Titanium tetrakis(2-ethylhexanolate)

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

migrated 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: see 'Remark'

Remarks:

Meets generally accepted scientific standards and is described in sufficient detail. 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:

Unnamed

Year:

1990

Report date:

1990

Materials and methods

Objective of study:

metabolism

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

Examination of the mitochondrial and peroxisomal fatty acid metabolism in the isolated perfused rat liver and in-vivo

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

2-ethylhexan-1-ol

EC Number:

203-234-3

EC Name:

2-ethylhexan-1-ol

Cas Number:

104-76-7

Molecular formula:

C8H18O

IUPAC Name:

2-ethylhexan-1-ol

Details on test material:

-Source: Sigma Chemical Co., St. Louis, MO

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Administration / exposure

Route of administration:

other: in-vitro: isolated perfused rat liver; in-vivo: i.p. injection

Results and discussion

Any other information on results incl. tables

(1) From experiments with perfused livers from starved rats it is concluded 
that 
(a) 2-ethylhexanol is oxidized via two independent pathways:
(i) in the peroxisomes by phenobarbital-inducible pathways via omega and 
omega-1 oxidation to metabolites which do not inhibit ketogenesis; 
(ii) in mitochondria via beta-oxidation
(b) that ethylhexanol inhibits beta-oxidation of fatty acids in mitochondria 
but not in peroxisomes. 

(2) Treatment of rats with ethylhexanol (0.32 g/kg i.p.) decreased plasma 
ketone bodies from 1.6 to 0.8 mM, increased hepatic triglycerides and increased 
lipid predominantly in periportal regions of the liver lobule.

As to the mechanism of the inhibition of ß-oxidation, the authors discussed:

(1) inhibition of acyl-Coenzyme A formation was regarded to be unlikely; reasons remain unclear

(2) inhibition of mitochondrial ß-oxidation system was regarded to be unlikely; reason: hexanoate metabolism was not affected by 2 -EH

(3) inhibition of long chain fatty acid transport into mitochondria was regarded to be likely; supporting observations include:

- valproic acid forms conjugates with carnitine; carnitine is, however, needed for the mitochondrial transporter

- accumulation of total lipids and triglycerides in-vivo after treatment with 2-EH

Applicant's summary and conclusion

Conclusions:

2-EH inhibits the fatty acid ß-oxidation in rat liver mitochondria, but not in peroxisomes.