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Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)

Data source

Reference
Reference Type:
other: Authoritative database
Title:
Unnamed
Year:
2012

Materials and methods

Objective of study:
absorption
distribution
excretion
metabolism
Test guideline
Qualifier:
according to
Guideline:
other:
Principles of method if other than guideline:
Data is taken from NTP Technical Report.

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material: N,N-dimethyl-p-toluidine
- Molecular formula: C9H13N
- Substance type: Organic
- Physical state: Liquid
Radiolabelling:
yes
Remarks:
14C uniformly ring-labeled N,N-dimethyl-p-toluidine

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female

Administration / exposure

Route of administration:
other: gavage or intravenous (IV) injection
Vehicle:
other: 10% aqueous Alkamuls®
Details on exposure:
Groups of three or four male rats received single doses of 2.5, 25, or 250 mg/kg by gavage (in 10% aqueous Alkamuls®) or 2.5 mg/kg by intravenous (IV) injection. Female rats received an oral dose of 25 mg/kg.
Duration and frequency of treatment / exposure:
Exposure period: 24 hours
Doses / concentrations
Remarks:
Doses / Concentrations:
Male rats : 2.5, 25, or 250 mg/kg by gavage (in 10% aqueous Alkamuls®) or or 2.5 mg/kg by intravenous (IV) injection
Female rats : oral dose of 25 mg/kg.

No. of animals per sex per dose:
3-4 animals
Details on dosing and sampling:
Observations were made within 0-24 hours of exposure.

Results and discussion

Main ADME resultsopen allclose all
Type:
absorption
Results:
absorption through gastro-intestinal tract
Type:
distribution
Results:
in blood, kidney, liver, urinary bladder
Type:
metabolism
Results:
major metabolite in urine: p-(N-acetylhydroxyamino)hippuric acid, Lesser metabolites: N,N-dimethyl-p-toluidine N-oxide and N-methyl-p-toluidine.
Type:
excretion
Results:
90% of the total dose in urine and 4% in feces, <1% as volatiles by gavaged rats

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Approximately 4% of the total dose remained in tissues and the gastrointestinal tract at the 24-hour terminal timepoint. Absorption of administered doses was estimated to be at or near 100% based on comparison of oral and IV data.
Details on distribution in tissues:
At the lower doses in rats, kidney and liver contained the highest amounts of residual 14C, and with the urinary bladder, were the only tissues with a tissue:blood ratio greater than one. The amounts in blood, kidney, and liver were generally proportional to dose. In contrast to results observed at the lower doses, adipose tissue of 250 mg/kg rats contained amounts of 14C similar to those observed in liver and kidney.
Details on excretion:
Rats excreted approximately 90% of the total dose in urine and 4% in feces within 24 hours of dosing. Less than 1% of the total administered 14C was excreted as volatiles by gavaged rats

In male rats, excretion of 14C in the urine over time was affected by dose. A lower rate of excretion of the 25 mg/kg dose was observed over the first 6 hours; however, cumulative excretion was similar to that of the 2.5 mg/kg dose by the 12-hour timepoint. Urinary excretion of the high dose (250 mg/kg) amounted to only 70% of the total dose at 24 hours postdosing. A small amount (approximately 2%) of the high dose was excreted in feces and an average of 18% remained in tissues and the gastrointestinal tract at this timepoint. Approximately 8% of this total was detected in the stomach. At 72 hours postdosing, only residual amounts (approximately 2%) of 14C remained in tissues and the gastrointestinal tract in male rats treated with 250 mg/kg. This result indicated near complete absorption and excretion of the high dose over the extended holding period.

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
Samples from these studies were analyzed by high performance liquid chromatography (HPLC) for the presence of N,N-dimethyl-p-toluidine and metabolites. In male rats, the major metabolite in urine was identified as p-(N-acetylhydroxyamino)hippuric acid by mass spectrometry and nuclear magnetic resonance analysis (Figure 1). Two lesser metabolites were identified as N,N-dimethyl-p-toluidine N-oxide and N-methyl-p-toluidine. A small amount (not quantitated) of unmetabolized N,N,-dimethyl-p-toluidine was also detected in the urine. Approximately 8% of the radiolabel administered to most of the treatment groups consisted of 14C-N-methyl-p-toluidine and may have contributed to the amount of the metabolite observed in rat urine. N-Methyl-p-toluidine was confirmed as a urinary metabolite of N,N-dimethyl-p-toluidine following intravenous treatment of a group of male rats with purified radiolabel. A small amount (not quantitated) of unmetabolized N,N,-dimethyl-p-toluidine was also detected in the urine.

Any other information on results incl. tables

Toxicity may have contributed to the delayed gastric emptying, absorption, and excretion observed in 250 mg/kg male rats. Clinical signs of toxicity (decreased activity, piloerection, excessive blinking, and hunched posture) were observed in the rats; however, the effects were transitory. No significant vehicle effects were observed in a group of male rats receiving 250 mg/kg in corn oil, indicating that the disposition data presented here using the aqueous-based vehicle would be applicable to oral toxicity studies of N,N-dimethyl-p-toluidine using a corn oil vehicle.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
Groups of three or four male F344 rats were exposed to single doses of 2.5, 25, or 250 mg/kg by gavage (in 10% aqueous Alkamuls®) or 2.5 mg/kg by intravenous (IV) injection of 14C uniformly ring-labeled N,N-dimethyl-p-toluidine. Female rats received an oral dose of 25 mg/kg.
Absorption: Approximately 4% of the total dose remained in tissues and the gastrointestinal tract at the 24-hour terminal timepoint. Absorption of these doses was estimated to be at or near 100% based on comparison of oral and IV data.
Distribution: At the lower doses in rats, kidney and liver contained the highest amounts of residual 14C, and with the urinary bladder, were the only tissues with a tissue:blood ratio greater than one. The amounts in blood, kidney, and liver were generally proportional to dose. At a higher dose of 250 mg/kg, adipose tissue of rats contained amounts of 14C similar to those observed in liver and kidney.
Metabolism: In male rats, the major metabolite in urine was identified as p-(N-acetylhydroxyamino)hippuric acid. Two lesser metabolites were identified as N,N-dimethyl-p-toluidine N-oxide and N-methyl-p-toluidine. A small amount (not quantitated) of unmetabolized N,N,-dimethyl-p-toluidine was also detected in the urine.
Excretion: Rats excreted approximately 90% of the total dose in urine and 4% in feces within 24 hours of dosing. Less than 1% of the total administered 14C was excreted as volatiles by gavaged rats.
Executive summary:

Groups of three or four male F344 rats were exposed to single doses of 2.5, 25, or 250 mg/kg by gavage (in 10% aqueous Alkamuls®) or 2.5 mg/kg by intravenous (IV) injection of 14C uniformly ring-labeled N,N-dimethyl-p-toluidine. Female rats received an oral dose of 25 mg/kg.

Absorption: Approximately 4% of the total dose remained in tissues and the gastrointestinal tract at the 24-hour terminal timepoint. Absorption of these doses was estimated to be at or near 100% based on comparison of oral and IV data.

Distribution: At the lower doses in rats, kidney and liver contained the highest amounts of residual 14C, and with the urinary bladder, were the only tissues with a tissue:blood ratio greater than one. The amounts in blood, kidney, and liver were generally proportional to dose. At a higher dose of 250 mg/kg, adipose tissue of rats contained amounts of 14C similar to those observed in liver and kidney.

Metabolism: In male rats, the major metabolite in urine was identified as p-(N-acetylhydroxyamino)hippuric acid. Two lesser metabolites were identified as N,N-dimethyl-p-toluidine N-oxide and N-methyl-p-toluidine. A small amount (not quantitated) of unmetabolized N,N,-dimethyl-p-toluidine was also detected in the urine.

Excretion: Rats excreted approximately 90% of the total dose in urine and 4% in feces within 24 hours of dosing. Less than 1% of the total administered 14C was excreted as volatiles by gavaged rats.