Titanium(4+) ethanolate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

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

Adequacy of study:

weight of evidence

Study period:

1994

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Acceptable study with sufficient documentation which meets basic scientific principles. 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

Reference Type:

publication

Title:

Biomonitoring, Performance and Well-Being under Exposure to Inhalation of Ethanol.

Author:

Seeber, A., Blaszkewicz, M., Kiesswetter, E., Bandel, T., Golka, K., Heitmann, P., Vangala, R.R., Bolt, H.M.

Year:

1994

Bibliographic source:

Transact German Soc Occup & Environ Med. 34th Ann Meet, Weisbaden, 1994

Materials and methods

Objective of study:

absorption

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

Human volunteer study examining blood ethanol concentrations resulting from differing inhalation exposures to ethanol vapour.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Constituent 2

Reference substance name:

Ethanol

EC Number:

200-578-6

EC Name:

Ethanol

Cas Number:

64-17-5

Molecular formula:

C2H6O

IUPAC Name:

ethanol

Details on test material:

- No further data

Test animals

Species:

human

Strain:

other: Assumed Caucasian

Sex:

male/female

Administration / exposure

Route of administration:

inhalation

Vehicle:

unchanged (no vehicle)

Duration and frequency of treatment / exposure:

4 hour(s)

Doses / concentrations

Remarks:

Doses / Concentrations:
Males: 150 mg/cu m; 750 mg/cu m and 1500 mg/cu m; and exceeding MAK Females: 150 mg/cu m; 750 mg/cu m and 1500 mg/cu m and exceeding MAK

No. of animals per sex per dose / concentration:

Males: 12 Females: 12

Control animals:

no

Statistics:

Statistical tests included analysis of variance, F-test and correlation coefficients.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

See remarks on results below.

Details on distribution in tissues:

not examined

Details on excretion:

not examined

Metabolite characterisation studies

Metabolites identified:

not measured

Any other information on results incl. tables

Blood alcohol levels were between 0.00023 and 0.0021 mg/ml in the first series and 0.00066 and 0.0056 mg/ml in the second (Units of concentration not clear in results). There was a very good correlation between inhalation exposure concentrations and resultant blood ethanol concentrations.

In both experiments there were no significant exposure-related effects in the psychological performance variables in both men and women. In the second experiments where concentrations varied about the MAK there were no significant effects at and below the MAK but at concentrations above the MAK (1000ppm), exposure was 'troublesome' (interpreted as caused discomfort to the volunteers).

The highest dose was below the prevailing MAK value of 1900 mg/cu m (= 1000 ppm) and it is concluded that the maximum blood alcohol level will remain below 0.001% both in men and in women. Regression analysis of the data shows that the blood ethanol concentration (BEC) can e modeled using the following equation: It follows from this result of a linear relationship between BEC and exposure concentration that the kinetics of elimination are first order and that metabolism is not saturated.

[BEC] (ppm) = [Exposure (ppm)] x 0.0029 (with a 7% error for 95 % confidence).

Adverse effects on prolonged exposure: no significant effects.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
In this human volunteer study it was established that exposures of up to 2000 ppm of ethanol for periods of up to 4 hours do not saturate metabolism and that elimination kinetics are first order.

Executive summary:

In a human volunteer study using 24 men and women, it was established that exposures of up to 2000 ppm of ethanol for periods of up to 4 hours do not saturate metabolism and that elimination kinetics are first order. A linear relationship was established between exposure concentration and resultant blood ethanol concentrations, leading to the prediction that the a maximum blood ethanol concentration of 2.9 mg/l results from an (indefinite) exposure to 1000 ppm of ethanol.