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Basic toxicokinetics

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basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference Type:
study report

Materials and methods

Objective of study:
Test guideline
equivalent or similar to
EU Method B.36 (Toxicokinetics)
GLP compliance:

Test material

Details on test material:
- Name of test material (as cited in study report): Sodium cyanurate monohydrate and 14C-labelled sodium cyanurate monohydrate
- Analytical purity: 99.5%
- Lot/batch No.: Unlabeled compound: Monsanto Industrial Chemicals Co., Lot No. 1219649-3 Radiolabeled compound: New England Nuclear Corp., Lot No. 1166-069
- Specific activity (if radiolabelling): 9.8 mCi/mmol
- Storage condition of test material: Unlabeled compound was stored in dark at room temperature and radiolabeled compound was stored at -20°C.

Test animals

Details on test animals and environmental conditions:
- Source: Laboratory Research Enterprises, Inc., Kalamazoo, MI, USA
- Age at study initiation: 5.9 - 8.5 months
- Weight at study initiation: 7 - 9 kg
- Fasting period before study: 14 hours
- Housing: Housed in galvanized steel cages until administration of radiolabeled compounds and then transferred to stainless steel metabolism cages
- Individual metabolism cages: yes
- Water: ad libitum
- Acclimation period: At least 1 week to surroundings and for at least 48 hours to food and water conditions

- Temperature (°C): 23-25
- Humidity (%): 46-55
- Photoperiod: 12 hrs continuous light

Administration / exposure

Route of administration:
other: oral and intravenous
Details on exposure:
14C-labeled and unlabeled sodium cyanurate were dissolved in distilled water at 3 mg/mL or suspended in 8% carboxymethyl cellulose (Sigma Chemical Co., St. Louis, MO) in distilled water at 100 mg/L. Solutions or suspensions of the compound were freshly prepared on the day of each experiment and samples were removed for determination of the exact specific activity and for determination of the radiochemical purity of 14C-sodium cyanurate.

14C-Sodium cyanurate is stable in solution in distilled water at 2 mg/L. The stability of the compound in dog urine was determined by analysis of urine samples by HPLC. 14C-Sodium cyanurate was determined to be stable at room temperature in distilled water after 16 days and in dog urine after 24 hours.
Doses / concentrations
Doses / Concentrations:
i.v at 5 mg/kg bw
p.o. (oral intubation) at 5 mg/kg bw (in distilled water)
p.o. (oral intubation) at 500 mg/kg bw (in 8% carboxymethylcellulose)
p.o at 5 mg/kg (repeated dose, oral intubation; daily for 15 days, with radiolabelled material only for the last dose)
No. of animals per sex per dose:
2 males and 2 females / group.
Control animals:
Details on dosing and sampling:
Sampling times:
Blood – i. v.: 5, 15 and 30 min, 1, 2, 4, 6, 8, 12, 16, 24, 48 and 72 hours. Study terminated at 3 days.
Blood – p. o. dose: 15, and 30 min, 1, 2, 4, 6, 8, 12, 16, 24, 48 and 72 hours and 7 days after administration.
Urine and faeces – i. v.: 0-6, 6-12, 12-24, 24-48 and 48-72 hr.
Urine and faeces – 5 mg/kg single p.o. dose: 0-6, 6-12, 12-24, 24-48 and 48-72 and 72-96 hr.
Urine and faeces – 500 mg/kg p.o.: 0-6, 6-12, 12-24, and then at 24 h intervals for a total of 7 days.
Urine and faeces – 5 mg/kg repeated p.o. dose: 0-6, 6-24, 24-48 and 48-72, 72-96,96-120 and 120-146hr.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Sodium cyanurate was totally absorbed after administration at 5 mg/kg p.o but absorption after administration at 500 mg/kg p.o was highly variable ranging from less than 10% of the dose to total absorption with an average of around 50% of the dose absorbed. After repeated administration of the compound at 5 mg/kg p.o absorption of the final 14C-labeled dose was marginally reduced. Absorption was determined by comparison of the urinary recovery of the compound after i.v and p.o administration, and by comparison of the areas under the 0-8 hr blood concentration-time curves after i.v and p.o administration.
Details on distribution in tissues:
The concentrations of sodium cyanurate equivalents in tissues at the time of animal sacrifice were less than the limits of sensitivity for the assay for all treatment regimens.
Details on excretion:
After iv or oral administration at 5 mg/kg sodium cyanurate compound equivalents were primarily excreted via the urinary route during the first 12 h with only marginal excretion occurring after 24 h. The percentage of dose excreted in the urine was similar after either route of administration. Recovery of sodium cyanurate equivalents in the feces was negligible ie 2% of the dose or less except for three of the multiple dose animals in which 6-13% was recovered via the fecal route. The total percentage of the 5 mg/kg dose recovered in the urine and feces of both sexes varied from 80 to 100%. Similar total recoveries were observed after oral administration of the compound at 500 mg/kg. However, the percentage excreted in the urine after the higher dose varied from as low as 14% to a maximum of 73%. Urinary excretion of compound equivalents occurred primarily during the first 24 h after dosing, with only marginal excretion occurring after 48 h. There were no differences between the urinary excretion patterns of males and females.

Metabolite characterisation studies

Metabolites identified:
Details on metabolites:
Only parent compound was found in urine indicating that metabolism of sodium cyanurate did not occur or was minimal.

Any other information on results incl. tables

Sodium cyanurate was rapidly absorbed, with peak blood levels 1-3 hours post dose and a single elimination half life of 1.5-2 h.  Absorption was probably rate limiting, thus tmax was later and the terminal half-life was longer in high dose animals.

Sodium cyanurate was completely absorbed following administration at 5mg/kg to dogs, but absorption was highly variable at the 500 mg/kg dose level, averaging ~ 50%.  The absorbed compound was rapidly and almost quantitatively eliminated in the urine.

Metabolism, if it occurred at all, is negligible.

There is no evidence for bioaccumulation of the compound and there are no major changes in the disposition or metabolism of sodium cyanurate following repeated administration.

Applicant's summary and conclusion

There is no evidence for bioaccumulation of the compound and there are no major changes in the disposition or metabolism of sodium cyanurate following repeated administration.