3,3'-thiodi(propionic acid)

Endpoint summary

Description of key information

oral LD50 > 2000 mg/kg bw (rat, equivalent to OECD TG 401)

inhalation LC50 (4 h) >5.13 mg/L air (rat, OECD TG 403)

dermal LD40 > 2000 mg/kg bw (rat, OECD TG 402)

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

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

Only translated summary available, actual guideline not stated.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

Only summary available, guideline not stated

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories Japan, Inc.
- Age at study initiation: 5 weeks
- Weight at study initiation: males 133-150 g, females 111-126 g
- Fasting period before study: 18 h before until 3 h after dosing
- Housing: 5/cage
- Diet (e.g. ad libitum): solid feed for experimental animals (MF, Oriental Yeast Co. Ltd.), ad libitum
- Water (e.g. ad libitum): sterile-filtered and UV-radiated tap water, ad libitum
- Acclimation period: 7 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±2
- Humidity (%): 55±15
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 200 mg/mL in 0.5 % CMC-Na aqueous solution (CMC-Na, Wako Pure Chemical Industries; Water for injection: Otsuka Pharmaceutical Factory)
- Amount of vehicle (if gavage): 10 mL/kg bw, calculated based on the bodyweight determined immediately prior to administration.


MAXIMUM DOSE VOLUME APPLIED: 10 ml/kg bw


DOSAGE PREPARATION (if unusual): Preparation of test substance suspension in CMC-solution 6 days in advance of administration.

Doses:

0, 2000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Survival, appearance, mobility, and other abnormalities on administration day immediately prior to administration and 0.5, 1, 3, and 6 hours after administration, then once a day thereafter for the rest of the observation period; bodyweight was measured immediately prior to administration (day 1) and then on days 2, 4, 8, 10, and 15.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

Statistics:

F test was performed on bodyweights, in case of equal variance they were subjected to Student's t-test, in case of unequal variance they were subjected to Aspen-Welch's t-test. Significance level was 5 %.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Mortality:

No mortality occurred.

Clinical signs:

other: No effects were observed.

Gross pathology:

No effects were observed.

The test substance does not need to be classified according to the criteria of DSD or CLP.

Interpretation of results:

GHS criteria not met

Conclusions:

In an acute oral toxicity study equivalent to OECD TG 401, Crj: CD(SD) fasted rats (5/sex/dose) were orally administered with 0 (control) and 2000 mg/kg bw 3,3'-Thiobispropanoic acid in 0.5 % carboxymethyl cellulose by gavage. Animals were then observed for 14 d. No mortality occurred. No clinical signs were observed. There was no significant difference compared to controls. A low value for males in the treated group was found on day 8 due to food not being given to those animals from day 7 to day8. This observation was not attributed to test material administration. At necropsy, no macroscopic effects were observed. The LD50 was >2000 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

GLP compliance:

yes (incl. QA statement)

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River (UK) Ltd, Margate, Kent.
- Age at study initiation: approximately eight to twelve weeks old
- Weight at study initiation: weight range of 200g to 350g
- Fasting period before study:
- Housing: The animals were housed in groups of five by sex in solid-floor polypropylene cages with stainless steel lids, furnished with softwood f akes (Datesand Ltd., Cheshire, UK) and provided with environmental enrichment items: wooden chew blocks (B & K Universal Ltd, Hull, UK) and cardboard “fun tunnels” (Datesand Ltd., Cheshire, UK).
- Diet (e.g. ad libitum)+ Water (e.g. ad libitum): With the exception of the exposure period, free access to mains drinking water and food (EU Rodent Diet 5LF2, BCM IPS Limited, London, UK) was allowed throughout the study.

- Acclimation period: 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 25°C
- Humidity (%): 30 - 70%
- Air changes (per hr): fifteen changes per hour
- Photoperiod (hrs dark / hrs light): twelve hours continuous light and twelve hours darkness

Route of administration:

inhalation: dust

Type of inhalation exposure:

nose only

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION

- Exposure chamber volume: approximately 30 litres (dimensions: 28 cm diameter x 50 cm high)
- Method of holding animals in test chamber: Each rat was individually held in a tapered, polycarbonate restraining tube fitted onto a single tier
of the exposure chamber and sealed by means of a rubber ‘O’ ring. Only the nose of each animal was exposed to the test atmosphere.
- Method of conditioning air: Compressed air was supplied by means of an oil free compressor and passed through a water trap and respiratory quality filters before it was introduced to the SAG 410.
- System of generating particulates/aerosols: A dust atmosphere was produced from the test material using a SAG 410 Solid Aerosol Generator (TOPAS GmbH, Dresden, Germany) located adjacent to the exposure chamber. The SAG 410 was connected to a metered compressed air supply. A particle separator was introduced before the aerosol entered the exposure chamber in order to remove large particles and thereby increase the inhalable por ion of the generated aerosol.
- Method of particle size determination: Marple Personal Cascade Impactor (Westech IS Ltd, Beds., UK).
- Temperature, humidity, pressure in air chamber: The environmental controls were set to achieve values of 19 - 25°C and 30 - 70% relative
humidity.

Duration of exposure:

4 h

Concentrations:

5.13 mg/L

No. of animals per sex per dose:

5 male and 5 female

Control animals:

no

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 5.13 mg/L air

Exp. duration:

4 h

Mortality:

One animal showed a rapid decline in condition on Day 10 and was subsequently humanely killed, this animal exhibited significant weight loss and observations now included decreased respiratory rate, laboured respiration, noisy respiration, lethargy, hunched posture, piloerection and red/brown staining around the snout.

Clinical signs:

other: During exposure, there were frequent instances of increased respiratory rate. On removal from the chamber, animals showed increased respiratory rate and noisy respiration. One hour after removal, no change in the condition of the animals was observed. One

Body weight:

All male animals exhibited bodyweight loss or reduced bodyweight gain during Week 1, four of these animals recovered to show normal development during Week 2. Normal bodyweight development was noted for all female animals during the study.

Gross pathology:

Apart from one instance of dark patches on the lungs no macroscopic abnormalities were detected amongst animals that survived until Day 14 at necropsy.

Mortality Data:

Mean Achieved Atmosphere Concentration (mg/L)	Deaths:
	Male	Female	Total
5.13	1/5	0/5	1/10

Only one death occurred in a group of ten rats exposed to a mean achieved atmosphere

concentration of 5.13 mg/L for four hours. It was therefore considered that the acute inhalation

median lethal concentration (4 hr LC50) of TDPA, in the Sprague-Dawley Crl:CD® (SD) IGS BR

strain rat, was greater than 5.13 mg/L.

Interpretation of results:

GHS criteria not met

Conclusions:

In an acute inhalation toxicity study according to OECD TG 403 Sprague-Dawley rats (5/sex) were exposed to 5.13 mg/L air 3,3'-Thiobispropanoic acid (nose only; dust) for 4 h. Animals were then observed for 14 d.
One animal showed a rapid decline in condition on Day 10 and was subsequently humanely killed, this animal exhibited significant weight loss and observations now included decreased respiratory rate, laboured respiration, noisy respiration, lethargy, hunched posture, piloerection and red/brown staining around the snout.
During exposure, there were frequent instances of increased respiratory rate. On removal from the chamber, animals showed increased respiratory rate and noisy respiration. One hour after removal, no change in the condition of the animals was observed. One day after exposure, all animals exhibited increased respiratory rate, hunched posture and piloerection. There were frequent instances of noisy respiration and red/brown staining around the head. The majority of animals showed good signs of recovery over the recovery period, one animal exhibited a scab on the head on Days 8 and 9 but this was not considered to be treatment related. Female animals recovered quicker than male animals such that they appeared normal from Days 3 to 8 post-exposure. Three out of the four surviving male animals appeared normal from Days 5 to 12, however, one male animal still exhibited noisy respiration by Day 14.
All male animals exhibited bodyweight loss or reduced bodyweight gain during Week 1, four of these animals recovered to show normal development during Week 2. Normal bodyweight development was noted for all female animals during the study.
Apart from one instance of dark patches on the lungs no macroscopic abnormalities were detected amongst animals that survived until Day 14 at necropsy.
The 4 h LC50 was 5.13 mg/L air.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LC50

Value:

5.13 mg/m³ air

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

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

GLP compliance:

yes (incl. QA statement)

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River (UK) Ltd, Margate, Kent.
- Age at study initiation: approximately eight to twelve weeks old
- Weight at study initiation: approximately 200g
- Housing: The animals were housed in groups of five by sex in solid-floor polypropylene cages with stainless steel lids, furnished with softwood f akes (Datesand Ltd., Cheshire, UK) and provided with environmental enrichment items: wooden chew blocks (B & K Universal Ltd, Hull, UK) and cardboard “fun tunnels” (Datesand Ltd., Cheshire, UK).
- Diet (e.g. ad libitum)+ Water (e.g. ad libitum): Free access to mains drinking water and food (EU Rodent Diet 5LF2, BCM IPS Limited, London, UK) was allowed throughout the study.

- Acclimation period: 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 25°C
- Humidity (%): 30 - 70%
- Air changes (per hr): fifteen changes per hour
- Photoperiod (hrs dark / hrs light): twelve hours continuous light and twelve hours darkness

Type of coverage:

semiocclusive

Vehicle:

water

Details on dermal exposure:

TEST SITE
- Area of exposure: shorn skin
- % coverage: approximately 10 % of the body surface
- Type of wrap if used: surgical gauze was placed over the treatment area and semi-occuled with a peace of self-adhesive bandage.


REMOVAL OF TEST SUBSTANCE
- Washing (if done): the treated skin and surrounding hair wiped with cotton wool moistured with distilled water to remove any residual test material.

Duration of exposure:

24 h

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

ten animals (five males and five females)

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: 1/2, 1, 2 and 4 hours after dosing and subsequently once daily for fourteen days.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Mortality:

No mortality during the study

Clinical signs:

other: No signs of systemic toxicity

Other findings:

No abnormalities were noted at necropsy.

The acute dermal median lethal dose (LD50) of the test material in the Sparque-Dawley CD strain rat was found to be greater than 2000 mg/kg bodyweight.

Interpretation of results:

GHS criteria not met

Conclusions:

In an acute dermal toxicity study according to OECD TG 402, Sprague-Dawley rats (5/sex/dose) were dermally exposed to 2000 mg/kg bw 3,3'-Thiobispropanoic acid in water for 24 h under semiocclusive conditions. Animals were then observed for 14 d.
No mortality occurred during the study. No signs of systemic toxicity were observed. All animals showed the expected gains in bodyweight over the study period.
The dermal LD50 was >2000 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Additional information

Oral toxicity

In an acute oral toxicity study equivalent to OECD TG 401, fasted Crj: CD(SD) rats (5/sex/dose) were orally administered with 0 (control) and 2000 mg/kg bw 3,3'-Thiobispropanoic acid in 0.5 % carboxymethyl cellulose by gavage. Animals were then observed for 14 d. No mortality occurred. No clinical signs were observed. There was no significant difference compared to controls. A low value for males in the treated group was found on day 8 due to food not being given to those animals from day 7 to day 8. This observation was not attributed to test material administration. At necropsy, no macroscopic effects were observed. The LD50 was >2000 mg/kg bw.

 

inhalation toxicity

In an acute inhalation toxicity study according to OECD TG 403 Sprague-Dawley rats (5/sex) were exposed to 5.13 mg/L air 3,3'-Thiobispropanoic acid (nose only; dust) for 4 h. Animals were then observed for 14 d.

One animal showed a rapid decline in condition on Day 10 and was subsequently humanely killed, this animal exhibited significant weight loss and observations now included decreased respiratory rate, laboured respiration, noisy respiration, lethargy, hunched posture, piloerection and red/brown staining around the snout.

During exposure, there were frequent instances of increased respiratory rate. On removal from the chamber, animals showed increased respiratory rate and noisy respiration. One hour after removal, no change in the condition of the animals was observed. One day after exposure, all animals exhibited increased respiratory rate, hunched posture and piloerection. There were frequent instances of noisy respiration and red/brown staining around the head. The majority of animals showed good signs of recovery over the recovery period, one animal exhibited a scab on the head on Days 8 and 9 but this was not considered to be treatment related. Female animals recovered quicker than male animals such that they appeared normal from Days 3 to 8 post-exposure. Three out of the four surviving male animals appeared normal from Days 5 to 12, however, one male animal still exhibited noisy respiration by Day 14.

All male animals exhibited bodyweight loss or reduced bodyweight gain during Week 1, four of these animals recovered to show normal development during Week 2. Normal bodyweight development was noted for all female animals during the study.

Apart from one instance of dark patches on the lungs no macroscopic abnormalities were detected amongst animals that survived until Day 14 at necropsy.

The 4 h LC50 was 5.13 mg/L air.

 

Dermal toxicity

In an acute dermal toxicity study according to OECD TG 402, Sprague-Dawley rats (5/sex/dose) were dermally exposed to 2000 mg/kg bw 3,3'-Thiobispropanoic acid in water for 24 h under semiocclusive conditions. Animals were then observed for 14 d.

No mortality occurred during the study. No signs of systemic toxicity were observed. All animals showed the expected gains in bodyweight over the study period.

The dermal LD50 was >2000 mg/kg bw.

 

Justification for classification or non-classification

Based on the available data, 3,3'-Thiobispropanoic acid does not need to be classified for acute toxicity via the oral, inhalation, or dermal route according to regulation (EC) 1272/2008. Thus, no labelling is required.