Registration Dossier

Administrative data

Description of key information

The acute toxicity of 5,5'-Dithiodi-1,3,4-dithiazole-2(3H)-thione was evaluated by oral and dermal route in rats.

LD50 are higher than 2000 mg/kg bw in the oral and dermal acute studies.

No study by inhalation is available.

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:
February - March 2014
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.1 bis (Acute Oral Toxicity - Fixed Dose Procedure)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: Japanese MAFF, 2000
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
fixed dose procedure
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals or test system and environmental conditions:
Female Wistar (RccHan™:WIST) strain rats were supplied by Harlan Laboratories UK Ltd., Oxon, UK.
The females were nulliparous and non-pregnant.
Acclimatization period of at least five days.
At the start of the study the animals were approximately nine to eleven weeks of age.
The body weight variation did not exceed ±20% of the mean weight at the start of treatment
The animals were housed in groups of up to four in suspended solid-floor polypropylene cages with stainless steel mesh lids and furnished with woodflakes.
With the exception of an overnight fast immediately before dosing and for approximately three to four hours after dosing, free access to mains drinking water and food was allowed throughout the study.

The temperature and relative humidity remained within 19 to 25 °C and 30 to 70%, respectively, during the study.
The rate of air exchange was at least fifteen changes per hour.
The lighting was controlled by a time switch to give twelve hours continuous artificial light (06:00 to 18:00) and twelve hours darkness.
Route of administration:
oral: gavage
Vehicle:
DMSO
Details on oral exposure:
All animals were dosed once only by gavage, using a metal cannula attached to a graduated syringe. The volume administered to each animal was calculated according to the fasted body weight at the time of dosing.

The test item was formulated within two hours of being applied to the test system. No analysis was conducted to determine the homogeneity, concentration or stability of the test item formulation. This is an exception with regard to GLP and has been reflected in the GLP compliance statement.
Doses:
2000 mg/kg
No. of animals per sex per dose:
Dose group 1: 1 Female
Dose group 2: 4 Females
Control animals:
no
Details on study design:
In the absence of mortality at a dose level of 2000 mg/kg in the sighting test with one female animal, an additional group of four female animals was treated. At least 24 hours was allowed between each dose group to confirm the survival of the previously dosed animals.

Clinical observations were made ½, 1, 2, and 4 hours after dosing and then daily for fourteen days.

Morbidity and mortality checks were made twice daily, early and late during normal working days and once daily on weekends and public holidays.

Individual body weights were recorded on Day 0 (the day of dosing) and on Days 7 and 14.

At the end of the observation period the animals were killed by cervical dislocation.

All animals were subjected to gross necropsy.
Sex:
female
Dose descriptor:
LD0
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
There were no unscheduled deaths.
Clinical signs:
Hunched posture and lethargy were noted during the day of dosing.
Body weight:
All animals showed expected gains in body weight.
Gross pathology:
No abnormalities were noted.
Interpretation of results:
GHS criteria not met
Conclusions:
The acute oral median lethal dose (LD50) of 5,5'-Dithiodi-1,3,4-thiadiazole-2(3H)-thione in the female Wistar strain rat is greater than 2000 mg/kg body weight.
Executive summary:

The study was performed to assess the toxicity of the test item following a single oral dose to the Wistar strain rat.

Following a sighting test at a dose level of 2000 mg/kg in one fasted female, an additional four fasted female animals were given a single oral dose of test item, as a solution in dimethyl sulphoxide, at a dose level of 2000 mg/kg body weight. Clinical signs and body weight development were monitored during the study. All animals were subjected to gross necropsy.

There were no unscheduled deaths. Hunched posture and lethargy were noted during the day of dosing in the initial treated animal. There were no signs of systemic toxicity noted in the additional treated animals. Based on historical data from the supplier for this strain, all animals showed expected gains in body weight over the observation period.

No abnormalities were noted at necropsy.

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

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
2 000 mg/kg bw
Quality of whole database:
The oral acute study is considered to be reliable (performed with OECD and GLP guidelines).

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
November 1982
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
not applicable
Qualifier:
according to guideline
Guideline:
other: Methods in 40 CFR, Part 163, Section 163.81-2, Federal register, August 22, 1978
Deviations:
not specified
GLP compliance:
no
Remarks:
Conducted prior to GLP
Test type:
standard acute method
Limit test:
yes
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals or test system and environmental conditions:
Ten animals in total were used in the study (5 males and 5 females).

Weight: 200 - 300g Animals were housed and maintained according to the Animal Welfare Act (Pub. L-94-279) 9 C.F.R. Part 3.

Animal Husbandry Conditions:
Temperature - 70ºF ± 2ºF
Relative Humidity - 45% ± 5%
Light - 12 hour light/dark cycle
Diet Wayne 15% Rabbit Ration and tap water were provided ad libitum.
Caging - Stainless steel with elevated wire mesh flooring 1 Rabbit per cage.
Weight: 2.0 - 3.0 kg
Age: 9-10 weeks old
Acclimatisation: at least 5 days
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
A group of ten rabbits (5 male & 5 female) had their backs clipped free of hair 24 hours prior to testing. All animals had their backs abraded within 2 hours prior to dosing.
The sample material dosed as supplied.
The substance was applied to approximately 10% of the body surface on each animal. The treated areas were covered with large gauze patches and an impervious material wrapped snugly around the trunk of each animal.
Duration of exposure:
The duration of exposure was 24 hours. After 24 hours, the wrapping was removed, excess material was removed by wiping but not washing, and the approximate amount remaining was noted. The animals were observed for a 14 day period for signs of toxicity (systematic and topical) and for mortalities.
Doses:
2000 mg/kg
No. of animals per sex per dose:
5 male and 5 female rabbits.
Control animals:
no
Details on study design:
Animals were observed frequently on the day of dosage, and twice per day thereafter (morning and afternoon). Individual weights were recorded on the day of dosage, weekly thereafter, and prior to sacrifice. Gross autopsies were performed on all animals that either dies during the 14 day observation period or on surviving animals that were sacrificed with carbon dioxide at the conclusion of the 14 day observation period.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: One animal died.
Mortality:
1 female animal found dead on day 12 of the study.
Clinical signs:
Males: All animals appeared normal throughout the duration of the 14 day observation period.

Females: One female lost weight during the first 7 days, exhibited diarrhea on day 8 and was found dead on day 12. The other four animals appeared normal throughout the 14 day observation period.
Body weight:
Average day 7 weights were as follows:
Males: 2.79 kg
Females: 2.88 kg.
Gross pathology:
No gross abnormalities were noted in any of the ten animals necropsied.
Interpretation of results:
GHS criteria not met
Conclusions:
The dermal LD50 of 5,5'-dithiodi-1,3,4-thiadiazole-2(3H)-thione in male and female New Zealand White rabbits is greater than 2000 mg/kg body weight
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
The dermal acute study is considered to be reliable (performed with OECD and GLP guidelines).

Additional information

Acute toxicity by oral route

In an OECD 420 study (key study), conducted according to GLP, the acute oral LD50 to female Wistar rats of 5,5'-Dithiodi-1,3,4-thiadiazole-2(3H)-thione is greater than 2,000 mg/kg bodyweight (Harlan Laboratories Ltd, 2014a). There were no unscheduled deaths observed in all five females exposed to 2000 mg/kg bw. Hunched posture and lethargy were noted during the day of dosing in the initial treated animal. There were no signs of systemic toxicity noted in the additional treated animals. Based on historical data from the supplier for this strain, all animals showed expected gains in body weight over the observation period. No abnormalities were noted at necropsy.

In the supporting study conducted similar or equivalent to OECD 401 study, not conducted according to GLP, the acute oral LD50 to male and female rats of 5,5'-Dithiodi-1,3,4-dithiazole-2(3H)-thione is 6,480 mg/kg bodyweight (Biosearch Incorporated, 1983a).

Acute toxicity by dermal route

In a study conducted similar or equivalent to OECD 402 study, not conducted according to GLP, the acute dermal LD50 to male and female New Zealand White rabbits of 5,5'-Dithiodi-1,3,4-dithiazole-2(3H)-thione is greater than 2,000 mg/kg bodyweight (Biosearch Incorporated, 1983b). In this study, one female lost weight during the first 7 days, exhibited diarrhea on day 8 and was found dead on day 12. All other animals appeared normal throughout the duration of the 14 day observation period. No gross abnormalities were noted in any of the ten animals necropsied.

Justification for classification or non-classification

Based on the available data, no classification for acute toxicity is required for 5,5'-Dithiodi-1,3,4-dithiazole-2(3H)-thione according to the Regulation EC 1272/2008.

Justification of the non-classification : Oral and dermal LD50 higher than 2000 mg/kg bw.