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Basic toxicokinetics

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basic toxicokinetics
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
The study investigated the toxicokinetics of n-butanol measured according to standard protocol but guideline followed was not mention. Read-across justification: The substance is hydrolytically unstable. When it comes in contact with water or moisture complete hydrolysis will take place with no significant reaction products other than alcohol and hydrated titanium dioxide. This rapid hydrolysis (hydrolysis half-life < 3 minutes to < 2 hours) is the driving force for the toxicokinetics of target substance. Because of the rapid hydrolysis, the influence of the mode of administration through inhalation, dermal and oral is related to the hazardous degradation product (alcohol) released from the target substance. The identification of degradation products from the hydrolysis study conducted for the target substance verifies that there are no impurities in the alcohol released from the target substance, which might change the hazardous properties of the target substance compared to the properties of the pure alcohol. As there is a mechanistic reasoning to the read-across, the unnecessary animal testing is avoided by using the read-across data from the degradation product (relevant alcohol) to evaluate irritation, sensitization and the short term and long-term toxicological effects and mutagenicity of the target substance.

Data source

Reference Type:
Fate of n-Butanol in Rats after Oral Administration and Its Uptake by Dogs after Inhalation or Skin Application
DiVincenzo, G.D. and Hamilton, M.L.
Bibliographic source:
Toxicology and Applied Pharmacology 48, 317-325

Materials and methods

Objective of study:
Test guideline
equivalent or similar to
OECD Guideline 417 (Toxicokinetics)

Test material

Details on test material:
- Name of test material (as cited in study report): n-butanol
- Physical state: liquid
- Radiochemical purity (if radiolabelling): >97%
- Specific activity (if radiolabelling): 1.71 mCi/mmol
- Stability under test conditions: stable
- Storage condition of test material: stable
- Locations of the label (if radiolabelling): n-(1-14C) Butanol

Test animals

Crj: CD(SD)
Details on test animals and environmental conditions:
- Source: Charles RIver Laboratories
- Weight at study initiation: 200-250 g
- Fasting period before study: 16 hours
- Housing: Glass Delmar Roth metabolism chambers
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum

- Temperature (°C): 22 deggres
- Photoperiod (hrs dark / hrs light): 12 hours light and 12 hours night

Administration / exposure

Route of administration:
oral: gavage
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Radiolablelled n-(1-14C) Butanol was mixed with corn oil
Duration and frequency of treatment / exposure:
single dose administration
Doses / concentrations
Doses / Concentrations:
4.5, 45, 450 mg/kg of body weight
Control animals:
Positive control:
Details on study design:
- Dose selection rationale: Not reported
- Rationale for animal assignment (if not random): not reported
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled (delete / add / specify): urine, serum or other tissues, cage washes, expired CO2
- Time and frequency of sampling: 4, 8, 24 hpurs

- Tissues and body fluids sampled : urine, faeces, tissues, cage washes, bile
- Time and frequency of sampling: 4, 8, 24 hours
- Method type(s) for identification (e.g. GC-FID, GC-MS, Liquid scintillation counting, NMR, TLC)

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Concentration of n-butanol in the plasma of rats dosed with 450 mg/kg. Each point is the mean + SE for three rats. The highest concentration of n-butanol was 70.9 pg/ml at I hr. n-Butanol disappeared from the plasma rapidly and at 4 hr was below the limit of detection.
Details on distribution in tissues:
The tissue distribution of radioactivity in rats dosed with 450 mg/kg n-[1J4C]butanol is presented in Table 2. Values are expressed as the percentage of the dose for four rats. The highest concentrations of radioactivity were found in the liver (3.88%) and blood (0.74%) at 8 hr. The overall distribution of radioactivity in other tissues was relatively low. Pooled 24-hr urine collections from rats Dosed with 450 mg/kg were treated with 3 N hydrochloric acid or fi-glucuronidase and then extracted with diethyl ether. The extract was counted and analyzed by gas chromatography. About 75 % of the radioactivity was detected as n-butanol, presumably both as an O-sulfate (44.4%) and as an O-glucuronide (30.7 o/0). Urea accounted for the remainder of the radioactivity.
Details on excretion:
Percentage of the total radioactivity recovered in the breath, urine, feces, and carcasses of rats dosed with it- [ 1 J4C]butanol. Radioactivity was eliminated rapidly in expired air as 14C0,. In rats dosed with 450 mg/kg over 44% of the administered dose was eliminated within 4 hr; 69.3 and 83.3 % were eliminated at 8 and 24 hr, respectively. Urinary radioactivity accounted for 4.4% of the dose at 24 hr. Fecal radioactivity was negligible at 4 and 8 hr and was less than 1.0% of the dose at 24 hr. The radioactivity remaining in the carcass was 42.2 % at 4 hr, 27.2 % at 8 hr, and 12.3 % at 24 hr. The overall recovery of 14C was 86.7 “/:, at 4 hr, 99.6% at 8 hr, and 101 % at24 hr. Unchanged n-butanol in expired air accounted for less than 1.0 % of the dose. Rats dosed with 4.5 or 45 mg/kg showed a
similar excretion pattern to that of rats dosed with 450 mg/kg.

Metabolite characterisation studies

Metabolites identified:
Details on metabolites:
Butanol was excreted in the urine apparently as an o-sulfate and as an o-glucuronid both of which accounted for 75% of the radioactivity.

Any other information on results incl. tables

Read-across justifications and data matrices are presented in IUCLID section 13.

Applicant's summary and conclusion

Interpretation of results (migrated information): no bioaccumulation potential based on study results
According to this study oral administration of radiolabelled butanol dosed at 4.5, 45, 450 mg/kg. Less than 1% of the administered dose was excreated unchanged and 2.6 to 5.2 % of the dose was excreated in urine.