Registration Dossier

Diss Factsheets

Toxicological information

Basic toxicokinetics

Currently viewing:

Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1997
Report date:
1997

Materials and methods

Objective of study:
excretion
Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 417 (Toxicokinetics)
Deviations:
no
GLP compliance:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
methyl (2E)-3-methoxy-2-[2-({[6-(trifluoromethyl)pyridin-2-yl]oxy}methyl)phenyl]acrylate
EC Number:
601-478-9
Cas Number:
117428-22-5
Molecular formula:
C18H16F3NO4
IUPAC Name:
methyl (2E)-3-methoxy-2-[2-({[6-(trifluoromethyl)pyridin-2-yl]oxy}methyl)phenyl]acrylate
Test material form:
solid
Details on test material:
- Purity: 93.3-99.8% (see individual test record for specific details)
Specific details on test material used for the study:
99.8% purity for the unlabeled test substance
>97% purity for the radiolabeled pyridyl and phenyl moieties of the test substance
Radiolabelling:
yes

Test animals

Species:
rat
Strain:
other: Alpk:APf SD
Details on species / strain selection:
The Alpk:Apr SD strain of rat was selected because this strain was used during other toxicology studies with this test substance and since substantial background information is available for its use in the testing laboratory. The oral route of administration was used to represent a possible route of human exposure.
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: Not reported
- Weight at study initiation: 180-208 g
- Housing: The rats were housed in groups of the same sex in stock rat cages. Following acclimatization, they were transferred to glass metabolism cages, in which they were individually housed and acclamatised for approximately 1 day prior to dosing.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): mains water ad libitum
- Acclimation period: at least 4 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3°C
- Humidity (%): 30-70%
- Air changes (per hr): At least 15 changes/hour, giving positive pressure with respect to the access corridor
- Photoperiod (hrs dark / hrs light): 12 hours light, 12 hours dark

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Remarks:
PEG 600
Duration and frequency of treatment / exposure:
24 hours
Doses / concentrations
Dose / conc.:
10 mg/kg bw (total dose)
No. of animals per sex per dose / concentration:
2 male and 2 females
Control animals:
yes, concurrent vehicle
Positive control reference chemical:
No
Details on study design:
- Dose selection rationale: The dose level was selected to represent a 'no-effect' dose following single oral administration.
Details on dosing and sampling:
The [14C]-pyridyl dosing solution was prepared by dissolving 8.6 mg of unlabeled test substance and 9.6 MBq (equivalent to 1.9 mg) of the [14C]-pyridyl moiety in the dosing vehicle to give a final weight of 11.2 g and concentrations of 0.9 mg/g and 0.9 MBq/g of dosing solution. The specific activity of the test substance in the dosing solution was 912.8 kBq/mg of the test substance.

The [14C]-phenyl dosing solution was prepare by dissolving 8.6 mg of unlabeled test substance and 9.8 MBq (equivalent to 1.8 mg) of the [14C]-phenyl moiety in the dosing vehicle to give a final weight of 11.3 g and concentrations of 0.9 mg/g and 0.9 MBq/g of dosing solution. The specific activity of the test substance in the dosing solution was 945.5 kBq/mg of the test substance.

After dosing, the animals were returned to separate metabolism cages. Urine only was collected at 6 hours after dosing and urine and feces were separately collected at 12 and 24 hours from all animals. The exhaled air from each animal was passed through two sequential Nilox© columns (A and B) each containing 2 M sodium hydroxide solution followed by a single trap containing 2 M hydrochloric acid and a water trap and finally through a single Draegar tube pre-packed with activated charcoal. Subsamples of the contents of each trap were removed for radiochemical analysis at 12 and 24 hours after dosing.
Statistics:
The use of one rat of each sex precludes any statistical analysis.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:
For the [14C]-pyridyl moiety, in the WBA sections, the majority of the radioactivity was observed in the intestinal tract contents of both sexes. Tissue radiolabeling was apparent in the liver with lower levels in the kidneys. Lower intensities of radioactivity were observed in all other tissues.

For the [14C]-phenyl moiety, in the WBA sections, the highest intensity of radioactivity was observed in the gastrointestinal tract contents of both sexes and also the stomach mucosa of the male rat. Tissue radiolabelling was apparent in the liver and kidneys, with lower intensities of radioactivity observed in all other tissues.
Details on excretion:
Twenty-four hours after dosing with the [14C]-pyridyl moiety, the male rat excreted 21.0% of the administered dose in the urine and 13.4% in the faeces. The similarly dosed female rat excreted 25.0% of the dose in the urine and 19.1% in the faeces over the same period. For both sexes, less than 0.4% of the administered dose was exhaled as volatile metabolites over 24 hours after dosing.

Twenty-four hours after dosing with [14C]-phenyl moiety, the male rats excreted 17.8% of the administered dose in the urine and 19.6% in the faeces. The female rats excreted 30.2% of the administered dose in the urine and 19.6% in the faeces over the same period. For both sexes, less than 0.1% of the dose was exhaled as volatile metabolites.

Applicant's summary and conclusion

Conclusions:
Based upon the small number of animals used and the short duration of this study, no conclusions can be made about the rate or extent of absorption. However, for both the [14C]-pyridyl and [14C]-phenyl moieties, negligible proportions of the dose were metabolized to volatile exhaled metabolites. Twenty-four hours after dosing the greatest intensity of radiolabeling was in the contents of the gastrointestinal tract with radiolabeling apparent in the liver with lesser amounts in the kidneys and lower levels in other tissues.
Executive summary:

Male and female rats were administered a single oral dose of 10 mg/kg of the 14C radiolabeled pyridyl or phenyl moiety of the test substance. The excretion of radioactivity was monitored in urine, feces and exhaled air. Twenty-four hours after dosing, the rats were killed to investigate the distribution of radioactivity using whole body autoradiography (WBA).

Twenty-four hours after dosing with the [14C]-pyridyl moiety, the male rat excreted 21.0% of the administered dose in the urine and 13.4% in the feces. The similarly dosed female rat excreted 25.0% of the dose in the urine and 19.1% in the feces over the same period. For both sexes, less than 0.4% of the administered dose was exhaled as volatile metabolites over 24 hours after dosing. In the WBA sections, the majority of the radioactivity was observed in the intestinal tract contents of both sexes. Tissue radiolabeling was apparent in the liver with lower levels in the kidneys. Lower intensities of radioactivity were observed in all other tissues.

Twenty-four hours after dosing with [14C]-phenyl moiety, the male rats excreted 17.8% of the administered dose in the urine and 19.6% in the feces. The female rats excreted 30.2% of the administered dose in the urine and 19.6% in the feces over the same period. For both sexes, less than 0.1% of the dose was exhaled as volatile metabolites. In the WBA sections, the highest intensity of radioactivity was observed in the gastrointestinal tract contents of both sexes and also the stomach mucosa of the male rat. Tissue radiolabelling was apparent in the liver and kidneys, with lower intensities of radioactivity observed in all other tissues.