3-(m-tert-butylphenyl)-2-methylpropionaldehyde

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP, guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2009

Report date:

2009

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

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

GLP compliance:

yes (incl. QA statement)

Remarks:

BASF Aktiengesellschaft, Experimentelle Toxikologie und Ökologie

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

3-(m-tert-butylphenyl)-2-methylpropionaldehyde

EC Number:

263-580-6

EC Name:

3-(m-tert-butylphenyl)-2-methylpropionaldehyde

Cas Number:

62518-65-4

Molecular formula:

C14H20O

IUPAC Name:

3-(3-tert-butylphenyl)-2-methylpropanal

Details on test material:

- Name of test material (as cited in study report): m-Lysmeral
- Physical state: liquid/colorless, clear
- Analytical purity: > 98.4 %
- Lot/batch No.: 9336/08 S.50
- Storage condition of test material: Ambient (room temperature); under Argon

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Sulzfeld, Germany
- Age at study initiation: 33 +/-1 day
- Housing: 5 animals per cage
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 9 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30 – 70
- Photoperiod (hrs dark / hrs light):12/12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

olive oil

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The stability of the test substance in Olive Oil Ph. Eur at room temperature for a period of 7
days was proven with a comparable batch before the start of the administration period.
Homogeneity and concentration control analyses of the test-substance preparations were
performed in samples of all concentrations at the start of the administration period.

Duration of treatment / exposure:

4 weeks

Frequency of treatment:

daily

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 50, 150, 450
Basis:

No. of animals per sex per dose:

5

Control animals:

yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily before and after the administration

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: prior to the administration period and thereafter at weekly intervals.

BODY WEIGHT: Yes
- Time schedule for examinations: During the administration period on day 0 (start of the administration period) and thereafter at weekly intervals.

FOOD CONSUMPTION:
- Food consumption for each animal determined : Yes, weekly over a period of 1 day and calculated as mean food consumption grams per animal and day.

FOOD EFFICIENCY:
Food efficiency (group means) was calculated based upon individual values for body weight and food consumption.

WATER CONSUMPTION : Yes
- Time schedule for examinations: weekly over a period of 4 days and calculated as mean water consumption in grams per animal and day.

HAEMATOLOGY: Yes
- Time schedule for collection of blood: study day 29
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes
- How many animals: all animals
- Parameters checked: Leukocyte/Erythrocyte/Platelet/Differential blood count, Hemoglobin, Hematocrit, Mean corpuscular volume, Mean corpuscular hemoglobin/concentration, Reticulocytes, Prothrombin time

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: study day 29
- Animals fasted: Yes
- How many animals: all animals
- Parameters checked: Alanine aminotransferase, Aspartate aminotransferase, Alkaline phosphatase, gamma-Glutamyltransferase, Sodium, Potassium, Chloride, Inorganic phosphate, Calcium, Urea, Creatinine, Glucose, Total bilirubin, Total protein, Albumin, Globulins, Triglycerides, Cholesterol, Magnesium, Bile acids

URINALYSIS: Yes
- Time schedule for collection of urine: study day 27
- Metabolism cages used for collection of urine: Yes / No / No data
- Animals fasted: Yes
- Parameters checked: pH, Protein, Glucose, Ketones, Urobilinogen, Blirubin, Blood, Spec. Gravity, Sediment, Color, Turbidity, Volume

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: at the end of the administration period
- Dose groups that were examined: all animals
- Battery of functions tested: Home cage observations, Open field observations, Sensorimotor Tests/Reflexes, Motor activity assessment

OTHER:
Estrous stages: Vaginal smears for cycle determination were prepared in the morning of study termination and evaluated.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
ORGAN WEIGHTS: Yes
Liver; Kidneys; Adrenal glands; Testes; Epididymides; Cauda epididymides; Ovaries; Uterus; Spleen; Brain; Heart; Thymus; Thyroid glands (with parathyroid glands); Seminal vesicles including coagulation glands; Prostate
HISTOPATHOLOGY: Yes
All gross lesions; Liver, Spleen, Kidneys, Testes, Epididymides, Prostate, Seminal vesicle

Statistics:

Clinical pathology parameters, urine volume, urine specific gravity, organ weights: KRUSKAL-WALLIS test (two-sided); WILCOXON test as post test

Urinalysis, except color, turbidity, volume and specific gravity: FISHER's exact test

Body weight, body weight change: DUNNETT's test (two-sided)

FOB (Feces, rearing, grip strength length forelimbs, grip strength length hindlimbs, footsplay test), motor activity : KRUSKAL-WALLIS test (two-sided); WILCOXON test as post test

Results and discussion

Results of examinations

Details on results:

CLINICAL SIGNS AND MORTALITY
No animal died prematurely within the study.
Salivation (slight and moderate) before and after treatment :
450 mg/kg bw/d: 5/5 males, 5/5 females
150 mg/kg bw/d: 3/5 males, 5/5 females
Caused by a conditioning effect due to the daily gavage, assessed as not adverse. No other test substance related effects observed.

BODY WEIGHT AND WEIGHT GAIN
450 mg/kg bw/d: Statistically non-significant reduction in body weights/gain in males (96%/88% vs ctrl.) and females (96%/83 vs ctrl.).
No other substance-related effects observed

FOOD CONSUMPTION
No substance-related effects observed

FOOD EFFICIENCY
No substance-related effects observed

WATER CONSUMPTION
No substance-related effects observed

HAEMATOLOGY
No substance-related effects observed

CLINICAL CHEMISTRY
450 mg/kg bw/d - Males: decrease in Calcium, Total protein, Globulin, Total bilirubin, cholesterol; increase in Urea
450 mg/kg bw/d - Females:increase in trigycerides (within historical control range, regarded as non-adverse)
150 mg/kg bw/d - Males: decrease in Calcium, Total protein, Globulin, Total bilirubin; increase in Urea
50 mg/kg bw/d - Males: decrease in Total protein, Globulin (within historical control range, regarded as non-adverse)
No other substance-related effects observed

URINALYSIS
450 mg/kg bw/d - Males: higher incidences of crystals
450 mg/kg bw/d - Females: higher incidences of crystals, increase in protein
150 mg/kg bw/d - Males: higher incidences of crystals
150 mg/kg bw/d - Females: higher incidences of crystals

NEUROBEHAVIOUR
Functional observational battery (FOB): No substance-related effects observed
Motor activity measurement:
450 mg/kg bw/d: significantly decreased in males, caused by reduced motor activity within the first 30 minutes of measurement, which is the so called habituation phase.

ORGAN WEIGHTS (vs ctrl)
450 mg/kg bw/d:
Increase in liver weights: absolute male/ female (167%/143%), relative male/female (177%/153%);
Decrease in thymus weights: absolute male (80%)
150 mg/kg bw/d:
Increase in liver weights: absolute male/ female (141%/125%), relative male/female (138%/125%)
50 mg/kg bw/d:
Increase in liver weights: absolute male (113%); relative male (112%)
No other substance-related effects observed.

GROSS PATHOLOGY
450 mg/kg bw/d: enlarged livers (5/5 males; 5/5 females)
150 mg/kg bw/d: enlarged livers (2/5 females)
No other substance-related effects observed.

HISTOPATHOLOGY:
450 mg/kg bw/d: Liver (centrilobular hypertrophy of hepatocytes) in 5/5 males and 5/5 females
150 mg/kg bw/d: Liver (centrilobular hypertrophy of hepatocytes) in 2/5 females
No other substance-related effects observed.

OTHER FINDINGS:
Estrous stages: No substance-related effects observed

Effect levels

Dose descriptor:

NOAEL

Effect level:

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

Sex:

male/female

Basis for effect level:

other: body weights, clincal chemistry/urinalysis

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

There was one male animal in the 450 and 150 mg/kg bw/day group each that exhibited a diffuse degeneration of seminiferous tubules in the testes and an oligospermia in the epididymides. These single cases are interpreted as spontaneous and incidental lesions,

which were not related to treatment. All other organs, including those of the male reproductive system, showed no lesions that could be related to treatment.