2,2'-thiodiethanethiol

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1990

Report date:

1990

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Version / remarks:

1981

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

2,3-bis((2-mercaptoethyl)thio)-1-propanethiol

EC Number:

411-290-7

EC Name:

2,3-bis((2-mercaptoethyl)thio)-1-propanethiol

Cas Number:

131538-00-6

Molecular formula:

C7 H16 S5

IUPAC Name:

2,3-bis((2-mercaptoethyl)thio)-1-propanethiol

Test material form:

solid - liquid: suspension

Details on test material:

- Lot/batch No.: B-DMPT-EC1-05/2010-F4/2

Test animals

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc. Raleigh, North Carolina 27610
- Age at study initiation: Males: 7 weeks; Females: 9 weeks
- Weight at study initiation: Males, Means: 218 and 224g; Females, Means: 199 and 206g
- Fasting period before study: no
- Housing: Animals were doubly housed in suspended, stainless steel, wire mesh cages during the first week of the acclimation period and individually housed during the remainder of the acclimation period and all other non-exposure periods.

- Diet (e.g. ad libitum): ad libitum; standard pellet laboratory diet (Purina Rodent Laboratory Chow® Brand Animal Diet #5001). Fresh food presented as required.
- Water (e.g. ad libitum): ad libitum; by automated watering system (Elizabethtown Hater Company).
- Acclimation period: 1 week
- Method of randomisation in assigning animals to test and control groups: Prior to the initiation of exposure to the test substance, animals were arbitrarily selected from the
Bio/dynamics‘ in-house population based on acceptable pretest physical examinations and body weights.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-26
- Humidity (%): 9-44
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

whole body

Vehicle:

air

Mass median aerodynamic diameter (MMAD):

4.2 µm

Geometric standard deviation (GSD):

1.9

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 100 liter Plexiglas ® chamber with a glass front
- Exposure chamber volume: 100L
- Source and rate of air (airflow): House-line air was delivered from a Union Carbide regulator and backpressure gauge
- System of generating particulates/aerosols: Approximately 340 milliliters (ml) of the test substance were placed in a 500 milliliter Erlenmeyer flask connected to an FMI fluid metering pump (Model RP G-20) with a 1/8" piston and an initial pump setting of 75% . The test substance was fed from the pump directly into the liquid inlet of a Spraying Systems air atomizing nozzle, via 1/8" Teflom® tubing. House-line air was delivered from a Union Carbide regulator and a USG backpressure gauge , via 1/4" Tygon® tubing, to a Dwyer® flowmeter fitted with a USG backpressure gauge regulated by a Nupro® metering valve and into the air inlet of the atomizer to generate the aerosol. The test atmosphere was directed into the exposure chamber which housed the animals. The animals remained in the chamber for 30 minutes following the exposure to allow the chamber to clear, using clean air at the same airflow rate used during exposure.
- Method of particle size determination: Samples for particle size distribution assessment were drawn once per hour using a Delron DCI-6 cascade impactor. Chamber air was drawn through the impactor by a pump regulated by a Dwyen® flowmeter and a Nupro® metering valve. The mass median aerodynamic diameter, geometric standard deviation and percent of particles ≤1 and ≤10 microns were calculated based on the amount of material collected on the impactor stages using a graphical analysis of an assumed lognormal distribution.


TEST ATMOSPHERE
- Brief description of analytical method and equipment used: LC,
120 ml amber glass bottles
10.0, 50.0 and 100 ml Class A volumetric flasks
0.5, 1.0, 2.5, 5.0, 10.0 and 25.0 ml Class A volumetric pipets
Analytical balances, Mettler H33AR or the equivalent
Disposable glass pipets and labeling tape
A liquid chromatograph:
Waters 510 Pump,
HISP 710 B Autoinjector;
waters 481 Detector
Flatron Column Oven and Controller
Hewlett Packard 3390 A Integrator
Approximately 1.00 g of GST analytical standard was weighed out and transferred to a 100 ml volumetric flask. This flask was diluted to volume with acetonitrile for an approximate stock external standard concentration of 10,000 µg/ml.
Approximately 1.0 g of DM-DPA was weighed out and transferred to a 100 ml volumetric flask. This flask was diluted to volume with acetonitrile for an approximate stock concentration of 10,000 µg/ml.
An additional dilution of 5 ml to 10 ml for a concentration of 5,000 µg/ml was performed.
A standard curve for the analyses was constructed by injecting three different concentrations at the initiation of the chromatographic run, a standard after every fourth sample and at the end of the run. The standard response was plotted at the peak height of GST versus the concentration of GST in the standard. A standard correlation coefficient was then calculated by linear regression and the sample concentrations were obtained using this coefficient.

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

0 and 4.2 mg/L

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: All animals were observed individually, immediately prior to exposure, as a group at approximately fifteen minute intervals during the first hour of exposure, and hourly for the remainder of the exposure period. All survivors were observed individually upon removal from the chamber (half-hour after exposure was completed) and hourly for two hours post-exposure. Detailed physical observations were recorded at each interval. Neurological examinations were performed on all animals immediately prior to exposure and at 1 hour and 4 hours post-exposure. Detailed observations were recorded for survivors once daily; viability was assessed twice daily. Neurological examinations were performed on Test Days 2, 8 and 15. Body weight: Day 1 (immediately prior to exposure) and on Days 2, 3, 5, 8 and 15 (just prior to sacrifice)
- Necropsy of survivors performed: yes
- Clinical signs including body weight: yes
- Other examinations performed: clinical signs, body weight, neurological examinations

Results and discussion

Effect levels

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 4.2 mg/L air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Mortality:

A single male rat was found dead 5 days after exposure.

Clinical signs:

other: During the Group II exposure, the most commonly noted signs of toxicity were labored breathing, decreased activity and eye closure.

Body weight:

The Group I animals showed fairly regular weight gains. Substantial weight losses were observed during the first day or two following the Group II exposure. Recovery of weight occurred over time and all surviving animals were in excess of their pre-exposure body weight by termination of the study.

Gross pathology:

All animals were examined postmortem for the presence of grossly visible morphologic abnormalities.
The lungs in 3/5 treated females were reddened; this appears related to treatment. There appears to be an effect on the eyes and the skin; with chromodacryorrhea, brown stains on the face, hair loss and scabs only in the treated animals.
Other postmortem findings observed grossly occurred sporadically and were not considered to be related to the test article.

Other findings:

Neurologic Examinations:
The Group I animals were unremarkable. However, the Group II animals showed decreased muscle tone and reflexes as well as abnormal gait during the first week after exposure before mostly recovering.

Applicant's summary and conclusion

Conclusions:

A four-hour, whole-body inhalation exposure was performed with one group,
consisting of five male and five female Sprague-Dawley CD® rats, to determine
the acute toxic effects of GST. The animals were exposed to GST as an aerosol
at a gravimetric concentration of 4.2 mg/l. A single male animal was found dead
five days after exposure apparently as a result of the treatment. A similar control group was exposed to house-line air only.
Signs of treatment with the GST including labored breathing were commonly
noted during exposure. During the 14-day post-exposure observation period,
signs of toxicity included labored breathing, secretory responses and red/flaky
skin. The responses did not fully abate prior to sacrifice.
Detailed neurological examinations showed decreased muscle tone and
reflexes as well as abnormal gait during the first week after exposure before
mostly recovering.
An adverse effect upon body weight was produced by treatment. In general,
a recovery in body weight was seen in surviving animals prior to sacrifice.
Postmortem findings included discolored lungs (red), possibly as a result
of treatment.

Executive summary:

In an acute inhalation toxicity study according to OECD test guideline 403 (1981), groups of young adult Sprague Dawley rats (5/sex) were exposed by inhalation route to 2,3-bis((2-mercaptoethyl)thio)-1-propanethiol in air (aerosol)  for 4 hours to the whole body at concentrations of 0 and 4.2 mg/L. Animals then were observed for 14 days. Beside body weight changes and clinical signs also neurological examinations were performed.

LC50 Combined > 4.2 mg/L

 

      (limit test)

(2,3-bis((2-mercaptoethyl)thio)-1-propanethiol is classified as being of low Toxicity based on the clinical signs that were observed after treatment. During the 14-day post-exposure observation period, signs of toxicity included labored breathing, secretory responses and red/flaky skin. The responses did not fully abate prior to sacrifice. Detailed neurological examinations showed decreased muscle tone and reflexes as well as abnormal gait during the first week after exposure before mostly recovering. No Mortality occurred thus the LD50 value is above 4.2 mg/L. Based on the non-reversibility of signs the substance is classified according to Regulation (EU) No. 1272/2008 (CLP) as acute inhalation toxicity Category 4.