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Diss Factsheets

Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1991
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1991
Report date:
1991

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
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
β-methyl-3-(1-methylethyl)benzenepropanal
EC Number:
412-050-4
EC Name:
β-methyl-3-(1-methylethyl)benzenepropanal
Cas Number:
125109-85-5
Molecular formula:
C13H18O
IUPAC Name:
3-[3-(propan-2-yl)phenyl]butanal
Test material form:
liquid
Specific details on test material used for the study:
Batch number 183831
Purity 97.3%

Test animals

Species:
rat
Strain:
other: Fü-Albino
Sex:
male/female
Details on test animals or test system and environmental conditions:
Standard lab conditions

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: Standard Suspending Vehicle (5g sodium-carboxymethylcellulose, 4mL Tween 80, 5mL Benzyl aclohol, 9g NaCl, distilled water up to 1000mL)
Details on oral exposure:
Daily volume of 10ml/kg/d of a dilution of the tiest item in SSV was given to rats by gavage.
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
28 d
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Dose / conc.:
60 mg/kg bw/day (actual dose received)
Dose / conc.:
300 mg/kg bw/day (actual dose received)
Dose / conc.:
1 500 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
6
Control animals:
yes, concurrent vehicle
Details on study design:
According to guideline.
Positive control:
none

Examinations

Observations and examinations performed and frequency:
bodyweight (on D0 and weekly), symptoms (8hrs following administration daily), mortalities (continuously), opthalmoscopy (prior to termination), lab investigation and blood analysis, full necropsy and histological investigations.
Sacrifice and pathology:
At the termination of the study the animals were euthanized by the use of CO2 and rapidly exsanguinated by incision of the neck. Immediately afterwards, all animlas were subjected to a full necropsy and macroscopy.
Statistics:
Data were processed to give group mean values (X) and standard desviations, where applicable. Appropriate statistical analyses (eg Kruskal-Wallis Anova and Mann-Whitney U-tests, Dunn-test, Jonckheere-test) were used to assess the significance of the results, where inspection of the data indicated the possibility of a response to treatment.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
At 1500 mg/kg/d, males showed slight sedation on D2 and D3 10-15 minutes after test item administration, that lasted for up to 1 hour. Females showed slight sedation on D1 starting 45 minutes after test item administration and lasting up to 90 minutes. Sedation effects increased in females following further administration leading in some cases to a need for euthanasia.
At 300mg/kg/d, slight sedation only noticed in one female and one male on D2 and D3.
At 60mg/kg/d, no symptomes detected.
Mortality:
mortality observed, treatment-related
Description (incidence):
At 1500 mg/kg/d, 2 females were euthanized for humane reasons in a deeply comatose and moribund state approximately 6 hours after receiving the 3rd dose.
3 accidental casualties (1 M + 1F in the low-dose group on day 5 and 11, and 1F of mid-dose on day 10) due to aspiration of test article into the lungs followed by alveolar haemorrage and oedema.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
At 1500 mg/kg/d, body weight gain statisitically inferior to control in males.
No statistical difference in males of mid- and low-dose and for females of all doses.
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Description (incidence and severity):
All parameters remained within physiological range for the rat strain used, no biological relevance was detected.
At 1500 mg/kg/d, statistically significant increase in leukocyte count and marginal but statistically significant reduction in fibrinogen was found in males. Relation with treatment is unclear.
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
Measured parameters generally remainde within physiological range known to be valide for Fü-albino rats of similar age and no biologically meaningful alterations were shown.
At 1500 mg/kg/d, statistically significant decrease in total protein was noticed in males but remained within normal range.
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
At 1500 mg/kg/d, increase in relative kidney weight of the male and female high-dose groups.
At 1500 mg/kg/d and 300mg/kg/d, statistically significant increase of the absolute and relative liver weights in males and females.
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Other effects:
not examined

Effect levels

Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
From the results present in this study, the NOAEL for systemic toxicity of the test item is 300mg/kg/d.
Executive summary:

Groups of 6 animals per sex per dose were used. Test material in Standard Suspending Vehicle (SSV) was administered daily by oral gavage to outbred stock.Ibm:RORO(SPF) animals of both sexes for a period of 28 days. Dose volume was 10 ml/kg bodyweight per day. A control group with 6 males and 6 females was also included. The control group received the vehicle SSV. Animals were 6-7 weeks old at the start of the study. Male animals weighed 205 +/- 4.51 grams and females weighed 192 +/- 4.65 grams at the beginning of the study. Animals were housed in in stainless steel wire mesh cages, 2 rats of the same sex and group per cage. Food and water were provided ad libitum. The animal room temperature was 22 +/- 2 C with relative humidity between 55% +/- 10%. A 12 hour fluorescent light/12 hour dark cycle was used. Observations for mortality were continuous. Animals were inspected daily for up to 8 hours following the test material administration for behaviour, appearance, and signs of toxicity. Individual body weights were recorded on day 0, at weekly intervals thereafter and prior to feed withdrawal at termination of the study. Opthalmoscopy was performed prior to termination of the study. At the end of the dosing period, blood samples were withdrawn for hematology and clinical chemistry analyses. In addition, urine was collected for urinalysis. All animals were sacrificed, necropsied and examined post mortem. Organ weights were determined and a series of tissues were removed and prepared for histological evaluation

SSV contained: 5 grams sodium-carboxymethylcellulose, 4 ml Tween 80, 5 ml benzyl alcohol p.a. Merck, 9 grams NaCl p. a. Merck and distilled water ad 1000 ml.

OECD guidelines for testing of chemicals, ed. May 12, 1981; repeated dose oral toxicity - rodent: 28 day study; Part No. 407: pages 1-8.

NOAEL was set at 300mg/kg/d