabolites concerning protein binding relating to some metabolites, where the mechanism is no longer relevant in the case of the source EHTG.
- Additionally no hazardous fragments for acute oral toxicity were identified in any of the metabolites.


Concluding, target and source compounds exhibited high similarity in terms of their potential metabolites. The identified potential metabolites showed high structural and mechanistic similarity as well. It is highlighted that the Phase I metabolites predicted for the source EHTG were confirmed by the available experimental data, thus reducing the uncertainty associated with the use of in silico predicted metabolites in the similarity assessment. However, the following issue is highlighted: identification of potential metabolites and related structural and mechanistic profile was based on in silico predictions.

Source experimental data: for the assessment of acute dermal toxicity, one acute dermal experimental study a source substances EHTG was available. The study for EHTG was reported by the registrant to be reliable withou restrictions (Klimisch score 1), w. An experimental Acute dermal LD50 value greater than 2000 mg/kg bw was derived for source EHTG. The study assessed as adequate for the read-across prediction of the target EHMP.

4. DATA MATRIX
EHTG was selected as source compounds in the present read-across study.
The similarity assessment, which consisted of a comparison of structural, mechanistic, physicochemical, ADME and metabolism profiles, showed that the source EHTG and the target GDMA are sufficiently similar to justify the read-across approach.
The data matrix is included in the attached report.
Reason / purpose:
read-across source
Remarks:
Source EHTG (CAS No: 7659-86-1)
Qualifier:
according to
Guideline:
other: ECHA, 2015: Read-Across Assessment Framework (RAAF).
Specific details on test material used for the study:
SMILES: O=C(OCCOC(=O)CS)CS
InChI: InChI=1S/C6H10O4S2/c7-5(3-11)9-1-2-10-6(8)4-12/h11-12H,1-4H2

Key result
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
other: Source
Remarks on result:
other: Read-across
Interpretation of results:
GHS criteria not met
Remarks:
Based on read-across
Conclusions:
An acute dermal toxicity study in rat was available for the source EHTG (LD50 value > 2000 mg/kg bw) and was assessed as adequate for the read-across prediction for the target GDMA. Based on the read-across study presented, it is concluded that the acute dermal toxicity data available for the source could be used to support the same classification of the target GDMA.
Executive summary:

This study was designed to generate read-across predictions of acute dermal toxicity for GDMA to be used for its safety assessment in the regulatory framework of REACH.

In the read-across analysis, EHTG was selected as source chemical for the target GDMA. The similarity assessment, which consisted of a comparison of structural, mechanistic, physicochemical, ADME and metabolism profiles, showed that the source EHTG and the target GDMA are sufficiently similar to justify the read-across approach.

An acute dermal toxicity study in rat was available for the source EHTG (LD50value > 2000 mg/kg bw) and was assessed as adequate for the read-across prediction for the target GDMA.

In the present read-across study, an overall medium uncertainty was associated with similarity justification, based on the following issues: i) mechanistic bases of the endpoint to be read-across are not yet well defined; ii) some differences identified in relation to the phys-chem profile; iii) ADME assessment for target was based on simulated data only, which do not cover rate and extent of dermal and systemic metabolism and elimination; iv) identification of potential metabolites (for target) and related mechanistic profiles was based on in silico predictions only. The main uncertainties associated with the read-across argument were related to the following issues: i) endpoint-type, ii) analogue set limited to one source compound.

Concluding, the read-across from the existing acute dermal toxicity study available for the source substance EHTG could be used to predict the acute dermal toxicity of the target substance GDMA in order to fulfil the information requirement of Annex VIII 8.5 of the REACH Regulation.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
Read across from analogue substance

Additional information

Justification for classification or non-classification

Based on an estimated oral LD50 of 312 mg/kg bw, GDMA should be classified as Acute Tox 4 - H302: Harmful if swallowed.

Based on an estimated 4-h LC50 of >0.563 mg/L, GDMA should be classified as Acute Tox 3 - H331: Toxic if inhaled.

Based on an estimated dermal LD50 of >2000 mg/kg bw, GDMA should not be classified for acute dermal toxicity.