3-(methylthio)propionaldehyde

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

short-term repeated dose toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Remarks:

Test material not fully characterised, particle size distribution (MMAD and GSD) not reported, no data of individual animals given, 13 days study with 9 days exposure instead of 28 day study with 5 days exposure/week

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Remarks:

mass median aerodynamic diameter not given

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Principles of method if other than guideline:

- Principle of test: Groups of male and/or female rats were exposed to a saturated vapor atmosphere of the test item for different times of exposure. The test atmosphere was generated statically or dynamically.
- Short description of test conditions:
1. Static exposure: Whole body exposure
120 - 250 g of liquid test substance were placed in an open tray at the top of a sealed 120 or 250 L stainless steel and glass exposure chamber. The atmosphere was allowed to equilibrate for a minimum of 6 h. The animals were then introduced into the chamber through a gasketted door. The test item atmosphere was generated as supplied or from test item which was previously sparged with nitrogen in an attempt to remove volatile impurities, notably acrolein.
The animals were exposed for 24, 40, 49, 60, 80, 97, 100, 195, 240, 360 and 380 min (refer to Table no. 1 under "Any other information on materials and methods incl. tables").
- Parameters analysed / observed: clinical signs, mortality, gross necropsy, histopathological examination of lungs (only from animals exposed for 60 and 240 min); analytical determinations of the test item in the exposure chamber atmosphere.

2. Dynamic exposure: Whole body and nose-only exposure
The atmosphere was generated by metering liquid test substance from a piston pump into a heated evaporator maintained at the lowest temperature (91°C) sufficient to vaporise the liquid.
Whole body exposure was performed in a 900 L stainless steel glass and steel chamber, in which a countercurrent flow of air was passed through the vaporiser and vapor containing air was passed through the chamber.
For nose-only exposure, test item containing air was introduced at the top of the chamber, flowed past the nose-only ports and exhausted at the bottom of the chamber. The atmosphere was sampled at 6 min intervals to measure the test item and acrolein concentration (refer to Table no. 2 under "Any other information on materials and methods incl. tables").
- Parameters analysed / observed: clinical signs, mortality, body weights, gross necropsy, histopathological examination of lungs (only from nose-only exposed animals); analytical determinations of the test item in the exposure chamber atmosphere.

GLP compliance:

not specified

Test type:

traditional method

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Route of administration:

inhalation: vapour

Type of inhalation exposure:

other: whole body and nose only

Vehicle:

air

Remarks:

in some cases sparged with liquid nitrogen, refer to table no. 1

Analytical verification of test atmosphere concentrations:

yes

Remarks:

for 60, 240, 360 and 380 min exposure only

Duration of exposure:

24 - 380 min

Concentrations:

60 min static exposure: 408 ± 4.5, 733 ± 22 and 935 ppm
240 min static exposure: 957 ± 220 ppm
360 min static exposure: 261 ± 20, 270 ± 51 and 328 ± 4.5 ppm
380 min static exposure: 261 ± 2 ppm
(Please refer to Tables no. 1 and 2 under "Any other information on materials and methods incl. tables".)

No. of animals per sex per dose:

5/sex (except for 935 ppm: 3 male, 7 female)

Control animals:

no

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 289 ppm

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

other: whole body exposure

Remarks:

corresponding to 1.19 ± 0.0081 mg/L air

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 306 ppm

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

other: nose-only exposure

Remarks:

corresponding to 1.32 ± 0.344 mg/L air

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 320 ppm

Based on:

test mat.

Exp. duration:

1 h

Remarks on result:

other: nose only exposure

Remarks:

corresponding to 1.38 mg/L air

Mortality:

Static exposure (whole body exposure for 24 - 380 min at 261 - 957 ppm): all animal of all concentrations and all exposure durations died (refer to Table no. 3 under "Any other information on results incl. tables").
Dynamic exposure (4 h exposure, whole body at 277 and 289 ppm): no mortality occurred.
Dynamic exposure (1 h exposure, nose-only at 320 ppm): no mortality occurred.
Dynamic exposure (4h exposure, whole body at 306 ppm): 1/5 males and 0/5 females died on Day 4 post exposure.

Clinical signs:

other: Please refer to "Any other information on results incl. tables"

Body weight:

Static exposure (whole body exposure for 24 - 380 min at 261 - 957 ppm): body weights were not recorded
Dynamic exposure (4 h whole body exposure at 277 and 289 ppm): reduced body weight gain during the whole study period
Dynamic exposure (1 and 4 h nose only exposure at 320 and 306 ppm): reduced body weight gain during the first week

Gross pathology:

Static exposure (whole body exposure for 24 - 380 min at 261 - 957 ppm): dark red lungs, clear fluid in the trachea and thoracic cavity, livers with dark purple appearance, epithelium of the trachea and major bronchi were detached and there were areas of eosinophilic fibrillar material along the walls.
Dynamic exposure (4 h whole body exposure at 277 and 289 ppm, 1 and 4 h nose only exposure at 320 and 306 ppm): no abnormalities observed.

Other findings:

Histopathology of lungs:
Static exposure (whole body exposure for 24 - 380 min at 261 - 957 ppm): mild to marked congestion, edema, scattered areas of alvolar haemorrhage.
Dynamic exposure (4 h whole body exposure at 277 and 289 ppm, 1 and 4 h nose only exposure at 320 and 306 ppm): no abnormalities observed.

Clinical signs of toxicity:

Static exposure (whole body exposure for 24 - 380 min at 261 - 957 ppm): lacrimation, nasal discharge, mouth and laboured breathing during exposure, wheezing rales and gasping breathing post-exposure.

Dynamic exposure (4 h whole body exposure at 277 and 289 ppm, 1 and 4 h nose only exposure at 320 and 306 ppm): slight lacrimation, bleopharospasm, occasional slight uniform salivation.

Table 3: Time to death in animals exposed under static conditions

Exposure time [min]	Sex	No. of animals/sex	Atmosphere sparged	Concentration [ppm] mean ± SD	Time of death
24	female	5	No	NM	1-9 days post exposure
40	male	5	No	NM	1-2 days post exposure
49	female	5	No	NM	1-2 days post exposure
60	female	5	No	408 ± 4.5	4 h to 1 day post exposure
60	male/female	3 male, 7 female	No	935	Day 1 post exposure
60	male/female	5	Yes	733 ± 22	Day 1 post exposure
80	male	5	No	NM	1 during exposure, 4 on Day 4 post exposure
97	female	5	No	NM	3 during exposure, 2 on Day 1 post exposure
100	male	5	No	NM	during exposure
195	female	5	No	NM	during exposure
240	male/female	5	No	957 ± 220	during exposure
360	female	5	No	261 ± 20	during exposure
360	female	5	Yes	328 ± 4.5	during exposure
360	male/female	5	Yes	270 ± 51	during exposure
380	male	5	No	261 ± 2.4	during exposure

Interpretation of results:

study cannot be used for classification

Conclusions:

The LD50 values in male and female rats were > 1.19 ± 0.0081 mg/L air (for 4 h whole body exposure) and > 1.32 ± 0.344 mg/L air (for 4 h nose-only exposure). The dose levels were below the recommended limit dose of current guidelines, therefore no conclusion on classification can be drawn.

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Acute and repeated exposure toxicity of 3-(Methylthio) propionaldehyde.

Author:

Ballentyne B, Cawley TJ

Year:

2000

Bibliographic source:

Veterinary and Human Toxicology, 42 (6), 330-336

Reference 2

Reference Type:

study report

Title:

Unnamed

Year:

1998

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

- Principle of test: Determination of systemic toxicity in rats upon repeated exposure via inhalation in a 13 day study.
- Short description of test conditions: Groups of 5 male and 5 female rats were exposed to the test item in whole body chambers at concentrations of 0.5, 5 and 50 ppm, corresponding to 0.00215, 0.0215 and 0.215 mg/L air or 2.15, 21.5 and 215 mg/m3 air. The animals were treated for 6 hours/day for 9 days (5 days in the first week and 4 days in the second week).
- Parameters analysed / observed: Physical observations, body weight, food consumption, haematology, clinical chemistry and urinalysis.

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

3-(methylthio)propionaldehyde

EC Number:

221-882-5

EC Name:

3-(methylthio)propionaldehyde

Cas Number:

3268-49-3

Molecular formula:

C4H8OS

IUPAC Name:

3-(methylthio)propionaldehyde

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River laboratories (Kingston, New York, USA)
- Age at study initiation: 6 weeks
- Weight at study initiation: 177 g (males, range: 167 - 189 g) and 119 g (females, range 112 - 129 g)
- Fasting period before study: No
- Housing: Individually in stainless steel wire mesh cages
- Diet: Certified Rodent Diet No. 5002 (PMI Nutrition International, St. Louis, Missouri, USA), ad libitum
- Water: ad libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 23
- Humidity (%): 34 - 75
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

inhalation

Type of inhalation exposure:

whole body

Vehicle:

air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
The air-alone controls were exposed in a 100 L chamber through which air was passed at 20 L/min. For the test item exposures, liquid test material was metered from a syringe pump on to the heated glass helix of a countercurrent volatization chamber. Air was fed through a flow meter into the volatization chamber countercurrent to the flow of the test item. The vapour-containing air was further diluted with additional air to achieve the desired concentration in the 200 L exposure chambers.

TEST ATMOSPHERE
Air was sampled 4 times each hour for measurement of the test item by means of an air pump drarwing chamber air into a 2-HMP coaed XAD-2 resin tube. The test item was extracted from the sampling tubes with carbon disulfide, and measured by a gas chromatography-flame ionization technique. Nominal concentrations were calculated based on a knowledge of the total amount of test item used and the air flow rates.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Exposure concentrations were measured by gas chromatography (GC) four times per chamber per day. Mean chamber concentrations were 0.47 ± 0.05 ppm, 4.99 ± 1.1 ppm and 50.5 ± 5.5 ppm.

Duration of treatment / exposure:

6 h

Frequency of treatment:

6 hours/day for 9 days (5 days in first week, 4 days in second week)

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0.5 ppm (nominal)

Remarks:

corresponding to 2.15 mg/m3 air; corresponding to an analytical concentration of 0.47 ± 0.05 ppm or 2.0 mg/m3 air (dose levels in mg/m3 air were calculated as follows: [dose level in ppm x molecular weight] / 24.2)

Doses / concentrations 2

Dose / conc.:

5 ppm (nominal)

Remarks:

corresponding to 21.5 mg/m3 air; corresponding to an analytical concentration of 4.99 ± 1.1 ppm or 21.5 mg/m3 air (dose levels in mg/m3 air were calculated as follows: [dose level in ppm x molecular weight] / 24.2)

Doses / concentrations 3

Dose / conc.:

50 ppm (nominal)

Remarks:

corresponding to 215 mg/m3 air; corresponding to an analytical concentration of 50.5 ± 5.5 ppm or 217.4 mg/m3 air (dose levels in mg/m3 air were calculated as follows: [dose level in ppm x molecular weight] / 24.2)

No. of animals per sex per dose:

5

Control animals:

yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:

CAGE SIDE AND CLINICAL OBSERVATIONS: Yes
- Time schedule: during exposure and daily thereafter

BODY WEIGHT: Yes
- Time schedule for examinations: 6 and 2 days before exposure and on study Days 7 and 11.

FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
- Food consumption was measured for the week before exposures and for the 1st and 2nd exposure week.
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Not specified
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Not specified

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No

WATER CONSUMPTION AND COMPOUND INTAKE: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Blood was collected on the day following the final exposure from the retro-orbital sinus
- Anaesthetic used for blood collection: Yes (CO2/O2 anesthesia)
- Animals fasted: No
- How many animals: all animals
- Parameters examined: Hemoglobin (Hb), hematocrit (PCV), erythrocyte count, reticulocyte count, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), platelet count, total and differential leukocyte counts, prothrombin time and activated thromboplastin time.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Blood was collected on the day following the final exposure from the retro-orbital sinus
- Anaesthetic used for blood collection: Yes (CO2/O2 anesthesia)
- Animals fasted: No
- How many animals: all animals
- Parameters examined: glucose, total protein, albumin, globulin, urea nitrogen, creatinine, bilirubin (total, conjugated and unconjugated), Na+, K+, chloride, inorganic phosphorus, aspartate and alanine aminotransferases, alkaline phosphatase, lactate and sorbitol dehydrogenases, creatinine kinase and gamma-glutamyl transferase.

URINALYSIS: Yes
- Time schedule for collection of urine: Urine was collected over an 16 h interval following the final exposure
- Metabolism cages used for collection of urine: Yes
- Animals fasted: No
- Parameters examined: appearance, specific gravity, osmolality, protein, glucose, ketones, pH, occult blood, bilirubin, urobilinogen, creatinine and N-acetyl-ß-D-glucosaminidase.

NEUROBEHAVIOURAL EXAMINATION: No

IMMUNOLOGY: No

BRONCHOALVEOLAR LAVAGE FLUID (BALF): No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes. After 9 exposures, all animals were sacrificed, selected organs were weighed and organ/body weight and organ/brain weight ratios calculated. The following organs were weighed: Adrenal glands, brain, kidneys, liver, lungs, ovaries and testes. Complete macroscopic postmortem examinations were conducted on all animals.

HISTOPATHOLOGY: Yes. Histopathological evaluation of selected tissues were conducted on all animals. Histology was conducted on the organs that were weighed and additionally on the heart, larynx, trachea, nasopharyngeal tissues, spleen and urinary bladder.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not examined

Effect levels

Key result

Dose descriptor:

NOAEC

Effect level:

50.5 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no adverse effect observed

Remarks on result:

other: corresponding to 0.217 mg/L air or 217.4 mg/m3 air

Remarks:

(dose levels in mg/m3 air were calculated as follows: [dose level in ppm x molecular weight] / 24.2)

Target system / organ toxicity

Key result

Critical effects observed:

no

Applicant's summary and conclusion

Conclusions:

Based on the results of this study, the NOAEC for systemic toxicity was 50.5 ppm in male and female rats, corresponding to 217.4 mg/m3 air or 0.2174 mg/L air.