Registration Dossier

Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Guideline Study (EPA OTS 798.2650), but as read-across from supporting substance maximum reliability is 2 Read-across hypothesis: for details please see read-across report in section 13

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

Test guideline
Qualifier:
according to guideline
Guideline:
EPA OTS 798.2650 (90-Day Oral Toxicity in Rodents)
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/kgbw/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
Details on test material:
- Name of test material (as cited in study report): normal butanol
- Lot/batch No.: #3597 KVVE

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 (e.g. ad libitum): Purina Certiofied Rodent Laboratory Chow #5002 (pellet)
- Water (e.g. ad libitum): filtered municipal water
- Acclimation period: 7 days before the pretreatment week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 +/- 1
- Humidity (%): 48 +/- 9
- 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 (if gavage): 10 ml/kg 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 (interim sacrifice) or 13 weeks
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 30, 125, 500 mg/kg bw
Basis:
actual ingested
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: no data


HAEMATOLOGY: Yes
- Time schedule for collection of blood: before the start of the study, during week 6 and during week 13
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: 10 males and 10 females
- 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, during week 6 and during week 13
- Animals fasted: No data
- How many animals: 10 males and 10 females
- 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: No data
- 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.
Statistics:
Bartlett's test for homogeneity (body weight, food consumption, clinicopathologic and organ weight); Dunnett's test for homogeneous and Gill's test for non homogeneous data to test for statistical significance

Results and discussion

Results of examinations

Details on results:
CLINICAL SIGNS AND MORTALITY
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.
No significant changes between treated groups and controls were observed concerning mortality (three rats were found dead or sacrificed in extremis, but these deaths could not be attributed to the test article.).

BODY WEIGHT AND WEIGHT GAIN
no significant changes between treated groups and controls were observed

FOOD CONSUMPTION
no significant changes between treated groups and controls were observed

OPHTHALMOSCOPIC EXAMINATION
no significant changes between treated groups and controls were observed

HAEMATOLOGY
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.

CLINICAL CHEMISTRY
no significant changes between treated groups and controls were observed

URINALYSIS
no significant changes between treated groups and controls were observed

ORGAN WEIGHTS
no significant changes between treated groups and controls were observed

GROSS PATHOLOGY
no significant changes between treated groups and controls were observed

HISTOPATHOLOGY: NON-NEOPLASTIC
no significant changes between treated groups and controls were observed

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
125 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: no effects observed
Dose descriptor:
LOAEL
Effect level:
500 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: clinical signs of CNS depression (ataxia and hypoactivity)

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Oral application of n-butanol to rats (0, 30, 125, 500 mg/kg bw/d) in a 90-day toxicity study caused CNS effects in the highest dose group (ataxia and hypoactivity). The NOAEL in this study is 125 mg/kg bw/d.