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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1985-08-19 to 1985-11-26
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1986
Reference Type:
secondary source
Title:
n-Butanol (CAS No. 71-36-3)
Author:
ECETOC
Year:
2003
Bibliographic source:
ECETOC JACC No. 41, ISSN-0773-6339-41, December 2003
Reference Type:
secondary source
Title:
OECD SIDS n-Butyl Alcohol
Author:
OECD
Year:
2001
Bibliographic source:
OECD SIDS, UNEP Publications

Materials and methods

Principles of method if other than guideline:
Four groups of male and female rats (30/sex/group) were administered daily by gavage 0, 30, 125 or 500 mg/kg bw/d for either 6 or 13 weeks.
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Butan-1-ol
EC Number:
200-751-6
EC Name:
Butan-1-ol
Cas Number:
71-36-3
Molecular formula:
C4H10O
IUPAC Name:
butan-1-ol
Test material form:
liquid
Specific details on test material used for the study:
- lot: 3597

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Portage, Michigan, U.S.A.
- Age at study initiation: 36-37 d
- Mean weight at study initiation: males 90 g, females 86 g
- Housing: individually
- Diet: ad libitum, Purina Certified Rodent Laboratory Chow #5002 (pellet)
- Water: ad libitum, filtered municipal water
- Acclimation period: 7 days before the pretreatment week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 +/- 1
- Humidity (%): 47.6 +/- 9.2
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
Dosing solutions of butanol in deionized water were used.

VEHICLE
- Concentration in vehicle: not specified
- Amount of vehicle: 10 mL/kg bw was the constant dosing volume
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
GC-FI
Duration of treatment / exposure:
6 weeks (42/43 days) for animals used for interim sacrifice or 13 weeks (91/92 days) for complete study
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Dose / conc.:
30 mg/kg bw/day (nominal)
Dose / conc.:
125 mg/kg bw/day (nominal)
Dose / conc.:
500 mg/kg bw/day (nominal)
No. of animals per sex per dose:
30 (further 10 were sacrificed prior to dosing for determination of clinicopathological baseline levels)
Control animals:
yes, concurrent vehicle
Positive control:
no data

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: Body weights were recorded weekly


FOOD CONSUMPTION: Yes
-Time schedule: Food consumption was recorded weekly


OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Ophthalmic examination was conducted prior to treatment and during week 13 before final necropsy.
- Dose groups that were examined: all rats


HAEMATOLOGY: Yes
- Time schedule for collection of blood: before the start of the study (only baseline group animals), during week 6 (only interim sacrifice animals) and during week 13 (final sacrifice animals)
- Anaesthetic used for blood collection: Yes, CO2
- Animals fasted: No data
- How many animals: 10 males and 10 females/ treatment group
- parameters: hemoglobin ( HGB), hematocrit (PCV), erythrocyte count (RBC), mean cell volume (MCV), mean cell hemoglobin (MCH),mean cell hemoglobin concentration (MCHC) total and differential leucocyte counts (WBC), estimated platelet count (PLT)


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: before the start of the study (only baseline group animals), during week 6 (only interim sacrifice animals) and during week 13 (final sacrifice animals)
- Animals fasted: No data
- How many animals: 10 males and 10 females/ treatment group
- parameters: alkaline phosphatase (Alk phos) blood urea nitrogen (BUN), glutamate pyruvate transaminase (SGPT), glutamate oxalacetate transaminase (SGOT), glucose (Gluc), total protein (TP), albumin (Alb), A/G ratio (calculated), globulin (calculated), total bilirubin (Tot. bili.), sodium (Na), potassium (K ), chloride (Cl), calcium (Ca), inorganic phosphate (Phos), carbon dioxide (TCO2), total serum cholesterol (Chol), creatinine.


URINALYSIS: Yes
- Time schedule for collection of urine: before the start of the study, during week 6 and during week 13
- Metabolism cages used for collection of urine: yes, for 4 h
- Animals fasted: No data
- parameters: pH, specfic gravity, glucose, protein, ketones, bilirubin, urobilinogen, microscopy of sediment


NEUROBEHAVIOURAL EXAMINATION: No data
Sacrifice and pathology:
GROSS PATHOLOGY: Yes: Ten male and ten female rats from each group were necropsied on study days 43 to 44 and the remaining animals on study days 92 to 93. Gross pathology of all animals was assessed and organs from animals necropsied on study days 92 to 93 were weighed.
HISTOPATHOLOGY: Yes: A complete histopathological investigation was made of all animals of the control and high-dose groups. In the low and mid-dose groups, histopathology included the liver, kidney, and heart from all animals and all gross lesions. All animals found dead or killed in extremis were also microscopically examined.
Tissues examined in control and high dose groups: Heart and attached aorta, thymus, lungs, trachea, esophagus, stomach, salivary glands (mandibular and sublingual glands), small intestine, jejunum, ileum, colon, liver, pancreas, spleen, lymph nodes (mesenteric), kidneys, urinary bladder, adrenal glands, pituitary gland, eyes with optic nerve, thyroid and parathyroid glands, lumbar spinal cord, brain, bone marrow (femur), testes with epididymides, ovaries, uterus, cervix, skin, mammary gland, skeletal muscle, sciatic nerve, tissue masses and all other gross lesions
Statistics:
Body weight, food consumption, clinicopathologic and organ weight data were tested for homogeneity of variance by Bartlett’s method. If data was homogeneous, differences between control and treatment means were tested for statistical significance by the method of Dunnett. If data was not homogeneous, the method of Gill (modified Dunnett’s) was used.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Ataxia and hypoactivity (lasting less than 1 h) were observed 2 to 3 minutes after dosing in both sexes of the high-dose group (500 mg/kg bw/d) during the final 6 weeks of dosing. Such ataxia and hypoactivity are typically seen following high oral doses of alcohols. The rapid induction/remission of these effects and the reported increased incidence after the interim kill may be due to the fact that personnel were able to collect post-dose observations more quickly since fewer animals required dosing.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
No significant changes between treated groups and controls were observed concerning mortality.
One mid-dose male rat died during week 1.
Three rats were found dead or sacrificed in extremis. These deaths could not be attributed to the test article but were related to treatment accidents.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No test substance related changes between treated groups and controls were observed.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No test substance related changes between treated groups and controls were observed.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
effects observed, non-treatment-related
Description (incidence and severity):
Chorioretinal hypoplasia was seen in 1 control and low-dose rat and in 3 mid and high-dose rats. This observation is commonly seen in rats of the corresponding age and not test substance related. One other unspecified lesion in one low-dose and one mid-dose rat and 2 in high-dose rats was observed. Those lesions were also considered non treatment related.
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
At the interim clinical pathological evaluation, red blood cell count (RBC) packed cell volume (PCV), and hemoglobin (HGB) averages of the 500 mg/kg/day dose group females were 5 % below control averages. Although these differences were statistically significant, they were small and no differences between the parameters were observed in the males of the interim evaluation or between control and treated groups of either sex at the final evaluation. Therefore, even if the lower red blood cell parameters in the 500 mg/kg/day females were an actual treatment-related effect, it was small and transitory and thus not considered as adverse.
In addition a higher (p ≤ 0.05) absolute neutrophil count in middle-dose males at interim evaluation, higher (p ≤ 0.05) relative lymphocyte count in low-dose females at final evaluation and a higher urine pH (p ≤ 0.05) in low-dose males (interim) and females (final) were detected. All those effects were statistically significant but small, occurred in one sex and at one time point only without a dose response relationship. Therefore those effects were not considered treatment related.
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
A lower (p ≤ 0.05) cholesterol average in the high-dose males at interim evaluation was detected. The effect was only observed in one sex at one time point, therefore it was considered not treatment related.
Urinalysis findings:
no effects observed
Description (incidence and severity):
No significant changes between treated groups and controls were observed.
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):
Only in thyroid weight of high-dose males a slight increase was detected. No dose response relationship was observed and the difference was considered to be a chance occurrence and not treatment related.
Gross pathological findings:
no effects observed
Description (incidence and severity):
No treatment related lesions were detected. All observed lesions were either in the normal range for the test animal species and age with no differences between control and treated animals or were caused by accidents during treatment.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
No treatment related lesions were detected. All observed lesions were in the normal range for the test animal species and age with no differences between control and treated animals.
Histopathological findings: neoplastic:
not examined
Other effects:
not examined

Effect levels

open allclose all
Key result
Dose descriptor:
NOEL
Effect level:
125 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effects observed
Key result
Dose descriptor:
LOEL
Effect level:
500 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: transient clinical signs of CNS depression (ataxia and hypoactivity)

Target system / organ toxicity

Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
500 mg/kg bw/day (nominal)
System:
central nervous system
Organ:
other: Not centered on a specific organ but general effects on neurological and behavioral functions as typically observed for alcohols (drowsiness and dizziness).
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
yes

Applicant's summary and conclusion