3-(methylthio)propionaldehyde

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1979-05-08 to 1979-06-05

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1979

Report date:

1979

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Version / remarks:

adopted 03 Oct 2008

Deviations:

yes

Remarks:

no recovery group included, no detailed clinical observations, no FOB, clinical chemistry and haematology were limited to a few parameters, organ weight analysis and histopathology were limited to a few organs

GLP compliance:

no

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:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Central Institute for Breeding of Laboratory Animals, Zeist, The Netherlands
- Age at study initiation: Weanings were used
- Weight at study initiation: 75 ± 1.3 g (males) and 65.6 ± 1.2 g (females)
- Housing: 5/sex in suspended stainless steel cages fitted with wire mesh floors and fronts
- Diet: powdered stock diet, ad libitum
- Water: ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 ± 1
- Humidity (%): 40 - 70
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 0.4, 2 and 10%
- Amount of vehicle: 5 mL/kg bw

Duration of treatment / exposure:

4 weeks

Frequency of treatment:

daily, 6 days/week

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0.02 other: mL/kg bw/day

Remarks:

corresponding to 20.72 mg/kg bw/day, dosel levels in mg/kg bw calculated with a density of 1036 mg/mL

Doses / concentrations 2

Dose / conc.:

0.1 other: mL/kg bw/day

Remarks:

corresponding to 103.6 mg/kg bw/day, dosel levels in mg/kg bw calculated with a density of 1036 mg/mL

Doses / concentrations 3

Dose / conc.:

0.5 other: mL/kg bw/day

Remarks:

corresponding to 518 mg/kg bw/day, dosel levels in mg/kg bw calculated with a density of 1036 mg/mL

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Details on study design:

Post-exposure period: none

Positive control:

no

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION AND FOOD EFFICIENCY: Yes
- Food consumption was measured weekly and the efficiency of food utilisation was calculated and expressed as grams weight gain per gram food consumed.

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Samples of blood were collected on study Day 22 by orbital puncture
- Anaesthetic used for blood collection: Not specified
- Animals fasted: Not specified
- How many animals: 5 rats per sex per group
- Parameters checked: haemoglobin concetration (Hb), packed cell volume (PCV), red blood cell count (RBC), white blood cell count (WBC), differential white blood cell count (eosinophils, basophils, neutrophils, lymphocytes and monocytes) and prothrombin time (PT).

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At autopsy on Day 28 blood samples were collected in heparinised tubes from the aorta of all rats.
- Anaesthetic used for blood collection: yes (ether)
- Animals fasted: Not specified
- How many animals: all rats
- Parameters checked: glutamic-oxalacetic transaminase (GOT), glutamic-pyruvic transaminase (GPT), alkaline phosphatase (ALP), total protein (TP), total bilirubin (BILIRU) and creatinine.

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

IMMUNOLOGY: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes. On completion of 28 days of treatment, all rats were anaesthetized by ether, exsanguinated by cannulating the aorta and examined grossly for pathological changes.
- The following organ weights were determined for all animals: kidneys, liver, spleen, lungs, heart and testes.

HISTOPATHOLOGY: Yes. Samples of the organs mentioned above from the control and high dose group were fixed in 4% aqueous phosphate buffered formaldehyde solution. The samples were processed, embedded in Paraplast and processed for haematoxyline eosin staining. Additionally, the spleens of the rats from the mid and low dose groups were microscopically analysed.

Statistics:

Body weight and organ weight data were analysed statistically by the student's t-test. Haematological findings and blood biochemical values were evaluated by the Wilcoxon test.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Description (incidence and severity):

No substance related clinical signs were observed in any dose group.

Mortality:

no mortality observed

Description (incidence):

No deaths were observed in any of the groups.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

0.5 mL/kg bw/day corresponding to 518 mg/kg bw/day: Slightly, but significantly decreased body weight gain in the high dose group males (7.6%); and small, statistically not significant decrease in body weight gain in females (2.9%) at the end of the exposure period. Body weight gains in the high dose animals were also reduced compared to controls (9.7 and 6.1%), but not analysed statistically. The findings were consistent with reduced food efficiency in these animals and considered to be treatment-related.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

Food intake was comparable in all groups.

Food efficiency:

effects observed, treatment-related

Description (incidence and severity):

0.5 mL/kg bw/day corresponding to 518 mg/kg bw/day: decreased in both sexes (statistically not significant, males: 0.34, contr. 0.37, females, 0.26, contr. 0.27), consistent with depressed body weight, treatment-related

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

0.5 mL/kg bw/day corresponding to 518 mg/kg bw/day: Reduced red blood cell count (statistically significant in females only) and reduced haemoglobin levels (statistically not significant) were observed in animals of both sexes (RBC count males: 5.7,contr. 6.1, females: 5.7, contr. 6.5; Hb: males: 8.4 mmol/l, contr. 8.9 mmol/l, females: 8.7 mmol/l, contr. 9.6 mmol/l). The findings were accompained by an increase in haematopoesis in the spleen and increased clinical chemistry parameters. The observations suggest that destruction of the red blood cells takes place and were considered to be treatment-related. Further, a statistically significant increase in white blood cell count was noted in males(16 x 10E9/L, contr. 11.8 x 10E9/L), the toxicological significance was unclear.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

0.1 mL/kg bw/day corresponding to 103.6 mg/kg bw/day: A slight increase (statistically not significant, 68.3 µmol/l compared to 63.3 µmol/l in control) was noted in creatinine levels of males. Without a clear dose-response and in the absence of findings in females the toxicological significance remained unclear.
0.5 mL/kg bw/day corresponding to 518 mg/kg bw/day: Total bilirubin levels were increased in animals of both sexes (males. 3.0 µmol/l, contr.1.9 µmol/l; females 2.8 µmol/l, contr. 2.0 µmol/l). The findings were consistent with haematological and histopathological findings in the spleen and considered to be treatment-related. In addition, a slight increase (statistically not significant, 69.1 µmol/l compared to 63.3 µmol/l in control)) was noted in creatinine levels of males. Without a clear dose-response and in the absence of findings in females the observation was considered not toxicologically relevant.

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, non-treatment-related

Description (incidence and severity):

0.5 mL/kg bw/day corresponding to 518 mg/kg bw/day: The absolute weight of lungs was slightly decreased in females (statistically not significant, 0.824 g, contr. 0.904 g). Without any histopathological abnormalities the observation was considered to be incidental.

Gross pathological findings:

no effects observed

Description (incidence and severity):

No treatment related changes were observed.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

0.5 mL/kg bw/day corresponding to 518 mg/kg bw/day: Extramedullary haematopoesis and an increased amount of blood and brown pigment in the red pulp was found in the spleen of males and females. The observations were consistent with haematological and clinical chemistry findings and attributed to treatment.

Histopathological findings: neoplastic:

not examined

Effect levels

1

Key result

Dose descriptor:

NOAEL

Remarks:

systemic

Effect level:

103.6 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no adverse effects observed

2

Key result

Dose descriptor:

LOAEL

Remarks:

systemic

Effect level:

518 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical biochemistry

haematology

histopathology: non-neoplastic

Remarks on result:

other: dosel levels in mg/kg bw calculated with a density of 1036 mg/mL

Target system / organ toxicity

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

518 mg/kg bw/day (actual dose received)

System:

haematopoietic

Organ:

spleen

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

yes

Applicant's summary and conclusion

Conclusions:

Based on the results of this study, the LOAEL for systemic toxicity was 0.5 mL/kg bw corresponding to 518 mg/kg bw/day in male and female rats. The NOAEL for systemic toxicity was 0.1 mL/kg bw/day, corresponding to 103.6 mg/kg bw/day in male and female rats.