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Reference
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.
Objective of study:
metabolism
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
Radiolabelling:
no
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
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
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
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.
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.

Description of key information

Short description of key information on bioaccumulation potential result: 
metabolites identified, mice, i.p., Howell 1988
metabolites/kinetics identified, humans, oral/rectal, de Boer 1983

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

A very large body of work exists in the literature (see literature search) addressing the pharmacokinetics and pharmacodynamics of salicylamide, both in vitro and in vivo (several species). Various aspects of ADME were addressed, but none according to guideline methods, and usually with non-standard methodology. For oral administration, almost complete metabolism was observed after absorption and first-pass through the liver. Two studies were selected which identified the main metabolites, as well as the absorption and elimination kinetics.

 

Basic toxicokinetics

Howell (1988) investigated the metabolism of salicylamide in mice 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.

 

Direct observations: clinical cases - toxicokinetics

De Boer et al. (1983) gave salicylamide to 6 human volunteers by oral or rectal administration at 500 or 1500 mg/person. Blood samples were obtained in regular intervals to quantify free salicylamide in plasma. Urinary samples were also collected and checked for salicylamide and its conjugates (sulfate and glucuronide). After oral administration, salicylamide was absorbed very quickly into the plasma with a mean peak time of 12±2.7 min. The peak concentration was then 30.9±9.2 g/mL (dose administered: 1500 mg). Elimination from plasma was also quite fast with half-lives of 12 and 31 min after administration of 500 and 1500 mg salicylamide, respectively. Excretion was performed mainly via urine after conjugation with sulfate or glucuronic acid. Urinary excretion half life was 63 min (dose: 1500 mg). After rectal administration plasma concentration of free salicylamide and urinary concentration of conjugates were significantly lower compared to oral administration.

The rapid metabolism and excretion indicate no potential for bioaccumulation.