Disodium 1,3,4-thiadiazole-2,5-dithiolate

Endpoint summary

Description of key information

Acute toxicity oral (Read-across from CAS 1072-71-5): OECD 401, Sherman-Wistar albino rats, male, LD50 = 930 mg/kg

Acute toxicity oral: similar to 16 CFR - P.114, Sherman-Wistar albino rats, male, LD50 = 2955 mg/kg (active ingredient)

Acute toxicity dermal (Read-across from CAS 1072-71-5): OECD 402, Wistar rats, female, LD50 >= 2000 mg/kg, LD0 >= 2000 mg/kg

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

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

Adequacy of study:

weight of evidence

Study period:

1980-09-24 - 1980-10-15 (experimental phase)

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

No guideline stated, given information allows the conclusion the study was well performed similar to adopted guidelines. Performed on read-across substance.

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
General remarks ahead:
The substance is unstable when isolation from water and amine stabilizers and / or manufacture without water is attempted. The solid DMTD-Na is, based on handling observations, only stable as aqueous solution in combination with stabilizers as set out in IUCLID section 1.2. As a pure substance, it is highly unstable towards oxygen (after contact the corresponding dimer is formed), and very hygroscopic. In consequence, the substance needs to be registered including water (required for stabilization) and water is hence part of the substance ID. The substance should still be regarded as a mono-constituent substance according to the “Guidance for identification & naming of substances under REACH & CLP” (v1.3). Analytics revealed that the substance is composed of Disodium 1,3,4-thiadiazole-2,5-dithiolate (CAS 55906-42-8), water and stabilizing amines, no other DMTD-species was found. This is comparable to the structurally related read-across substance DMTD (1,3,4-Thiadiazole-2,5-dithiol, CAS 1072-71-5). Water is toxicologically irrelevant, and so, only the similarities between the two solid substances need to be regarded.

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The read-across is justified out of the following reasons:
1. The substances are structural analogues. The registered substance is produced from a neutralization reaction of 1,3,4-Thiadiazole-2,5-dithiol (CAS 1072-71-5, EC 214-014-1; source) and Sodium hydroxide (CAS 1310-73-2, EC 215-185-5) in the presence of stabilizers. So the organic ring remains intact. During analysis of DMTD-Na via HPLC, it cannot even be detected anymore but is transformed in the source substance. So the prerequisites of common functional group(s) and common precursor(s) are fulfilled.
2. The source and target substance exhibit both similar properties, or the source substance properties can be regarded as worst case, while the target substance bear toxicologically less relevant properties, see point 4. Data Matrix.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
For the properties of the target substance, please refer to section 1.2
Property Source chemical Target Chemical
CAS RN 1072-71-5 55906-42-8
Name 1,3,4-Thiadiazole-2,5-dithiol Disodium 1,3,4-thiadiazole-2,5-dithiolate
EC-No. 214-014-1 259-886-4
Other contained substances None; substance is pure Water
Stabilizing amines (see section 1.2), either not classified or not contained to a relevant amount
In both substances, only the substance was found analytically. There was no indication that possibly dimers or other oligomeric substances are present.

3. ANALOGUE APPROACH JUSTIFICATION
First, the substances are structural analogues. They have common functional group(s) and common precursor(s). Second, the impurity profile does not hinder the read-across. The source chemical is pure, and the target substance does only contain other substances which are not relevant for classification. They have the same basic structure, no dimers or oligomers are found. Third, during analysis in a slightly acidic, aqueous eluent, which is relevant for body fluids, too, the registered substance was even transformed back into the source chemical. Fourth, they have the same toxicological properties, based on the actually available information, see 4. Data matrix.

4. DATA MATRIX
Endpoint Source chemical Target Chemical
CAS RN 1072-71-5 55906-42-8
Name 1,3,4-Thiadiazole-2,5-dithiol Disodium 1,3,4-thiadiazole-2,5-dithiolate
Acute oral toxicity LD50 = 930 mg/kg (males) 9850 mg/kg (males; solution)
2955 mg/kg (males, active ingredient)
Skin irritation Not irritating Not irritating
Eye irritation Eye Dam. Cat. 1 Not irritating
It can be reasonably assumed, that the effects are similar also in ecotoxicity tests.

In summary, the read-across from 1,3,4-Thiadiazole-2,5-dithiol to Disodium 1,3,4-thiadiazole-2,5-dithiolate is justified.

Reason / purpose for cross-reference:

read-across source

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

not applicable

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

other: Sherman-Wistar albino rats

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 200-300g
- Fasting period before study: The rats were deprived of food but not water overnight prior to dosing.
- Housing: The animals were housed and maintained in compliance with the Animal Welfare Act (Pub. L-94-279) 9 CPR Part 3.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 50% w/v suspension in corn oil

Doses:

0.25, 0.50, 1.0, 2.0, 4.0 g/kg

No. of animals per sex per dose:

5 males

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Mortality daily, weight at the beginning and after 14 days
- Necropsy of survivors performed: yes
- Other examinations performed: body weight

Statistics:

The LD50 was calculated employing the Thompson Moving Average Method as modified by Weil, (Biometrics, September, 1952, Vol. 8, No. 3, page 249-263).

Key result

Sex:

male

Dose descriptor:

LD50

Effect level:

930 mg/kg bw

Based on:

test mat.

95% CL:

>= 660 - <= 1 310

Mortality:

Observed, 3/5 rats at 2 g/kg, 5/5 at 4 g/kg

Clinical signs:

other: 0.25 gm/kg: No untoward symptoms were observed. 0.50 gm/kg: No untoward symptoms were observed during the first 4-6 hours. After 24 hours the animals were slightly ruffled and dirty . They appeared normal within 48 hours. 1.0 gm/kg: After 4-6 hours the an

Gross pathology:

Gross pathologic examination of the 4 g/kg group revealed nothing remarkable.

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

Study was performed scientifically reasonable similar to OECD TG 401 on 1,3,4-Thiadiazole-2,5-dithiole, and is sufficiently documented. Hence, the results can be considered as reliable to assess the acute oral toxicity of 1,3,4-Thiadiazole-2,5-dithiole towards rats. The LD50 was determined as 0.93 (0.66 - 1.31) g/kg, which is within the boundary values of 300 and 2000 mg/kg, which triggers according to Regulation 1272/2008 the classification as acute toxic Cat. 4.

Executive summary:

In an acute oral toxicity study similar to OECD 401, groups of fasted, male Sherman-Wistar rats (5/group) were given a single oral dose of 1,3,4-Thiadiazole-2,5-dithiole, 50% in corn oil at doses of 250, 500, 1000, 2000, 4000 mg/kg bw and observed for 14 days.

The LD50 was determined as 0.93 (0.66 - 1.31) g/kg in males .

1,3,4-Thiadiazole-2,5-dithiole is of slight Toxicity based on the LD50 in males and needs to be classified as acute toxic oral Cat. 4.

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1980-09-19 - 1980-09-24 (experimental phase)

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Remarks:

Documentation poorer compared to recent standards, but given information allows the conclusion the study was well performed

Qualifier:

according to guideline

Guideline:

other: similar to that described in Section 1500.3 Federal Hazardous Substances Act Regulations ― 16 CFR - P.114

Version / remarks:

The method employed in the testing, evaluation and the scoring of the results was similar to that described in Section 1500.3 Federal Hazardous Substances Act Regulations ― 16 CFR - P.114

Deviations:

not specified

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

other: albino rats of the Sherman-Wistar Strain

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 200 - 300 g
- Fasting period before study: The rats were deprived of food but not water overnight prior to dosing.
- Housing: The animals were housed and maintained in compliance with the Animal Welfare Act (Pub. L-94̶-279) 9 CFR Part 3.

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Doses:

1, 2, 4, 8, 16 g/kg

No. of animals per sex per dose:

5 males per dose

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: daily (mortality), 1st & last day (body weight)
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

Statistics:

The LD50 was calculated employing the Thompson Moving Average Method as modified by Weil, (Biometrics, September, 1952, Vol. 8, No. 3, page 249-263).

Key result

Sex:

male

Dose descriptor:

LD50

Remarks:

test material

Effect level:

9 850 mg/kg bw

Based on:

test mat.

95% CL:

>= 7 460 - <= 12 990

Key result

Sex:

male

Dose descriptor:

LD50

Effect level:

2 955 mg/kg bw

Based on:

act. ingr.

Remarks:

solid disodium 1,3,4-thiadiazole-2,5-dithiolate

Mortality:

One death occurred after 6 hours in the 8 g/kg group, all animal in the 16 g/kg group died within 6 hours.

Clinical signs:

other: 8.0 gm/kg: After 1-2 hours the animals were depressed, ruffled and ataxic. One death occurred after 6 hours. Within 24 hours the surviving animals appeared essentially normal. 16.0 gm/kg: Within 1 hour the animals were depressed, ruffled and ataxic. Most

Gross pathology:

Gross pathologic examination revealed nothing remarkable.

Interpretation of results:

GHS criteria not met

Conclusions:

Study was performed scientifically reasonable according to Section 1500.3 Federal Hazardous Substances Act Regulations ― 16 CFR - P.114 on a 30% aqueous solution of disodium 1,3,4-thiadiazole-2,5-dithiolate, and is sufficiently documented. Hence, the results can be considered as reliable to assess the acute oral toxicity of disodium 1,3,4-thiadiazole-2,5-dithiolate towards rats. The LD50 was determined as 9850 (7460 - 12990) mg/kg of the 30% aqueous solution, which corresponds to a LD50 = 2955 mg/kg of pure disodium 1,3,4-thiadiazole-2,5-dithiolate. This value is above the limit value of 2000 mg/kg, which triggers according to Regulation 1272/2008 the classification as acute toxic, hence, disodium 1,3,4-thiadiazole-2,5-dithiolate does not need to be classified.

Executive summary:

In an acute oral toxicity study according to Section 1500.3 Federal Hazardous Substances Act Regulations ― 16 CFR - P.114, groups of fasted, male Sherman-Wistar rats (5/group) were given a single oral dose of on a 30% aqueous solution of disodium 1,3,4-thiadiazole-2,5-dithiolate at doses of 1000, 2000, 4000, 8000, 16000 mg/kg bw and observed for 14 days.

The LD50 was determined as 9850 (7460 - 12990) mg/kg of the 30% aqueous solution in males, which corresponds to a LD50 = 2955 mg/kg of pure disodium 1,3,4-thiadiazole-2,5-dithiolate.

Disodium 1,3,4-thiadiazole-2,5-dithiolate is of low Toxicity based on the LD50 in males and does not need to be classified as acute toxic oral.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

930 mg/kg bw

Quality of whole database:

acceptable for classification

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

2018-01-24 - 2018-02-14 (experimental phase)

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Remarks:

Klimisch 1 study, but performed on read-across substance

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

OECD Guideline for the Testing of Chemicals No. 402 “Acute Dermal Toxicity” (2017)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

fixed dose procedure

Limit test:

yes

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: sponsor

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: approximately 4 °C in the dark

Species:

rat

Strain:

Wistar

Remarks:

Wistar (RccHan(TM):WIST)

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Envigo RMS (UK) Limited, Oxon, UK
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: At the start of the study the animals were 8 to 12 weeks of age.
- Weight at study initiation: At the start of the study the animals weighed at least 200 g. The weight variation did not exceed ±20% of any previously treated animal.
- Fasting period before study: no
- Housing: The animals were individually housed throughout the study in suspended solid floor polypropylene cages furnished with woodflakes. The animals were provided with environmental enrichment items which were considered not to contain any contaminant of a level that might have affected the purpose or integrity of the study.
- Diet (e.g. ad libitum): 2014C Teklad Global Rodent diet supplied by Envigo RMS (UK) Limited, Oxon, UK ad libitum
- Water (e.g. ad libitum): mains drinking water ad libitum
The diet, drinking water and bedding were routinely analyzed and were considered not to contain any contaminants that could reasonably be expected to affect the purpose or integrity of the study.
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): The temperature was set to achieve limits of 19 to 25 °C.
- Humidity (%): The relative humidity was set to achieve limits of 30 to 70%
- Air changes (per hr): The rate of air exchange was at least fifteen changes per hour.
- Photoperiod (hrs dark / hrs light): The lighting was controlled by a time switch to give 12 hours continuous light and 12 hours darkness.

IN-LIFE DATES: From: To:

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Remarks:

skin was moistened ahead with arachis oil BP

Details on dermal exposure:

TEST SITE
- Area of exposure: back and flanks
- % coverage: approximately 10% of the total body surface area
- Type of wrap if used: A piece of surgical gauze was placed over the treatment area and semi occluded with a piece of self adhesive bandage. Shortly after dosing the dressings were examined to ensure that they were securely in place.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): After the 24 Hour contact period the bandage was carefully removed and the treated skin and surrounding hair wiped with cotton wool moistened with arachis oil BP to remove any residual test item.
- Time after start of exposure: 24h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg bw
- For solids, paste formed: no

Duration of exposure:

24h

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

3 in total

Control animals:

not required

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The animals were observed for deaths or overt signs of toxicity 30 minutes, 1, 2, 4 and 6 hours after dosing and subsequently once daily for 14 days.
After removal of the dressings and subsequently once daily for 14 days, the test sites were examined for evidence of primary irritation
Individual body weights were recorded prior to application of the test item on Day 0 and on Days 7 and 14.
- Necropsy of survivors performed: yes
At the end of the study the animals were killed by cervical dislocation. All animals were subjected to gross necropsy. This consisted of an external examination and opening of the abdominal and thoracic cavities. The appearance of any macroscopic abnormalities was recorded. No tissues were retained.
- Other examinations performed: clinical signs, body weight, skin reactions

Preliminary study:

no mortalities noted in the first female

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Key result

Sex:

female

Dose descriptor:

LD0

Effect level:

>= 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: none of the three animals died

Mortality:

There were no deaths.

Clinical signs:

other: No signs of systemic toxicity were noted during the observation period.

Gross pathology:

No abnormalities were noted at necropsy.

Other findings:

Dermal reactions:
Signs of dermal irritation noted included very slight to well defined erythema and very slight edema. Crust formation, small superficial scattered scabs and scab lifting to reveal glossy skin were also noted. Yellow staining of the treatment sites was also noted.

Interpretation of results:

GHS criteria not met

Remarks:

EU implementation

Conclusions:

The study was conducted under GLP according to OECD guideline 402 on the registered substance itself. The method is to be considered scientifically reasonable with no deficiencies in documentation. Hence, the results can be considered as reliable to assess the acute oral toxicity in rats. The acute dermal median lethal dose (LD50) of the test item in the female Wistar strain rat was found to be greater than 2000 mg/kg body weight.

Executive summary:

The study was performed to assess the acute dermal toxicity of the test item in the Wistar strain rat according to OECD TG 402 under GLP.

Methods: Initially, one female animal was given a single, 24 hour, semi‑occluded dermal application of the undiluted test item to intact skin at a dose level of 2000 mg/kg body weight. Based on the results of the initial test, a further two female animals were similarly treated. Clinical signs and body weight development were monitored during the study. All animals were subjected to gross necropsy.

Results:

Mortality. There were no deaths.

Clinical Observations. There were no signs of systemic toxicity.

Dermal Irritation. Signs of dermal irritation noted included very slight to well defined erythema and very slight edema. Crust formation, small superficial scattered scabs and scab lifting to reveal glossy skin were also noted. Yellow staining of the treatment sites was also noted. 

Body Weight. One animal showed body weight loss during the first week with expected gain in body weight during the second week. The remaining animals showed expected gains in body weight.

Necropsy. No abnormalities were noted at necropsy.

Conclusion: The acute dermal median lethal dose (LD50) of the test item in the female Wistar strain rat was found to be greater than 2000 mg/kg body weight.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD0

Value:

> 2 000 mg/kg bw

Justification for classification or non-classification

A suitable read-across substance has an oral LD50 = 930 mg/kg, which is the lowest LD50 in all available studies observed. Hence, the substance should be classified as acute tox oral Cat. 4 according to Regulation 1272/2008 and amendments.