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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
reproductive toxicity, other
Remarks:
subchronic repeated dose toxicity study
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1990
Report Date:
1990
Reference Type:
study report
Title:
Unnamed
Year:
1991
Report Date:
1991
Reference Type:
publication
Title:
Subchronic toxicity studies of 3-Methyl-1-butanol and 2-Methyl-1 -propanol in rats
Author:
Schilling K et al.
Year:
1997
Bibliographic source:
Human & Experimental Toxicology ( 1997) 16, 722-726

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: OECD TG 408
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): 3-methyl-1-butanol
- Test substance No. 88/56
- Lab. J. No.: H 21670
- Physical state: liquid/colourless
- Analytical purity: >98%
- Stability under test conditions: The stability was ensured for the study period under the specified storage conditions by reanalysis ( see report of Nov 25 1988)
- Storage condition of test material: at room temperature

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Dr. K. Thomae GmbH, D-7950 Biberach/Riss, FRG
- Age at study initiation: 42 d
- Identification: ear tattoo
- Weight at study initiation: mean 173 g (males), 150 g (females)
- Housing: singly in wire cages (type D III of Becker & Co, Castrop-Rauxel, FRG; floor area about 900 cm2))
- Diet (e.g. ad libitum): KLIBA maintenance diet rat/mouse/ hamster, 343 meal, Klingentalmuehle AG, CH-4303 Kaiseraugst, Switzerland; during the exposure-free observation period
- Water (e.g. ad libitum): tap water
- Acclimation period: at least 7 days

ENVIRONMENTAL CONDITIONS in fully air-conditioned rooms
- 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 exposure:
DRINKING WATER PREPARATION
- Rate of preparation (frequency): the drinking water solutions were prepared twice a week
- Mixing appropriate amounts with: the test substance was weighed for each particular test group and the specific quantity of drinking water (also weighed) added. To obtain a homogeneous solution of the test substance in the drinking water the mixture was then stirred for about 30 minutes using a magnetic stirrer.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Capillary gas chromatography using the area percentage method (under consideration of the water content).
Duration of treatment / exposure:
3 months
Frequency of treatment:
continuous exposure via drinking water
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
80, 340, 1250 mg/kg bw
Basis:
nominal in water
Remarks:
Doses / Concentrations:
appr. 73, 295 and 1068 mg/kg bw
Basis:
other: calculated, actually ingested in male animals
Remarks:
Doses / Concentrations:
appr. 90, 385 and 1431 mg/kg bw
Basis:
other: calculated, actually ingested in female animals
No. of animals per sex per dose:
10
Control animals:
yes, concurrent no treatment

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: a check was made twice (mondays to fridays) and once a day (saturdays, sundays and puplic holidays) for general observations. Furthermore, the animals were subjected once a week to an additional exact clinical examination.

BODY WEIGHT: Yes
- Time schedule for examinations: the body weights of the animals were determined once a week during the study and in each case on the same day of week (Tuesday). The animals were additionally weighed prior to the start of the study for randomization.

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: Yes

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: once a week during the administration period for a period of 4 days (Friday - Tuesday).
The mean daily intake of test substance (in mg) per kg body weight was calculated at the intervals at which water consumption was determined according to the following formula: (WTR CONS * D) / body weight on day x
WTR CONS = mean daily water consumption (in g) within 4 days of the study (from day x-4 to day x); D = dose in ppm
The values listed in the tables are group means, determined from the intake of test substance by the individual animals.

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: before the start of the study and toward the end of the study
- Dose groups that were examined: the eyes of the animals in the test group 0 (control) and in the test group 3 (16000 ppm) were examined for any changes to the refracting media using a HEINE FOCALUX hand-held slit lamp.

HAEMATOLOGY: Yes
- Time schedule for collection of blood: after 87 days
- Animals fasted: No
- Parameters examined: leukocytes, erythrocytes, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelets. The differential blood count and the reticulocytes were counted visually. The data were transferred into the computer. Clotting analyses were carried out by determining the thromboplastin time.

CLINICAL CHEMISTRY: Yes
- Parameters examined: enzymes (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, serum-γ-glutamyltransferase); blood chemistry (sodium, potassium, chloride, inorganic phosphate, calcium, urea, creatinine, glucose, total bilirubin, total protein, albumin, globulins, triglycerides, cholesterol)

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Oestrous cyclicity (parental animals):
no data
Sperm parameters (parental animals):
no data
Postmortem examinations (parental animals):
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

The exsanguinated animals were necropsied and assessed by gross pathology. The anesthezited animals, liver, kidneys, adrenal glands and testes were weighed.
Subsequently, the following organs and tissues were fixed in 4% formaldehyde solution:
brain, thyroid/parathyroid glands, trachea, heart, salivary glands (gl. mandibularis, gl. sublingualis), spleen, adrenal glands, testes / ovaries, prostate and seminal vesicle, esophagus, duodenum, jejunum, ileum, urinary bladder, female mammary gland, sciatic nerve, eyes, spinal cord (cervical, thoracic, lumbar), pituitary gland, thymus, lungs, aorta, liver, kidneys, pancreas, uterus, skin, stomach, cecum, colon, rectum, mesenteric lymph node, skeletal muscle, femur (with joint and marrow), sternum with marrow, extraorbital lacrimal glands, all gross lesions.

Fixation was followed by histotechnical processing carried out by EPS-UK (Hereford, England) and examination by light microscopy and assessment of findings. In the control and high dose groups all organs and tissues were examined; at the low and medium dose level only lungs, liver, kidneys and all gross lesions were assessed.
Statistics:
The statistical evaluation of the data was carried out on the computer systems of the testing laboratory. Means and standard deviation were calculated for the variables feed consumption, drinking water consumption, body weight and test substance intake for the animals in each test group. The statistical significance of the clinical data (body weight) was determined using an analysis of variance (ANOVA) with subsequent DUNNETT's test.

Results and discussion

Results: P0 (first parental generation)

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
1 250 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No effects on reproductive organs.

Results: F1 generation

Effect levels (F1)

Remarks on result:
not measured/tested

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

Regarding toxicity to reproductive organs, no abnormalities were found by histological analysis.

Thus, the highest dose level tested can be considered as the NOAEL under the conditions of the study.

Applicant's summary and conclusion