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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
N/A
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: The documentation is from secondary literature.
Justification for type of information:
A discussion and report on the read across strategy is given as an attachment in IUCLID Section 13.
Cross-reference
Reason / purpose for cross-reference:
read-across: supporting information
Reference
Endpoint:
basic toxicokinetics
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
N/A
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: The documentation is from secondary literature.
Justification for type of information:
A discussion and report on the read across strategy is given as an attachment in IUCLID Section 13.
Reason / purpose for cross-reference:
read-across source
Metabolites identified:
yes
Details on metabolites:
Nine urinary metabolites, namely, N-acetyl-S-[2-(4-ethenylphenyl)-2-hydroxyethyl]-L-cysteine, N-acetyl-S-[1-(4-ethenylphenyl)-2-hydroxyethyl]-L-cysteine, N-acetyl-S-[1-(4-formylphenyl)-2-hydroxyethyl]-L-cysteine, 1-(4-ethenylphenyl)ethane-1,2-diol, 4-ethenylbenzoic acid, 4-ethenylbenzoyl-glycine, 1-ethenyl-4-(1-hydroxyethyl)benzene, 4-(1,2-dihydroxyethyl)benzoic acid, (4-carboxymethylphenyl)acetylglycine, N-acetyl-S-[2-carboxy-1-(4-ethenylphenyl)ethyl]-L-cysteine, and two isomeric beta-D-glucosiduronates derived from 1-(4-ethenylphenyl)ethane-1,2-diol
Conclusions:
Interpretation of results: low bioaccumulation potential based on study results
Executive summary:

This data is being read across from the source study that tested 1,4-diethenylbenzene based on analogue read across.

Biotransformation of 1,4-diethenylbenzene in rat was studied. Nine urinary metabolites, namely, N-acetyl-S-[2-(4-ethenylphenyl)-2-hydroxyethyl]-L-cysteine, N-acetyl-S-[1-(4-ethenylphenyl)-2-hydroxyethyl]-L-cysteine, N-acetyl-S-[1-(4-formylphenyl)-2-hydroxyethyl]-L-cysteine, 1-(4-ethenylphenyl)ethane-1,2-diol, 4-ethenylbenzoic acid, 4-ethenylbenzoyl-glycine, 1-ethenyl-4-(1-hydroxyethyl)benzene, 4-(1,2-dihydroxyethyl)benzoic acid, (4-carboxymethylphenyl)acetylglycine, N-acetyl-S-[2-carboxy-1-(4-ethenylphenyl)ethyl]-L-cysteine, and two isomeric beta-D-glucosiduronates derived from 1-(4-ethenylphenyl)ethane-1,2-diol, were isolated and identified by n.m.r. and mass spectrometry.  GC-mass spectral analysis of the methylated urine extract allowed the identification of four other metabolites, as 4-ethenylphenylacetic acid, 4-ethenylphenylacetylglycine, 4-ethenylmandelic acid, and 4-ethenylphenylglyoxylic acid. The structures of the identified metabolites indicate that the main reactive intermediate in the metabolism of 1,4-diethenylbenzene is 4-ethenylphenyloxirane. The first step in the biotransformation of 1,4-diethenylbenzene is the formation of an oxirane. Subsequent steps lead to oxidation of the second ethenyl group leading to the aldehyde N-acetyl-S-[1-(4-formylphenyl)-2-hydroxyethyl]-L-cysteine metabolite. Rats dosed with a single i.p. dose excreted nearly 5.6% of the dose as the glycine conjugate 12, irrespective of the dose. In contrast, the total thioether fraction decreased significantly with increasing dose, being 23 +/- 3, 17 +/- 5 and 12 +/- 1% of dose at 100, 200 and 300 mg/kg, respectively (mean +/- SD).

Data source

Reference
Reference Type:
publication
Title:
Biotransformation of diethenylbenzenes. I. Identification of the main urinary metabolites of 1,4-diethenylbenzene in the rat.
Author:
Lindhart, I.
Year:
1989
Bibliographic source:
Xenobiotica. Jun;19(6):645-53. 1989

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 417 (Toxicokinetics)
Principles of method if other than guideline:
Biotransformation of 1,4-diethenylbenzene in rat was studied.
GLP compliance:
not specified

Test material

Constituent 1
Chemical structure
Reference substance name:
1,4-divinylbenzene
EC Number:
203-266-8
EC Name:
1,4-divinylbenzene
Cas Number:
105-06-6
Molecular formula:
C10H10
IUPAC Name:
1,4-divinylbenzene
Constituent 2
Reference substance name:
1,4-diethenylbenzene
IUPAC Name:
1,4-diethenylbenzene
Radiolabelling:
not specified

Test animals

Species:
rat
Strain:
not specified
Sex:
not specified

Administration / exposure

Control animals:
no

Results and discussion

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
Nine urinary metabolites, namely, N-acetyl-S-[2-(4-ethenylphenyl)-2-hydroxyethyl]-L-cysteine, N-acetyl-S-[1-(4-ethenylphenyl)-2-hydroxyethyl]-L-cysteine, N-acetyl-S-[1-(4-formylphenyl)-2-hydroxyethyl]-L-cysteine, 1-(4-ethenylphenyl)ethane-1,2-diol, 4-ethenylbenzoic acid, 4-ethenylbenzoyl-glycine, 1-ethenyl-4-(1-hydroxyethyl)benzene, 4-(1,2-dihydroxyethyl)benzoic acid, (4-carboxymethylphenyl)acetylglycine, N-acetyl-S-[2-carboxy-1-(4-ethenylphenyl)ethyl]-L-cysteine, and two isomeric beta-D-glucosiduronates derived from 1-(4-ethenylphenyl)ethane-1,2-diol

Applicant's summary and conclusion

Conclusions:
Interpretation of results: low bioaccumulation potential based on study results
Executive summary:

Biotransformation of 1,4-diethenylbenzene in rat was studied. Nine urinary metabolites, namely, N-acetyl-S-[2-(4-ethenylphenyl)-2-hydroxyethyl]-L-cysteine, N-acetyl-S-[1-(4-ethenylphenyl)-2-hydroxyethyl]-L-cysteine, N-acetyl-S-[1-(4-formylphenyl)-2-hydroxyethyl]-L-cysteine, 1-(4-ethenylphenyl)ethane-1,2-diol, 4-ethenylbenzoic acid, 4-ethenylbenzoyl-glycine, 1-ethenyl-4-(1-hydroxyethyl)benzene, 4-(1,2-dihydroxyethyl)benzoic acid, (4-carboxymethylphenyl)acetylglycine, N-acetyl-S-[2-carboxy-1-(4-ethenylphenyl)ethyl]-L-cysteine, and two isomeric beta-D-glucosiduronates derived from 1-(4-ethenylphenyl)ethane-1,2-diol, were isolated and identified by n.m.r. and mass spectrometry.  GC-mass spectral analysis of the methylated urine extract allowed the identification of four other metabolites, as 4-ethenylphenylacetic acid, 4-ethenylphenylacetylglycine, 4-ethenylmandelic acid, and 4-ethenylphenylglyoxylic acid. The structures of the identified metabolites indicate that the main reactive intermediate in the metabolism of 1,4-diethenylbenzene is 4-ethenylphenyloxirane. The first step in the biotransformation of 1,4-diethenylbenzene is the formation of an oxirane. Subsequent steps lead to oxidation of the second ethenyl group leading to the aldehyde N-acetyl-S-[1-(4-formylphenyl)-2-hydroxyethyl]-L-cysteine metabolite. Rats dosed with a single i.p. dose excreted nearly 5.6% of the dose as the glycine conjugate 12, irrespective of the dose. In contrast, the total thioether fraction decreased significantly with increasing dose, being 23 +/- 3, 17 +/- 5 and 12 +/- 1% of dose at 100, 200 and 300 mg/kg, respectively (mean +/- SD).