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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: Significant methodological deficiencies.

Data source

Reference
Reference Type:
publication
Title:
3-Hydroxylation of salicylamide in mice
Author:
Howell SR, Kotkoskie LA, Dills RL, Klaassen CD
Year:
1988
Bibliographic source:
J. Pharm. Sci. 1988, 77(4), 309-313

Materials and methods

Objective of study:
metabolism
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
The concentrations of salicylamide and its metabolites in blood and urine were determined at various time points after intraperitoneal injection of salicyclamide into mice.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): salicylamide
Radiolabelling:
no

Test animals

Species:
mouse
Strain:
CF-1
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Sasco, Omaha, NE, USA
- Weight at study initiation: 25-30 g
- Diet (e.g. ad libitum): ad libitum Purina Laboratory Rodent Chow
- Water (e.g. ad libitum): ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): controlled
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
intraperitoneal
Vehicle:
physiological saline
Details on exposure:
TEST MATERIAL
- concentration (if solution): 20 mL/kg bw
Duration and frequency of treatment / exposure:
Single exposure
Doses / concentrations
Remarks:
Doses / Concentrations:
274.3 mg/kg bw and 548.5 mg/kg bw (2 and 4 mmol/kg bw)
No. of animals per sex per dose:
274.3 mg/kg bw: 4 mice
548.5 mg/kg bw: 8 mice
Control animals:
yes
Positive control:
no
Details on dosing and sampling:
PHARMACOKINETIC STUDY
- Tissues and body fluids sampled: urine, blood

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine
- From how many animals: (samples pooled or not): 4-8, pooled samples
- Method type(s) for identification: HPLC-UV (240 nm)

TREATMENT FOR CLEAVAGE OF CONJUGATES (if applicable): beta-glucuronidase: sulfatase

Results and discussion

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
IDENTIFIED METABOLITES:
2.3-dihydroxybenzamide (2,3-DBA), 2.5-dihydroxybenzamide (gentisamide), and their sulfates and glucuronides

QUANTIFICATION IN BLOOD:
After intraperitoneal administration of salicylamide, gentisamide glucuronide and salicylamide glucuronide were the major metabolites present in blood, followed by 2,3-DBA glucuronide and salicylamide sulfate. Gentisamide and its sulfate were detected in trace amounts only whereas neither 2.3-DBA nor its sulfate were detected.

QUANTIFICATION IN URINE:
The relative amount of each metabolite in urine generally reflected its maximum concentration in blood. Gentisamide glucuronide was the most abundant metabolite, followed by 2,3-DBA glucuronide and salicylamide sulfate. Unconjugated gentisamide and 2,3-DBA only accounted for a minor proportion; salicylamide was not detected.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
After i.p. administration of salicylamide into mice, 2,3-dihydroxybenzamide, 2,5-dihydroxybenzamide (gentisamide), and its sulfates and glucuronides could be identified as metabolites of salicylamide in both blood and urine.
Executive summary:

Metabolism of salicylamide in mice was assessed after intraperitoneal administration of 274.3 and 548.5 mg/kg bw. The concentrations of salicylamide and its metabolites in blood and urine were determined at various time points using HPLC-UV. Glucuronides and sulfates were detected using glucuronidase/sulfatase treatment of samples before injection.

2.3-Dihydroxybenzamide (2,3-DBA), 2.5-dihydroxybenzamide (gentisamide), and their sulfates and glucuronides were identified besides the sulfates and glucuronides of salicylamide as major metabolites of salicylamide in blood and urine.