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Administrative data

Description of key information

The LD50 value of DMDS in the rat is between 50 and 300 mg/kg bw. The LD50-cut-off value according to OECD TG 423 was 200 mg/kg bw. DMDS should be classified as Acute Tox 3 - H301: Toxic if swallowed.

Based on read-across from DPMT and correction for molecular weight, HIDT may be toxic via inhalation with a 4-h LC50 of >0.746 mg spray mist/L

The dermal LD50 of HIDT 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:
experimental study
Adequacy of study:
key study
Study period:
09 May 2012 - 13 Jun 2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Version / remarks:
2008
Deviations:
yes
Remarks:
the study could have been terminated after 100% mortality in the 300 mg/kg group
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Version / remarks:
2001
Deviations:
yes
Remarks:
the study could have been terminated after 100% mortality in the 300 mg/kg group
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
no
Species:
rat
Strain:
other: Crl: CD(SD)
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Sulzfeld, Germany
- Females nulliparous and non-pregnant: yes
- Age at study initiation: Approx. 8 weeks
- Weight at study initiation: 161 - 185 g
- Fasting period before study: ca. 16 h
- Housing: in groups of 3 animals in MAKROLON cages on granulated textured wood
- Diet: Commercial diet, ssniff® R/M-H V1534, ad libitum
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22°C ± 3°C
- Humidity (%): 55% ± 15%
- Air changes (per hr): 12-18
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 2012-05-21 To: 2012-06-13
Route of administration:
oral: gavage
Vehicle:
other: 0.8% aqueous methylhydroxypropylcellulose
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 5, 30, 200 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg bw
Doses:
50, 300, 2000 mg/kg bw
No. of animals per sex per dose:
3-6
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observations were performed
before and immediately, 5, 15, 30 and 60 min, as well as 3, 6 and 24 hours after
administration. Individual body weights were recorded before administration of the test item and thereafter in weekly intervals up to the end of the study and at death.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 50 - < 300 mg/kg bw
Based on:
test mat.
Key result
Sex:
female
Dose descriptor:
LD50 cut-off
Effect level:
200 mg/kg bw
Based on:
test mat.
Mortality:
50 mg/kg bw: 0/6
300 mg/kg bw: 3/3 (death within 3 h post dose)
2000 mg/kg bw: 3/3 (death within 3 h post dose)
Clinical signs:
50 mg/kg bw: revealed slightly reduced motility, slight ataxia, slight tremor, slightly reduced muscle tone and slight dyspnoea
300 mg/kg bw: slightly to moderately reduced motility, slight to moderate ataxia, slight to moderate tremor, slightly reduced muscle tone, slight dyspnoea, tonic and clonic convulsions lateral position, lacrimation
2000 mg/kg bw: slightly to severely reduced motility, slight to severe ataxia, slight to moderate tremor, slightly reduced muscle tone, slight dyspnoea, tonic and clonic convulsions
Body weight:
Surviving animals gained body weight
Gross pathology:
no pathological findings
Interpretation of results:
Category 3 based on GHS criteria
Conclusions:
The LD50 value was ranked between 50 and 300 mg/kg bw. LD50-cut-off value according to OECD TG 423 was 200 mg/kg bw. DMDS should be classified as Acute Tox 3 - H301: Toxic if swallowed.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
200 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
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
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Route of administration:
inhalation
Type of inhalation exposure:
not specified
Duration of exposure:
4 h
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 50 ppm
Based on:
other: read across from DMPT
Exp. duration:
4 h
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 0.746 mg/L air
Based on:
other: read-across from DMPT
Exp. duration:
4 h
Interpretation of results:
Category 3 based on GHS criteria
Conclusions:
Based on read-across from DPMT and correction for molecular weight, HIDT may be toxic via inhalation with a 4-h LC50 of >0.746 mg spray mist/L
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
Value:
746 mg/m³

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)
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. 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 current study, the hypothesis to apply the read-across approach is based on the structural similarity of the three individual constituents of the target (i.e., HIDT, DMDS, and HIDT-adduct) with respect to the mono-constituent source (DMPT). The four structures are members of the same “pool” of structurally related constituents, which share the common group of the 2,2′-Thiodiethanethiol (i.e., DMDS). Moreover, it is highlighted that the multi-constituent target HIDT and the source DMPT belong to the same family of “mercaptans” . This grouping was based on the general structure of small molecules containing free thiol and thioether functions (with the exception of HIDT, which contains thiol and hydroxyl functions).
Supporting information to further justify the analogue approach is provided by analyzing similarities and differences among the individual constituents of the target and the source compounds in terms of mechanistic plausibility, physico-chemical properties and ADME profile.
As required in the RAAF guideline for multi-constituent substances and UVCBs, the impact of possible influences of the target’s constituents on each other’s toxicity, along with a comprehension of their individual potency, will be considered to assess the prediction from the source substance, which is a mono-constituent structurally similar to the constituents of the target compound.
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 three target’s constituents and the source compound exhibit moderate structural similarity, because of a few differences in terms of functional groups and molecular structure data (i.e., number of atoms and bonds). However, the four compounds are members of the same “pool” of structurally related constituents, and the target’s constituent DMDS is the common structural feature among the target’s constituents and the source compound. Overall, the uncertainty associated with structural similarity was assessed as low.

Mechanistic similarity: the three target’s constituents and the source compound exhibit high mechanistic similarity. In particular, the four compounds showed a similar mechanistic profile with respect to protein binding potential, since the same “Thiols” structural alert was identified. No hazardous fragments for acute systemic toxicity have been identified in the three target’s constituents as well as in the source compound. The uncertainty associated with mechanistic similarity was assessed as medium, due to limitations associated with the endpoint type.

Physico-chemical similarity: the target’s constituents and the source compound exhibit a moderate to high physico-chemical similarity, revealing a trend in physico-chemical properties due to the increasing molecular weight. An intermediate level of similarity of the source’s physico-chemical data to those of the two main target’s constituents, DMDS and HIDT, was noted. Based on this analysis, an overall higher dermal absorption is predicted for the target’s constituent DMDS, a low to moderate one for DMPT and HIDT, and a low dermal absorption for HIDT-adduct. The uncertainty associated with PC similarity was assessed to be medium.

ADME similarity: the target’s constituents and the source compound exhibit moderate to high similarity in terms of ADME profile. In particular, based on the predicted passive absorption across intestinal epithelium (HIA%) equal to 100%, all of the four compounds are expected to be well absorbed in the organism. Oral bioavailability (%F) was estimated to be moderate for HIDT, DMDS, DMPT, and poor for HIDT-adduct. The predicted volumes of distribution are all closed to each other and above the volume of total body water (0.7 L/kg), and this indicates that the four compounds have affinity to extravascular tissues. Prediction of metabolic stability, i.e. t1/2 in Human Liver Microsomes, resulted to be undefined for the four structures, thus preventing a comparison of metabolism rate. The overall ADME profile of the two main target’s constituents HIDT and DMDS was more closely similar to the source’s one. The ADME profile of the third target’s constituent HIDT-adduct was still similar to the other compounds, but it showed an estimated lower oral bioavailability than the three other structures. The uncertainty associated with ADME similarity was assessed as medium, due to limitations associated with the following issues: i) assessment based only on predicted properties; ii) in silico data do not cover the whole ADME profile, e.g. rate and extent of metabolism and elimination.

Potential metabolic products: As primary phase I reaction, all metabolites were derived from the sulphide oxidation of the target’s constituents and the source chemical (metabolites containing sulfoxide and sulphone functional groups were predicted). Concerning phase II metabolism, conjugation is predicted for all the compounds via methylation of the thiol group. The predicted metabolites of target and source compounds were profiled within 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 acute dermal toxicity. The results of this profiling are reported in Appendix A of the attached report, and are following summarised:
- “Sulfoxide” and “Thiol” functional groups were found among all of target’s constituents and source’s phase I and II metabolites. In addition, the “Aldehyde” functional group/chemical class was identified for some of the HIDT and HIDT adduct metabolites.
- No major mechanistic differences were identified among the target’s constituents and the source metabolites concerning protein binding and acute hazard toxicity, except for some HIDT and HIDT-adduct metabolites, for which the “Aldehydes” structural alert was identified.
Concluding, the target’s constituents and the source compound exhibited moderate similarity in terms of their potential metabolites. The identified potential showed moderate structural and mechanistic similarity, except for some HIDT and HIDT-adduct metabolites, which were characterised by an additional protein binding alert which was absent in both the source DMPT and DMDS. The uncertainty associated with the identification of potential metabolic products was assessed as medium. Moreover, it is highlighted that the identification of potential metabolites and related mechanistic profile was only based on in silico predictions.

Supporting toxicological data: In the read-across study for acute dermal toxicity, it is considered important to integrate the information gathered also from other toxicological studies, i.e. skin irritation, skin sensitisation and acute oral toxicity. Experimental toxicological data (available for the source DMPT and for one of the target constituents DMDS) were collected from the ECHA website. Skin irritation, skin sensitisation and acute oral toxicity were predicted for the target’s constituents by applying QSAR models. Positive skin irritating and skin sensitising QSAR predictions were achieved for all target’s constituents. Regarding acute oral toxicity, the overall estimated rat LD50 values ranged from 56 mg/kg to 480 mg/kg. These predictions were consistent with those generated for the source DMPT, but not consistent with source experimental data (reported as not skin irritating/sensitizer and with an experimental rat LD50 value > 2000 mg/kg bw), suggesting an overestimation of compounds toxicity by QSAR predictions.
The available experimental acute oral toxicity data for the target’s constituent DMDS resulted in a lower LD50 value in rat (50 < LD50 ≤ 300 mg/kg bw) than the source’s one, thus pointing out a higher acute oral toxicity for DMDS.
Based on the assessment of the supporting toxicological data, the toxicological profile of the source DMPT appeared to be less conservative than that of the target’s constituent DMDS. No further conclusions could be drawn for HIDT and HIDT-adduct. Only focusing on the available toxicological studies, these considerations increased the uncertainty for the present read-across justification.

Source experimental data: for the assessment of acute dermal toxicity, an acute experimental study in rabbit performed with the source substance DMPT was available. The study has been reported by the registrant as reliable with restrictions (Klimisch score 2), because of some missing data in the study report. The reported LD50 is > 2000 mg/kg bw. The study was assessed as adequate for the read-across prediction of the target HIDT.

4. DATA MATRIX
Data matrix is included in the attached report.

A worst-case scenario in terms of dermal uptake and systemic toxicity for DMDS compared to the other two target’s constituents and the source is highlighted.
However, it was also considered that DMDS represents about 40% of the chemical composition of the target, whilst HIDT and HIDT-adduct are about 40-45% and 15-20% of the target’s composition, respectively, and thus together representing almost 60% of the target HIDT. Furthermore, the overall similarity assessment highlighted a good general agreement between the source DMPT vs. the target’s constituents’ data (especially for HIDT and DMDS, with a few more differences for HIDT-adduct), again confirming the adequacy of using the source DMPT for this read-across study.
Additional details and considerations are reported in the attached report.
Reason / purpose:
read-across source
Remarks:
source DMPT / 411-290-7
Qualifier:
according to
Guideline:
other: ECHA, 2015: Read-Across Assessment Framework (RAAF).
Qualifier:
according to
Guideline:
other: ECHA, 2017: Read-Across Assessment Framework (RAAF). Considerations on multi-constituent substances and UVCBs.
Specific details on test material used for the study:
SMILES: SCCSCCSC(CCO)SCCSCCS
InChI=1S/C11H24OS6/c12-2-1-11(17-9-7-15-5-3-13)18-10-8-16-6-4-4/h11-14H,1-10H2

Key result
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
other: Source (DMPT)
Remarks on result:
other: Read-across
Interpretation of results:
GHS criteria not met
Remarks:
Based on read-across
Conclusions:
Based on the read-across study presented, it is concluded that the acute dermal toxicity data available for DMPT could be used to support the same conclusion of no classification for the target HIDT.
Executive summary:

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

In the read-across analysis, DMPT was selected as source chemical for the three main target’s constituents HIDT, DMDS and HIDT-adduct. The similarity assessment, which consisted of a comparison of structural, mechanistic, physicochemical, ADME and metabolism profiles, showed that the source DMPT and the target’s constituents were sufficiently similar to justify the read-across approach.

A higher dermal absorption was predicted for DMDS, a low to moderate one for DMPT and HIDT, and a low dermal absorption for HIDT-adduct.

A key experimental acute dermal toxicity study was available for the source DMPT, and this study was assessed as adequate for the read-across prediction of the multi-constituent target HIDT.

QSAR predictions for skin irritation, skin sensitization and acute oral toxicity (mouse, rat) were performed for the target’s constituents in order to further support the read-across prediction and likely contribute to the reduction of its uncertainty. Overall, QSAR predictions were quite in agreement among the three target’s constituents. However, a possible overestimation of toxicity could be expected for these QSAR results, since the corresponding QSAR predictions for the source DMPT were found to more conservative than the corresponding experimental results.

The level of confidence of the read-across prediction was assessed taking into account two main aspects: i) uncertainty associated with similarity justification; ii) uncertainty associated with the read-across argument. In the present read-across study, an overall medium uncertainty was associated with similarity justification, due to the following issues: i) the endpoint to read-across does not have yet well-defined mechanistic bases (high-tier endpoint); ii) ADME assessment was based on simulated data only, without coverage of rate and extent of dermal and systemic metabolism and elimination; iii) identification of potential metabolites and related mechanistic profiles was based on in silico predictions only; iv) the available experimental acute oral toxicity LD50 value for the target’s constituent DMDS, representing 40% of the target’s composition, was found to be worst-case than the source’s oral LD50 value, and its dermal absorption was predicted to be higher than the source’s one.

The main uncertainties associated with the read-across argument were related to the endpoint-type and to the fact that the analogue set was limited to one compound.

Concluding, the read-across from the existing acute dermal toxicity study available for the source substance DMPT was used to predict the acute dermal toxicity of the target HIDT, and its constituents HIDT, DMDS, and HIDT-adduct, in order to fulfil the information requirement of Annex VIII 8.5 of the REACH Regulation.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Additional information

Justification for classification or non-classification

The LD50-cut-off value according to OECD TG 423 was 200 mg/kg bw. DMDS should be classified as Acute Tox 3 - H301: Toxic if swallowed.