Fusel oil

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Publication of guideline study with basic raw data information.

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1997

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

Deviations:

no

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

2-methylpropan-1-ol

EC Number:

201-148-0

EC Name:

2-methylpropan-1-ol

Cas Number:

78-83-1

Molecular formula:

C4H10O

IUPAC Name:

2-methylpropan-1-ol

Constituent 2

Reference substance name:

2-methyl-1-propanol

IUPAC Name:

2-methyl-1-propanol

Details on test material:

- Name of test material (as cited in study report): MEP
- Physical state: liquid
- Analytical purity: 99.8%

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Dr. Thomae GmbH, Biberach/Riss, Germany
- Age at study initiation: 42 days
- Weight (mean) at study initiation: males = 173 g (164-191 g), females = 150 g (139-162 g)
- Housing: single housing in stainless-steel wire mesh cages (type DK III, Becker&Co, Castrop-Rauxel, Germany)
- Diet: KLIBA 343 rat/mouse/hamster diet (Klingentalmühle AG, Kaiseraugst, Switzerland), ad libitum
- Water: drinking water, ad libitum

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

Administration / exposure

Route of administration:

oral: drinking water

Vehicle:

water

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:
The drinking water solutions were prepared freshly twice a week. To ensure homogeneity of the solutions each mixture was stirred for about 30 min using a magnetic stirrer.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The stability and the homogeneity of the test substances in the drinking water over a period of 6 days were analyzed. To check the correctness of the target concentration, a sample was taken for analysis by capillary gas chromatography at the beginning and at the end of the application period.

Duration of treatment / exposure:

90 days

Frequency of treatment:

continuous via drinking water

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
1000, 4000, 16000 ppm
Basis:
nominal in water

Doses / concentrations 2

Remarks:

Doses / Concentrations:
75, 300, 1251 mg/kg bw (males) and 91, 385, 1657 mg/kg bw (females)
Basis:
actual ingested

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale:
A range finding study with 20000 ppm for 2 weeks and 16000 ppm for the next 2 weeks (3 rats per sex) revealed no remarkable differences with regard to body weight gain or food consumption. Slightly decreased water consumption was observed for the females within the first 2 weeks, being a sign of decreased palatability. The gross pathological examination did not reveal any differences between control animals and treated animals. On this basis 16000 ppm was concluded to be the highest dose in the main study.

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily examination for clinical signs and mortality

BODY WEIGHT: Yes
- Time schedule for examinations: At study begin and weekly afterwards.

FOOD CONSUMPTION AND COMPOUND INTAKE:
Food consumption was determined once a week for a period of 7 days.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: Water consumption was determined once a week for a period of 4 days. The mean daily intake of the test substances (in mg/kg bw) was calculated at the intervals at which water consumption was determined.

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Prior to the beginning of treatment and at the termination of the studies, using an ophthalmoscope.
- Dose groups that were examined: no details given

HAEMATOLOGY: Yes
- Time schedule for collection of blood: on day 87 of the study (before termination of the animals)
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- Parameters checked in table [No. 1] were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: on day 87 of the study (before termination of the animals)
- Animals fasted: No data
- Parameters checked in table [No.2] were examined.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
- Body weights and organ weights were determined (livers, kidneys, adrenal glands, testes).
HISTOPATHOLOGY: Yes
- Organs or tissues required by guidelines as well as all gross lesions were fixed in a 4% formaldehyde solution. Histological examination and assessment of the findings were carried out after histotechnical processing and staining with hematoxylin and eosin.

Statistics:

Mean values and standard deviations were calculated for body weight, food and water consumption, intake of the test substance, haematological and clinical chemistry parameters as well as for absolute and relative organ weights. The organ weights were statistically evaluated using the DUNNETT’s test for comparison of the dose groups with the control groups. The analysis of variance (ANOVA) with subsequent DUNNETT’s test was used to compare the body weights as well as the haematological and clinical biochemistry data of the dose groups with those of the control group.

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):

no effects observed

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY
No clinical signs attributable to the administration of MEP were observed throughout the study period. One animal of the control group was found dead after 42 days of the study.

BODY WEIGHT AND WEIGHT GAIN
The body weight gain of all animals of both sexes was comparable to that of the controls upon treatment with MEP, and fell within the biological range of variation

FOOD CONSUMPTION
Food consumption of the males treated with 1000 ppm MEP increased marginally: this occurred in only some cases during the second half of the study. In isolated cases females treated with MEP at the same level showed slightly increased food consumption throughout the study. Irrespective of these findings, no effects on the food consumption of the males and females treated with 4000 or 16000 ppm MEP were observed. On account of the isolated occurrences and the lack of a corresponding dose-response relationship, the observed slight increases in food consumption were assessed to be incidental in nature.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)
A sporadic increase in water consumption was observed in males and females of all treated groups throughout the course of the study in which MEP was administered to the animals. This phenomenon varied in extent within the groups; it showed no clear concentration-response relationship and was only evident in few animals over the whole study period. In consideration of this, the observed sporadic increases in water consumption were assessed as being not substance-related.

OPHTHALMOSCOPIC EXAMINATION
The ophthalmological examinations of the MEP treated animals revealed no substance-induced impairment of the refracting media.

HAEMATOLOGY and CLINICAL CHEMISTRY
Oral administration of MEP to male and female Wistar rats at concentrations of 1000, 4000 and 16000 ppm in drinking water for 90 days caused no changes related to this substance in either the haematological or the clinical chemistry examinations.

ORGAN WEIGHTS
No differences in organ weights were observed between the treated and control groups.

GROSS PATHOLOGY
The macroscopical examination for gross lesions at necropsy did not reveal any substance-induced changes due to the administration of MEP.

HISTOPATHOLOGY: NON-NEOPLASTIC
Histopathological changes of the testes (tubular degeneration and diffuse hyperplasia of Leydig’s cells), the spleen (minimal increase in extramedullary hematopoiesis) or the kidneys (dilation of the renal pelvis) occurred sporadically in control and/or animals treated with MEP.

Effect levels

1

Key result

Dose descriptor:

NOAEL

Effect level:

1 657 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: Highest dose tested.

2

Key result

Dose descriptor:

NOAEL

Effect level:

1 251 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: Highest dose tested.

Target system / organ toxicity

Critical effects observed:

not specified