Registration Dossier

Toxicological information

Basic toxicokinetics

Currently viewing:

Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
2009
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable well-documented study reports which meet basic scientific principles.
Cross-reference
Reason / purpose:
read-across: supporting information
Reference
Endpoint:
basic toxicokinetics in vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
2009
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable well-documented study reports which meet basic scientific principles.
Reason / purpose:
read-across source
Strain:
Abyssinian
Metabolites identified:
not specified
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-methylnaphthalene based on analogue read across.

The first step in the metabolism of methylnaphthalenes can occur either via ring epoxidation or via oxidation of the methyl side chain to generate an alcohol. Both processes are catalyzed by the cytochrome P450 monooxygenases. Investigators showed that the most catalytically active proteins involved in naphthalene metabolism (as assessed by Vmax/Km) were CYP1A2 and CYP2E1. CYP1A2 is localized primarily in the liver whereas CYP2E1 is found in a number of organs including respiratory tissue. More recent investigations have shown that CYP2A13 metabolizes naphthalene with relatively high turnover and low Km. Since this protein is expressed in human lung, albeit with a high degree of variability, it is a potential candidate for catalyzing the initial metabolism of naphthalene in human respiratory tissue. 

 

Other data available come from work conducted with a single recombinant protein, CYP2F2. Although this protein appears to be abundant in airways of the mouse, available evidence suggests that the rat and Rhesus macaque orthologues are present in far smaller amounts in the lung. This protein metabolizes naphthalene, 2-methylnaphthalene and 1-nitronaphthalene, all with relatively low Km and high Vmax, and, based on inhibition studies with 5-phenyl-1-pentyne, appears to play a major role in the epoxidation of closely related substrates, i.e. styrene. These data suggest that this protein plays a quantitatively important role in the metabolic activation of these substrates at least in the mouse. The presence of large quantities of this protein in target cells may explain the species differences in susceptibility to naphthalene and 2-methylnaphthalene in mouse but not in rat.

 

Urinary Metabolites. The most prominent metabolites isolated in rat urine after treatment with low doses of 2-methylnaphthalene originated from initial oxidation of the parent hydrocarbon on the methyl moiety. Thirty to thirty-five percent of a dose of 14C-2-methylnaphthalene was recovered as a glycine conjugate of 2-naphthoic acid. Six to eight percent of the dose was represented by dihydrodiols and 3-5% of the dose was recovered as parent hydrocarbon. Other polar metabolites appeared to account for 35-45% of the radioactivity in the urine. Later work, showed that approximately 75% of the radioactive metabolites eliminated in the urine of guinea pigs administered a low dose of 3H-2-methylnaphthalene resulted from oxidation of the methyl group. These metabolites included free naphthoic acid, the glucuronide of naphthoic acid as well as the glycine conjugate. In these studies, a cysteine derivative, accounting for approximately 10% of the total urinary radioactivity, was reported in the urine. Finally, small percentages of sulfate and glucuronide conjugates of 8-hydroxy-2-methylnaphthalene (<10% of total urinary radioactivity) were measured.

 

More recent studies on the disposition and metabolism of 3H-1,2-dimethylnaphthalene (28 mg/kg) in rats showed that the radioactive parent compound was rapidly absorbed after ip administration, reaching peak levels within 4 h. Sixty-five percent of the administered radioactivity was recovered in the excreta within 24 h, with roughly equal amounts eliminated in the urine and feces. Greater than 95% of the administered radioactivity was recovered in the excreta within 72 h of administration. The highest tissue concentrations of radioactivity were observed in fat, but these fell rapidly to very low levels within 48 h. This compound apparently distributes rapidly to the fat but redistributes easily due to the rapid clearance of the compound. Urinary metabolites were identified in ether extracts of acidified (pH 1) urine. The parent compound (representing roughly 30% of the ether-extractable metabolites from urine), several dimethylthionaphthols, at least 2 dimethylmethylthionaphthalene derivatives as well as several derivatives generated from oxidation of the methyl groups to the alcohol and subsequently to the acid were measured in the urine following dimethylnaphthalene administration. The most prominent metabolites were the dimethylthionaphthol derivatives and the metabolites generated from side chain oxidation. It is noted that the 30% of the radioactivity unextracted by ether at pH 1may include a number of conjugated metabolites including glucuronides, sulfates and mercapturic acids. The results from more recent studies of the metabolism and distribution of radioactivity from 3H-1,4-dimethylnaphthalene and 1,6-dimethylnaphthalene are nearly identical to those with the 1,2-dimethylnaphthalene derivative. Again, radioactivity is rapidly absorbed reaching peak plasma concentrations within 4 h of administration. Metabolites which were derived from both oxidation of the methyl groups and the aromatic nucleus were isolated from the urine of treated rats.

 

These metabolites included methylnaphthoic acid as well as the intermediates leading to this derivative (methylhydroxymethyl, methylnaphthaldehyde). Trace quantities of a methylthio metabolite were observed; these metabolites have been measured in the urine of naphthalene-treated rodents as well.

Data source

Reference
Reference Type:
publication
Title:
Toxicity and metabolism of methylnaphthalenes: Comparison with naphthalene and 1-nitronaphthalene
Author:
Ching Yu Lin, Asa M. Wheelock, Dexter Morin, R. Michael Baldwin, Myong Gong Lee, Aysha Taff, Charles Plopper, Alan Buckpitt, Arlean Rohde
Year:
2009
Bibliographic source:
Toxicology 260 (2009) 16–27

Materials and methods

Objective of study:
metabolism
Principles of method if other than guideline:
This is a review article that compiles data from many studies.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
other: various
Strain:
not specified
Sex:
not specified

Administration / exposure

Route of administration:
other: various
Vehicle:
not specified
Control animals:
not specified

Results and discussion

Metabolite characterisation studies

Metabolites identified:
not specified

Applicant's summary and conclusion

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

The first step in the metabolism of methylnaphthalenes can occur either via ring epoxidation or via oxidation of the methyl side chain to generate an alcohol. Both processes are catalyzed by the cytochrome P450 monooxygenases. Investigators showed that the most catalytically active proteins involved in naphthalene metabolism (as assessed by Vmax/Km) were CYP1A2 and CYP2E1. CYP1A2 is localized primarily in the liver whereas CYP2E1 is found in a number of organs including respiratory tissue. More recent investigations have shown that CYP2A13 metabolizes naphthalene with relatively high turnover and low Km. Since this protein is expressed in human lung, albeit with a high degree of variability, it is a potential candidate for catalyzing the initial metabolism of naphthalene in human respiratory tissue. 

 

Other data available come from work conducted with a single recombinant protein, CYP2F2. Although this protein appears to be abundant in airways of the mouse, available evidence suggests that the rat and Rhesus macaque orthologues are present in far smaller amounts in the lung. This protein metabolizes naphthalene, 2-methylnaphthalene and 1-nitronaphthalene, all with relatively low Km and high Vmax, and, based on inhibition studies with 5-phenyl-1-pentyne, appears to play a major role in the epoxidation of closely related substrates, i.e. styrene. These data suggest that this protein plays a quantitatively important role in the metabolic activation of these substrates at least in the mouse. The presence of large quantities of this protein in target cells may explain the species differences in susceptibility to naphthalene and 2-methylnaphthalene in mouse but not in rat.

 

Urinary Metabolites. The most prominent metabolites isolated in rat urine after treatment with low doses of 2-methylnaphthalene originated from initial oxidation of the parent hydrocarbon on the methyl moiety. Thirty to thirty-five percent of a dose of 14C-2-methylnaphthalene was recovered as a glycine conjugate of 2-naphthoic acid. Six to eight percent of the dose was represented by dihydrodiols and 3-5% of the dose was recovered as parent hydrocarbon. Other polar metabolites appeared to account for 35-45% of the radioactivity in the urine. Later work, showed that approximately 75% of the radioactive metabolites eliminated in the urine of guinea pigs administered a low dose of 3H-2-methylnaphthalene resulted from oxidation of the methyl group. These metabolites included free naphthoic acid, the glucuronide of naphthoic acid as well as the glycine conjugate. In these studies, a cysteine derivative, accounting for approximately 10% of the total urinary radioactivity, was reported in the urine. Finally, small percentages of sulfate and glucuronide conjugates of 8-hydroxy-2-methylnaphthalene (<10% of total urinary radioactivity) were measured.

 

More recent studies on the disposition and metabolism of 3H-1,2-dimethylnaphthalene (28 mg/kg) in rats showed that the radioactive parent compound was rapidly absorbed after ip administration, reaching peak levels within 4 h. Sixty-five percent of the administered radioactivity was recovered in the excreta within 24 h, with roughly equal amounts eliminated in the urine and feces. Greater than 95% of the administered radioactivity was recovered in the excreta within 72 h of administration. The highest tissue concentrations of radioactivity were observed in fat, but these fell rapidly to very low levels within 48 h. This compound apparently distributes rapidly to the fat but redistributes easily due to the rapid clearance of the compound. Urinary metabolites were identified in ether extracts of acidified (pH 1) urine. The parent compound (representing roughly 30% of the ether-extractable metabolites from urine), several dimethylthionaphthols, at least 2 dimethylmethylthionaphthalene derivatives as well as several derivatives generated from oxidation of the methyl groups to the alcohol and subsequently to the acid were measured in the urine following dimethylnaphthalene administration. The most prominent metabolites were the dimethylthionaphthol derivatives and the metabolites generated from side chain oxidation. It is noted that the 30% of the radioactivity unextracted by ether at pH 1may include a number of conjugated metabolites including glucuronides, sulfates and mercapturic acids. The results from more recent studies of the metabolism and distribution of radioactivity from 3H-1,4-dimethylnaphthalene and 1,6-dimethylnaphthalene are nearly identical to those with the 1,2-dimethylnaphthalene derivative. Again, radioactivity is rapidly absorbed reaching peak plasma concentrations within 4 h of administration. Metabolites which were derived from both oxidation of the methyl groups and the aromatic nucleus were isolated from the urine of treated rats.

 

These metabolites included methylnaphthoic acid as well as the intermediates leading to this derivative (methylhydroxymethyl, methylnaphthaldehyde). Trace quantities of a methylthio metabolite were observed; these metabolites have been measured in the urine of naphthalene-treated rodents as well.