Titanium tetrabutanolate

Basic toxicokinetics

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Administrative data

Endpoint:

basic toxicokinetics

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The study investigated the toxicokinetics of n-butanol measured according to standard protocol but guideline followed was not mention.

Cross-reference

Reference

Endpoint:

basic toxicokinetics

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The study investigated the toxicokinetics of n-butanol measured according to standard protocol but guideline followed was not mention.

Objective of study:

absorption

distribution

excretion

toxicokinetics

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

Radiolabelling:

yes

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- 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

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

Route of administration:

oral: gavage

Vehicle:

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

Remarks:

Doses / Concentrations:
4.5, 45, 450 mg/kg of body weight

Control animals:

yes

Positive control reference chemical:

none

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

METABOLITE CHARACTERISATION STUDIES
- 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)

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.

Metabolites identified:

yes

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.

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

Conclusions:

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.

Data source

Reference

Reference Type:

publication

Title:

Fate of n-Butanol in Rats after Oral Administration and Its Uptake by Dogs after Inhalation or Skin Application

Author:

DiVincenzo, G.D. and Hamilton, M.L.

Year:

1979

Bibliographic source:

Toxicology and Applied Pharmacology 48, 317-325

Materials and methods

Objective of study:

absorption

distribution

excretion

toxicokinetics

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

Test material

Test material information

Constituent 1

Constituent 2

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:

1-Butanol

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

Radiolabelling:

yes

Test animals

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- 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

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

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

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

Remarks:

Doses / Concentrations:
4.5, 45, 450 mg/kg of body weight

Control animals:

yes

Positive control reference chemical:

none

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

METABOLITE CHARACTERISATION STUDIES
- 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:

yes

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

Conclusions:

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.