Aluminium tributanolate

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Reference Type:

publication

Title:

Toxic Effects of Subchronic Combined Exposure to N-butylalcohol and m-Xylene in rats

Author:

Korsak et al.

Year:

1994

Bibliographic source:

International Journal of Occupational Medicine and Environmental Health, Vol. 7, N o 2, 155—166, 1994

Materials and methods

Test guideline

Qualifier:

no guideline followed

Version / remarks:

3 month toxicity study studying a limited number of endpoints

Principles of method if other than guideline:

In this study only a limited number of endpoints was included (see below)

GLP compliance:

not specified

Test material

Test material information

Constituent 1

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 animals

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Imp: DAK stock
- Age at study initiation:no data
- Weight at study initiation:322-329 g
- Housing: no data
- Diet/water: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C):no data
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE: no data (generated by heating liquid solvents in washers)

CHAMBER DESCRIPTION
- Exposure apparatus: dynamic inhalation chamber (1.3 m 3 volume).
- Method of holding animals in test chamber: no data

TEST ATMOSPHERE
- Brief description of analytical method used: GC with FID with 1.5 m metal column with 10% QV-17 on chromasorb W H P (80—100 mesh) as a stationary phase at column temperature of 100°C.
- Samples taken from breathing zone: no data (samples taken every 30 min)

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

GC with FID with 1.5 m metal column with 10% QV-17 on chromasorb W H P (80—100 mesh) as a stationary phase at column temperature of 100°C.

Duration of treatment / exposure:

3 months

Frequency of treatment:

6 hours/day, 5 days/week for 3 months.

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

154 mg/m³ air

Doses / concentrations 2

Dose / conc.:

308 mg/m³ air

No. of animals per sex per dose:

12/concentration (24 for controls)

Control animals:

yes, sham-exposed

Examinations

Observations and examinations performed and frequency:

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

HAEMATOLOGY: Yes
- Time schedule for collection of blood: before exposure and 1 week before termination
- Anaesthetic used for blood collection: no
- Animals fasted: Not specified
- How many animals: not specified
- Parameters checked: Erythrocyte count,
hemoglobin concentration, hematocrit, leucocyte count and differential leukocyte count

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: 24 h before termination of exposure
- Anaesthetic used for blood collection: yes, ether
- Animals fasted: Yes 24 hours before
- How many animals:no data
- Parameters checked: alanine aminotransferase, aspartate aminotransferase, sorbitol dehydrogenase, alkaline phosphatase, total protein, albumin and glucose, and electrolytes — sodium, potassium, calcium, chloride

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: rotarod performeance once per month; hot plate response (latency of paw-lick response) at study termination
- Dose groups that were examined: all

Sacrifice and pathology:

Organ weights: heart, lungs, liver, spleen, kidneys, adrenals, testes

Liver: microsomal monooxygenases and lipid peroxidation
livers were homogenized to yield a 25% homogenate.
The activity of aniline p-hydroxylase (EC 1.14.1.1) was assayed in 9000 g postmitochondrial supernatants of the liver according to Holtzman and Gillette (6) as adopted by Wiśniewska-Knypl and Jabłońska (21).
In liver microsome Cytochrome P —450 was determined according to Omura and Sato by Carbon monoxidedifference spectra of dithionite-reduced microsomes between 490 and 450 nm using Beckman ACTA CIII spectrophotometr and extinction coeficient of 91 m m ol-1 cm -1 was employed for quantifying cytochrome P —450.
Lipid peroxidation in fresh microsomal membranes was evaluated on the basis of detection of thiobarbituric acidreactive substance according to M ihara et al
An extinction coefficient of 1.56 x 10-5 m m ol-1 according to Wills (20) was used for malondialdehyde formation.
For assay of triglycerides, hepatic lipids were extracted by the method of Folch et al. (4): liver slices were homogenized with 20 volumes of chloroform-methanol (2:1, v/v) at 45°C and the extract washed with 0.1 mol NaCl, evaporated under vacuum and the residues dissolved in chloroform. Triglycerides were determined with a standard enzymatic kit of Boehringer-Mannheim.
“Test Combination-Triglycerides (neutral fat)” taking for analysis a lipid extract equivalent to 10 — 20 mg of fresh liver, and the decrease of NADH was
measured at 340 nm in a Perkin-Elmer Lambda 15 spectrophotometer. Concentration of triglycerides in the liver were adapted for nmol per g tissue using a factor 1.14 (mol wt. of glycerol trioleate = 885.4).

Statistics:

ANOVA, Dunnet's test and Fisher Exact test

Results and discussion

Results of examinations

Clinical signs:

not examined

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, non-treatment-related

Description (incidence and severity):

at both concentration significantly increased after 1 and 2 months (no relationhip with dose). No effect at 3 months

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:

not examined

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

sign decreased Hb at both concentrations (no concentration response relationship)
sign decreased red bloodcells at high concentration (decreased at low concentration) --> related with concentration
sign increase of eosinophils at high concentration (increased at low concentration) --> related with concentration

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not examined

Behaviour (functional findings):

effects observed, treatment-related

Description (incidence and severity):

Dose related significant increase of failures in rotarod test (increasing over time)
Significant decrease of decrease in latency of the paw-lick response at low and high concentration (no concentration related effect)

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

not examined

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Other effects:

effects observed, treatment-related

Description (incidence and severity):

sign dose related increase of lipid peroxidation (15% at low concentration and 30% at high concentration)

Effect levels

Dose descriptor:

LOAEC

Effect level:

154 mg/m³ air

Based on:

test mat.

Sex:

male/female

Basis for effect level:

behaviour (functional findings)

haematology

other: effect on lipid peroxidation

Target system / organ toxicity

Critical effects observed:

yes

Lowest effective dose / conc.:

154 mg/m³ air

System:

other: behavioural effects

Organ:

other: cannot be specified

Treatment related:

yes

Dose response relationship:

yes

Any other information on results incl. tables

The endpoints investigated in this study are too limited to allow a defnitive conclusion on 1 -butanol toxicity after repeated inhalation exposure.

Applicant's summary and conclusion

Conclusions:

Effects of butanol on behaviour and lipid peroxidation in in liver cells became apparent at 154 mg/m3

Executive summary:

Rats were exposed to vapours of n-butanol at concentrations of 50 and 100 ppm 6 h/day, 5 days/week for 3 months (154 and 308 mg/m3). No significant changes in body weight gain, in absolute and relative organ weights and clinical biochemistry parameters were observed. N-butanol caused significant disturbances of motor coordination disturbances at 100 ppm. Significant increase in sensitivity to pain in animals exposed to n-butyl alcohol was observed. N-Butyl alcohol provoked the increase of lipid peroxidation in hepatic microsomes without any induction of cytochrome P450 monooxygenases.