1,3,4-Thiadiazolidine-2,5-dithione, reaction products with tert-dodecanethiol and hydrogen peroxide

Endpoint summary

Description of key information

Acute toxicity
- Oral route: rat (Crj: CD(SD)), m/f (according to OECD 401 & EU method B1, 1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-dodecanethiol): LD50 > 2000 mg/kg bw
- Oral route: rat (Wistar), m/f (according to EU method B1, 1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-dodecanethiol): LD50 > 5000 mg/kg bw 
- Oral route: rat (Sprague-Dawley), m/f (similar to OECD 401, CAS 91648-65-6): LD50 > 10000 mg/kg bw
- Oral route: rat (Albino, Charles River strain), m/f (similar to OECD 401, CAS 50530-43-3): LD50 = 10250 mg/kg bw (males), LD50 = 6176 mg/kg bw (females)
- Inhalation route: rat (Sprague-Dawley), m/f (similar to OECD 403, CAS 91648-65-6): LD50 > 2.75 mg/L over 4h
- Inhalation route: rat (Crj:CD(SD)), m/f (similar to OECD 403, CAS 50530-43-3): LD50 > 0.62 mg/L over 4h
- Dermal route: : rabbit (New Zealand White), m/f (similar to OECD 402, CAS 91648-65-6): LD50 > 2000 mg/kg bw
- Dermal route: : rabbit (New Zealand White), m/f (similar to OECD 402, CAS 50530-43-3): LD50 > 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:

weight of evidence

Study period:

1988-03-23 - 1988-04-06

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP-Guideline study without deviations on ‘1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-dodecanethiol’.

Qualifier:

according to guideline

Guideline:

EU Method B.1 (Acute Toxicity (Oral))

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Winkelmann, Borchen, Germany
- Strain: Bor:WISW (SPF Cpb)
- Age at study initiation: about 9 weeks (males) and 14 weeks (females)
- Weight at study initiation: 178 g (males) and 168 g (females), mean values, scatter was less than 20% of mean
- Females were nulliparous and not pregnant
- Fasting period before study: 16 h
- Housing: in groups of 5 in Macrolon cages type III on dust-free wood granules (Ssniff, Soest/Westfalen, Germany)
- Diet: "fixed formula" standard diet, e.g. Altromin 1324 pellets (Altromin GmbH, Lage, Germany), ad libitum
- Water: tap-water, ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 +/- 2
- Humidity (%): 50 +/- 10
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

arachis oil

Details on oral exposure:

VEHICLE
- Amount of vehicle: 10 mL/kg bw
MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw

Doses:

5000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observations were done several times on the day of administration, twice daily in the following 14-day observation period (once daily at weekends and on public holidays); weighing was done prior to dosing , after one week and at the end of study.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Mortality:

There were no deaths.

Clinical signs:

other: Slightly roughed pelt was observed about 8 h after administration in 4 male and 5 female animals. From the second day after administration all the animals were free of symptoms.

Gross pathology:

No abnormalities noted.

Table 1. Body weights

		Bodyweight (g)
Sex	Animal number	Week 0	Week 1	Week 2
Male	1	178	210	252
	2	174	211	244
	3	179	212	248
	4	181	220	246
	5	178	221	258
	mean	178	215	250
Female	1	169	180	201
	2	168	179	193
	3	169	181	192
	4	170	188	198
	5	166	190	205
	mean	168	184	198

Interpretation of results:

not classified

Remarks:

Criteria used for interpretation of results: EU-GHS

Conclusions:

The study was performed according to the EU method B.1 without deviations and considered to be of high quality (reliability Klimisch 1). The test item was shown to produce only slight clinical signs (slightly rough pelt) at 5000 mg/kg bw. No mortalities were observed after an oral gavage of 5000 mg/kg bodyweight. So the acute lethal dose of the test item is greater than 5000 mg/kg bw, which does not require classification according to EC Regulation 1272/2008. The test substance can be regarded als relatively non-toxic.

Executive summary:

The study on acute oral toxicity of 1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-dodecanethiol was performed on each five male and female Wistar rats according to the EU method B.1 "Acute Toxicity Oral" (1984) without deviations and according to the principles of GLP. A dose of 5000 mg/kg body weight of the test substance was administered via oral gavage to the rats. About 8 h after administration, 4 male and 5 female rats showed a slightly roughened pelt which was reversible on the second day. During the post-exposure observation period of 14 days neither mortalities nor macroscopic abnormalities after sacrification were observed. Body weight gains were also not delayed. Consequently, the acute lethal dose of the test item was demonstrated to be greater than 5000 mg/kg bw, so it can be regarded to have a low toxicity and no classification is needed.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

5 000 mg/kg bw

Quality of whole database:

There are four studies on acute oral toxicity available, all assessed with Klimisch 2. The results are consistent and do all equivalently not trigger a classification of 1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-dodecanethiol as acute toxic. So, the whole database is of high quality.

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

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

Adequacy of study:

key study

Study period:

February 1981

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Guideline study on read-across substance. No GLP compliance is claimed, however, the final report includes an audit and quality assurance inspections. The test chamber concentration was not measured analytically. This result is read-across from ‘1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-nonanethiol’. Read-across is justified as the two substances ‘1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-dodecanethiol’ and ‘1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-nonanethiol’ are virtually the same: the only difference between those two UVCB substances is that one of the used raw materials (alkanethiol) has a diversity in the C-range, i.e. on the one hand a tert. C12-alkanethiol is used in the manufacturing process, on the other hand a tert. C9. Hence, based on the (structural) similarity of both substances it is safe to say that the physicochemical, toxicological and ecotoxicological properties are likely to be similar.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

not applicable

GLP compliance:

no

Remarks:

The final report includes an audit and quality assurance inspections.

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: King Animal Labs, Oregon, Wisconsin
- Age at study initiation: not reported
- Weight at study initiation: males (mean) 271g; females (mean) 197g
- Fasting period before study: no
- Housing: housed in groups of 3 per sex for one week prior to study initiation; for a further 2 weeks prior to study initiation the animals were individually in suspended, stainless steel cages (25 x 17.8 x 17.8 cm). During inhalation exposure the rats were individually housed in perforated metal exposure cages measuring 25 x 8 x 8 cm. Following exposure the rats were transferred into stainless steel cages measuring 18.4 x 16.5 x 15.9 cm
- Diet: Purina Rodent Chow 5001 (Ralston Purina Co.) ad libitum
- Water: ad libitum
- Acclimation period: 3 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22
- Humidity (%): 40
- Photoperiod (hrs dark / hrs light): 12 /12

IN-LIFE DATES:
From 3 February 1981 to 17 February 1981

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

air

Details on inhalation exposure:

The generating system consisted of a 2000 mL, 3-neck flask (Ace Glass #6947-40) containing 1L of the test article. A mineral bath (Model 220, National Appliance Co., Portland, Oregon) was heated to the desired temperature prior to immersing the test article flask. Air entered the flask via a gas dispersion tube (Ace Glass #7202-16, pore size 25-50 µm). The middle neck of the flask contained a thermometer for measuring the temperature of the test article. Air bubbles carried the test article vapour upward via a 105° elbow (Ace Glass #5075-10) into the exposure chamber. The entire air flow of the chamber passed through the generator flask.
The 50 x 24.3 x 30 cm (37 L) chamber was made of Plexiglas(R). The front of the chamber was removable to facilitate loading and unloading of animals. The test article vapour entered a port at the top of one side of the chamber and exited at the bottom of the opposite side. The vapour was vented into a California type fume hood followed by a filter system.

Analytical verification of test atmosphere concentrations:

no

Duration of exposure:

4 h

Concentrations:

2.75 mg/L

No. of animals per sex per dose:

5 male and 5 female

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: daily and more often on the day of dosing
- Necropsy of survivors performed: yes
- Other examinations performed: body weights and necropsies

Statistics:

No statistical methods are reported.

Preliminary study:

Not applicable.

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 2.75 mg/L air (nominal)

Based on:

test mat.

Exp. duration:

4 h

Mortality:

No mortalities during the study.

Clinical signs:

other: A clear nasal discharge, red encrustation around nose and eyes, and salivation were observed in four rats following exposure. One male rat exhibited diarrhoea immediately following exposure and on the following day. All remaining rats appeared normal.

Body weight:

The mean initial body weights of the male and female rats were 271 g and 197 g, respectively.

Gross pathology:

At necropsy, seven rats appeared normal. Three rats had spongy lungs and/or brown foci through all lung lobes.

Other findings:

None reported.

Interpretation of results:

study cannot be used for classification

Conclusions:

The test report describes a valid guideline study, with auditation and quality assurance inspections of the final report. The acute inhalation median lethal concentration (LC50) was estimated to be > 2.75 mg/L. Thus, the test substance can be considered as not acutely toxic via the inhalative route. The test item ‘1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-nonanethiol’ is virtually the same as the registered substance ‘1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-dodecanethiol’. The only difference between those two UVCB substances is that one of the used raw materials (alkanethiol) has a diversity in the C-range, i.e. on the one hand a tert. C12-alkanethiol is used in the manufacturing process, on the other hand a tert. C9. Hence, based on the (structural) similarity of both substances it can safely be concluded that the results can be safely transferred to the registered substance.

Executive summary:

An acute inhalation study was conducted using a similar procedure to that described in the current OECD Guideline 403 (Findlay, 1981).

The test material (CAS No. 91648-65-6) was administered at 2.75 mg/L by inhalation for 4 h to five male and five female rats. The rats were observed for 14 days after test material administration. No mortalities occurred during the study. The following clinical signs were noted during the study: a clear nasal discharge, red encrustation around nose and eyes, and salivation were observed in four rats following exposure, one male rat exhibited diarrhoea immediately following exposure and on the following day. All remaining rats appeared normal. At necropsy, seven rats appeared normal. Three rats had spongy lungs and/or brown foci through all lung lobes. The acute inhalation median lethal concentration (LC50) was determined to be > 2.75 mg/L. The read-across from the test item to ‘1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-dodecanethiol’ is scientifically justified.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

2.75 mg/m³ air

Quality of whole database:

There are two studies on acute toxicity via inhalation available, both assessed with Klimisch 2. The results are consistent and do equivalently not trigger a classification of 1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-dodecanethiol as acute toxic. There was in both studies no LD50 determinable as both values (> 2.75 mg/L and > 0.61 mg/L) were the highest ones tested. So, the whole database is of high quality.

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

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

Adequacy of study:

key study

Study period:

Feb/Mar 1981

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Guideline study. No GLP compliance is claimed, however, the final report includes an audit and quality assurance inspections. The study was conducted using skin that had been abraded (care was taken so as to only penetrate the stratum corneum and not the dermis). This deviates from the current OECD Guideline 402, however, this is not considered to affect the outcome of the study as the test material resulted in an LD50 of > 2000 mg/kg. This result is read-across from ‘1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-nonanethiol’. Read-across is justified as the two substances ‘1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-dodecanethiol’ and ‘1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-nonanethiol’ are virtually the same: the only difference between those two UVCB substances is that one of the used raw materials (alkanethiol) has a diversity in the C-range, i.e. on the one hand a tert. C12-alkanethiol is used in the manufacturing process, on the other hand a tert. C9. Hence, based on the (structural) similarity of both substances it is safe to say that the physicochemical, toxicological and ecotoxicological properties are likely to be similar.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

yes

Remarks:

This study was conducted using skin that had been abraded (care was taken so as to only penetrate the stratum corneum and not the dermis). However, this will not affect the outcome of the study.

GLP compliance:

no

Remarks:

The final report includes an audit and quality assurance inspections.

Test type:

fixed dose procedure

Limit test:

yes

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 2.0 to 2.4 kg
- Fasting period before study: No
- Housing: Individually housed in stainless steel cages (61.0 x 45.5 x 42.0 cm)
- Diet: Rabbits were fed Purina Rabbit Chow Complete Blend (Ralston Purina Co.) ad libitum
- Water: ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): approx. 22
- Humidity (%): approx. 40 (relative)
- Photoperiod (hrs dark / hrs light): 12 / 12

IN-LIFE DATES:
From 19 February 1981 to 6 March 1981

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: An area of 240 cm2 on the back of each animal
- Type of wrap if used: gauze pad and plastic film covered by towelling

REMOVAL OF TEST SUBSTANCE
- Washing (if done): skin washed clean of excess test material (solvent not reported)
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg
- Concentration (if solution): applied undiluted
- Constant volume or concentration used: yes

Duration of exposure:

24 h

Doses:

2000 mg/kg

No. of animals per sex per dose:

5 male and 5 female

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observations were performed at least once a day; animals were weighed immediately prior to dosing
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs

Statistics:

No statistical methods used.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortalities occured during the study.

Clinical signs:

other: One male rabbit had diarrhoea on days 2, 3 and 4, as did one female rabbit on day 3. This female and a different male rabbit had diarrhoea (immediately prior to dosing). All rabbits appeared normal on day 5 and for the remainder of the observation period.

Gross pathology:

No abnormal findings noted.

Other findings:

No other findings are reported.

Interpretation of results:

study cannot be used for classification

Conclusions:

The test report describes a valid guideline study, with auditation and quality assurance inspections of the final report. The acute dermal LD50 was determined to be greater than 2000 mg/kg. Thus, the test substance can be considered as not acutely toxic via the dermal route.
The test item ‘1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-nonanethiol’ is virtually the same as the registered substance ‘1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-dodecanethiol’. The only difference between those two UVCB substances is that one of the used raw materials (alkanethiol) has a diversity in the C-range, i.e. on the one hand a tert. C12-alkanethiol is used in the manufacturing process, on the other hand a tert. C9. Hence, based on the (structural) similarity of both substances it can safely be concluded that the results can be safely transferred to the registered substance and so, ‘1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-dodecanethiol’ does not need to be classified, too.

Executive summary:

An acute dermal study was conducted using a similar procedure to that described in the current OECD Guideline 402 (Reckers, 1981). The test material (CAS No. 91648-65-6) was applied at a dose of 2000 mg/kg to the backs of five male and five female rabbits. The test item was left in contact with the skin for 24 hours and then the test sites were washed and the rabbits observed during this time and for 14 days after its removal. One male rabbit had diarrhea on days 2, 3 and 4, as did one female rabbit on day 3. This female and a different male rabbit had diarrhea (immediately prior to dosing). All rabbits appeared normal on day 5 and for the remainder of the observation period. Therefore this finding probably is not treatment related. There were no mortalities during the study and gross necropsy findings in all rabbits were within normal limits. The acute dermal LD50 was determined to be greater than 2000 mg/kg.

The read-across from the test item to ‘1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-dodecanethiol’ is scientifically justified and so the registered substance does not need to be classified as acute toxic according to Regulation 1272/2008/EC, too.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

There are two studies on acute dermal toxicity available, both assessed with Klimisch 2. The results are consistent and do equivalently not trigger a classification of 1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-nonanethiol as acute toxic via dermal route. So, the whole database is of high quality.

Additional information

There are eight studies attributed to the endpoint “acute toxicity” available, four via oral route and each two via inhalation and dermal route:

Mason, 1998, oral route, 1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-dodecanethiol:

The study on acute oral toxicity of the test item was performed on each five male and female Sprague-Dawley rats according to the OECD Guideline 401 "Acute Oral Toxicity" and EU method B.1 "Acute Toxicity Oral" without deviations and according to the principles of GLP (Mason, 1998). A dose of 2000 mg/kg body weight of the test substance was administered via oral gavage to the rats. Within 13 min after administration, all rats showed clinical signs such as piloerection, hunched posture or waddling / unsteady gait. During the post-exposure observation period of 14 days no mortalities were observed, and neither were macroscopic abnormalities nor reduced body weight gains. Consequently, the acute lethal dose (LD50) of the test item was demonstrated to be greater than 2000 mg/kg bw, which does not require classification according to EC Regulation 1272/2008.

 

Bomhard, 1988, oral route, 1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-dodecanethiol:

The study on acute oral toxicity of '1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-dodecanethiol' was performed on each five male and female Wistar rats according to the EU method B.1 "Acute Toxicity Oral" (1984) without deviations and according to the principles of GLP. A dose of 5000 mg/kg body weight of the test substance was administered via oral gavage to the rats. About 8 h after administration, 4 male and 5 female rats showed a slightly roughened pelt which was reversible on the second day. During the post-exposure observation period of 14 days neither mortalities nor macroscopic abnormalities after sacrification were observed. Body weight gains were also not delayed. Consequently, the acute lethal dose of the test item was demonstrated to be greater than 5000 mg/kg bw, so it can be regarded to have a low toxicity and no classification is needed.

Reckers, 1981, oral route, ‘1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-nonanethiol’:

An acute oral study was conducted using a similar procedure to that described in the current OECD Guideline 401 (Reckers, 1981). The test material (CAS No. 91648-65-5) was administered at dose levels of 5000 mg/kg, to two male and two female rats, and 10000 mg/kg to five male and five female rats by oral gavage. The rats were observed for 14 days after test material administration. General signs of intoxication exhibited by the rats following dosing included decreased motor activity and diarrhoea. There were no mortalities in either dose group. No gross pathologic alterations were noted among the animals at study termination. The acute oral median lethal dose (LD50) for the test material was determined to be greater than 10000 mg/kg in male and female rats. Hence, it can be concluded that '1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-nonanethiol' is not acutely toxic via oral route.

 

Anonymus, 1973, oral route, 5-(dodecyldithio)-1,3,4-thiadiazole-2(3H)-thione:

An acute oral study was conducted using a similar procedure to that described in the current OECD Guideline 401 (Anonymous, 1973). The test material (CAS No. 50530-43-3) was administered at dose levels of 4556, 6834, 10250 and 15380 mg/kg by oral gavage to four male and four female rats. The rats were observed for 14 days after test material administration. General signs of intoxication exhibited by the rats following dosing included hypoactivity, ruffed fur, diarrohea, salivation and muscular weakness. There were no mortalities in the lowest dose group (4556 mg/kg), no mortalities in the males and 3/4 females in the 6834 mg/kg dose group, 2/4 dead males and 4/4 dead females in the 10250 mg/kg dose group and no surviving animals in the highest dose group, 15380 mg/kg. Necropsy of the animals that died revealed enteritis. No gross pathologic alterations were noted among the animals.

The acute oral median lethal dose (LD50) was calculated to be 10250 mg/kg in male albino rats or 6176 mg/kg in female albino rats.Thus, the test substance can be considered as not acutely toxic via oral route.

 

Findlay, 1981, inhalation route, ‘1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-nonanethiol’:

The test material (CAS No. 91648-65-6) was administered at a concentration of 2.75 mg/L by inhalation for 4 h to five male and five female rats, using a similar procedure to that described in the current OECD Guideline 403 (Findlay, 1981). The rats were observed for 14 days after test material administration. No mortalities occurred during the study. The following clinical signs were noted during the study: a clear nasal discharge, red encrustation around nose and eyes, and salivation were observed in four rats following exposure, one male rat exhibited diarrhoea immediately following exposure and on the following day. All remaining rats appeared normal. At necropsy, seven rats appeared normal. Three rats had spongy lungs and/or brown foci through all lung lobes. The acute inhalation median lethal concentration (LC50) was determined to be > 2.75 mg/L.Thus, the test substance can be considered as not acutely toxic via inhalation route.

 

Anonymus, 1979, inhalation route,5-(dodecyldithio)-1,3,4-thiadiazole-2(3H)-thione:

An acute inhalation study was conducted using a similar procedure to that described in the current OECD Guideline 403 (Anomynous, 1979). The test material (CAS No. 50530-43-3) was administered at 0.62 mg/L by inhalation for 4 h to five male and five female rats. The rats were observed for 14 days after test material administration. No mortalities occurred during the study. No gross pathologic alterations were noted among the animals.

The acute inhalation median lethal dose (LD50) was estimated to be > 0.62 mg/L, which does not trigger classification as acute toxic via inhalation route.

 

Reckers, 1981, dermal route,‘1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-nonanethiol’:

An acute dermal study was conducted using a similar procedure to that described in the current OECD Guideline 402 (Reckers, 1981). The test material (CAS No. 91648-65-6) was applied at a dose of 2000 mg/kg to the backs of five male and five female rabbits. The test item was left in contact with the skin for 24 hours and then the test sites were washed and the rabbits observed during this time and for 14 days after its removal. One male rabbit had diarrhea on days 2, 3 and 4, as did one female rabbit on day 3. This female and a different male rabbit had diarrhea (immediately prior to dosing). All rabbits appeared normal on day 5 and for the remainder of the observation period. Therefore this finding probably is not treatment related. There were no mortalities during the study and gross necropsy findings in all rabbits were within normal limits. The acute dermal LD50 was determined to be greater than 2000 mg/kg.Thus, the test substance can be considered as not acutely toxic via the dermal route.

 

Reckers, 1982, dermal route, 5-(dodecyldithio)-1,3,4-thiadiazole-2(3H)-thione:

The test material (CAS No. 50530-43-3) was applied at a dose of 2000 mg/kg to the backs of five male and five female rabbits, using a similar procedure to that described in the current OECD Guideline 402. The test substance was left in contact with the skin for 24 hours and then the test sites were washed with 0.9 % sodium chloride and the rabbits observed during this time and for 14 days after its removal. No rabbits died during the study, dermal irritation was present in all rabbits during the majority of the 14 day observation period following removal of the wrappings. Gross necropsy findings in all rabbits were within normal limits. The acute dermal LD50 was determined to be > 2000 mg/kg, which does not trigger classification as acute toxic.

All four available acute oral toxicity were classified as Klimisch 2 and are consequently of a sufficient quality to cover this endpoint. These studies include data on the target substance itself (1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-dodecanethiol) and the results of the two other studies are obtained from read-across. Hence, the study by Huntingdon, 1998, is generally considered to be the most reliable one as it was performed on the registered compound itself and the only restriction is that no GLP compliance is claimed, but, the final report includes an audit as well as quality assurance inspections. However, for the outcome of the testing for acute toxicity, here, the selection of the Key study is only of minor relevance, because the results of all four available studies are consistent and do not trigger the classification of 1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-dodecanethiol as acutely toxic.

One may argue that the available LD50 values vary over a wide range which diminishes their consistency. However, this difference is mainly attributed to the test design: The two lower LD50 values, >2000 mg/kg bw (Mason, 1998) and > 5000 mg/kg bw (Bomhard, 1988), were the highest doses tested in each study, did not induce any mortalities and therefore the LD50(oral) can be even much higher, as it was shown in the following tests: In the study on 5-(dodecyldithio)-1,3,4-thiadiazole-2(3H)-thione (Anonymus, 1973), the LD50(oral) was determined to be LD50 = 10250 mg/kg bw in males and LD50 = 6176 mg/kg bw in females. This is an acceptable deviation from the value derived in the study by Reckers, 1981 (LD50 > 10000 mg/kg bw), which can be explained by the very high dosing range and inter-strain variations.

The limit value for classification as acutely toxic is 2000 mg/kg bw according Regulation 1272/2008/EC. These observed LD50 values are way above this limit values and is also magnitudes above the values relevant for human exposure, i.e. the accidental ingestion. So it can be concluded that the available data is sufficient for further risk assessment and to cover this endpoint.

 

The same applies to the acute toxicity testing via the dermal route. Both available studies, assessed with Klimisch 2, reveal an LD50(dermal) value > 2000 mg/kg bw in rabbits. This was the highest dose tested (limit test) and could be even higher. The available studies are of sufficient quality and reveal equivalent and so consistent results.

Since the limit value for classification is LD50(dermal) = 2000 mg/kg bw,‘1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-dodecanethiol’ does not need to be classified as acute toxic according Regulation 1272/2008/EC.

 

In both available studies on acute toxicity via inhalation route (Findlay, 1981, on '1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-nonanethiol’, and Anonymus, 1979, on 5-(dodecyldithio)-1,3,4-thiadiazole-2(3H)-thione), no LC50(inhalation) could be determined. These studies only state that the LD50(inhalation) is greater than 2.75 mg/L (Findlay, 1981) or 0.65 mg/L. In both studies, no mortalities occurred.

 

In the study by Findlay, 1981, a clear nasal discharge, red encrustation around nose and eyes, and salivation were observed in four rats following exposure, and one male rat exhibited diarrhea immediately following exposure and on the following day. At necropsy after 14 days post-exposure, only three rats had spongy lungs and/or brown foci through all lung lobes. So, at the available dose of 2.75 mg/kg bw, not only no mortalities occurred, but also less than the half of the tested animals were affected at all. Furthermore, the observed clinical signs are unlikely to lead to acute toxic / lethal effects. So, it is reasonable to state that much higher doses than required for classification would be needed to reveal any acute toxic effects.

 

In the study on 5-(dodecyldithio)-1,3,4-thiadiazole-2(3H)-thione (Anonymus, 1979), no mortalities occurred during the study and no gross pathologic alterations were noted among the animals. Since no effects relevant for toxicity at all were denoted, it can reasonably be concluded that the actual LD50(inhalation) would be much higher and the available data do not indicate any need for classification.

 

For humans, the available data gained during the two inhalation studies, are less relevant and it can be reasonably assumed that no toxic effects will occur during handling of the substance, because the experimental design is not relevant for normal exposure conditions. The test compound has a low vapour pressure (0.0021 Pa) and does not boil but decompose (decomposition temperature approx. 223 °C). This also applies to

'1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-doceanethiol' which has a vapour pressure of ≤ 6.1 Pa (Henkel, 2012) and boils or decomposes at 237°C (Henkel, 2012)

In order to convert the compound into an inhalable form, the test item was heated up, e.g. at 93 °C, and air was saturated with these vapours by passing it through the test item. The air containing test item was then introduced into the exposure chamber. This exposure is not relevant for humans as these non-naturally conditions do not occur during foreseen use of the substance, and so no inhalable forms will be generated and the compound is unable to exhibit toxic effects via the inhalative route, as the substance is a non-volatile and has a rather low vapour pressure, which indicates only low availability for inhalation.

Regarding absorption in the respiratory tract, the higher molecular weight and the very high LogPow also indicate no possibility for absorption through aqueous pores. Based on this data and even though the LogPow value above 0 indicates the potential for absorption directly across the respiratory tract epithelium (which is unlikely as the substance is ionisable), it can be expected that '1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-dodecanethiol' is marginally available in the air for inhalation and any inhaled substance is expected not to be absorbed.

 

So, taking into account the high LD50 values via the oral route, the test design creating an unrealistic availability of the substance and the available toxicokinetic data '1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-dodecanethiol' does also not need to be classified as acute toxic when regarding the inhalative route.

So, in general, the whole database is of high quality. Consequently, no data gaps were identified as the available data are sufficient to cover this endpoint, no further testing is required and '1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-dodecanethiol' does not need to be classified as acute toxic, neither according Regulation 1272/2008/EC nor Directive 67/548/EEC. No inter-species differences were identified which might give an indication on non-suitability of these results for human risk assessment, an so the non-classification as acutely toxic is fully relevant for humans.

Justification for selection of acute toxicity – oral endpoint
The selected study is one of 4 available acute oral toxicity studies, all assessed with Klimisch 2. Nevertheless the present study is the most reliable one as it was performed on the registered compound itself and does not present read-across data, and the only restriction is that no GLP compliance is claimed, but, the final report includes an audit as well as quality assurance inspections.
Although the present study did not reveal the lowest LD50 of all studies, it was nevertheless chosen as it was performed on the registered substance itself. Additionally, the lowest LD50 of > 2000 mg/kg bw (Mason, 1998, 1,3,4-Thiadiazolidine-2,5-dithione, reaction products with hydrogen peroxide and tert-dodecanethiol) was only determined to be > 2000 mg/kg bw because of the test design: This value was determined in a limit test and is the only dose tested; hence, it could even be much higher, as shown in the present study.

Justification for selection of acute toxicity – inhalation endpoint
One of two available acute toxicity studies via inhalation route on read-across substances, all assessed with Klimisch 2. Nevertheless the present study is the most reliable one as the only restriction (besides read-across) is that no GLP compliance is claimed, but, the final report includes an audit as well as quality assurance inspections.
Although the present study did not reveal the lowest LD50 of both studies (> 2.75 mg/L vs. > 0.61 mg/L), it was nevertheless chosen as it was the more reliable one and both values do not trigger a classification as acutely toxic.

Justification for selection of acute toxicity – dermal endpoint
One of two available acute dermal toxicity studies, both assessed with Klimisch 2, both revealing an dermal LD50 >2000 mg/kg bw.

Justification for classification or non-classification

There is no classification as acutely toxic required because in all available acute oral and dermal toxicity studies the determined was > 2000 mg/kg bw. Furthermore, no inhalative LC50 could be determined, because no animal died at the concentration tested, i.e. the LC50 is > 2.75 mg/L over 4h. Also, the observed adverse effects are not sufficiently severe to indicate an LC50 of =< 20 mg/L triggering classification.

In one of the two inhalation studies, a clear nasal discharge, red encrustation around nose and eyes, and salivation were observed in four rats following exposure. Generally, this would have to be considered as irritative effect. However, for humans, the available data gained during this study, is less relevant and it can be reasonably assumed that no toxic / irritating effects, neither local nor systemic, will occur during handling of the substance, because the experimental design is not relevant for normal exposure conditions. The test compound has a low vapour pressure and is likely not to boil but decompose. In order to convert the compound into an inhalable form, the test item was heated up, e.g. at 93 °C, and air was saturated with these vapours by passing it through the test item. The air containing the test item was then introduced into the exposure chamber. This exposure is not relevant for humans as these non-naturally conditions do not occur during foreseen use of the substance, and so no inhalable forms will be generated and the compound is unable to exhibit toxic systemic or local effects via the inhalative route. Hence, the necessity for classification as STOT-SE according to Regulation 1272/2008/EC is not given, too.