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Basic toxicokinetics

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basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
key study
Study period:
October 1998
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP study in compliance with guidelines

Data source

Reference Type:
study report
Report date:

Materials and methods

Objective of study:
other: Absorption, distribution and excretion
Test guidelineopen allclose all
according to guideline
OECD Guideline 417 (Toxicokinetics)
according to guideline
other: Commission Directive 87/302/EEC of 18th November, 1987 -Toxicokinetics- (adopting to technical progress on Council Directive 67/548/EEC)
GLP compliance:

Test material

Constituent 1
Chemical structure
Reference substance name:
EC Number:
EC Name:
Cas Number:
Molecular formula:
Details on test material:
Test Compound: Ametryn Technical
Common name: Ametryn
Test Compound Code: 016/2-AU
Declared Purity: 960 g/kg
Lot No.: S 351
Mfd.Date: October, 1996
Expiry Date: October, 1998
14C Ametryn

Test animals

Details on test animals or test system and environmental conditions:
Species : Wistar rats (HsdOla strain)
Source : Toxicology Department, Rallis Research Centre, Bangalore - 560 058, India
Age: 8- 10 weeks
Body weight range at start of treatment: 209 to 325 g
Identification: By rat accession number, cage card and picric acid colour body markings.
Acclimatization: After veterinary examination the animals were acclimatized for one week before the start of the experiment.

Administration / exposure

Route of administration:
oral: gavage
peanut oil
Details on exposure:
The radiolabelled (14C)ametryn was orally administered in refined groundnut oil (peanut oil) to 3 dose groups of rats, viz;
(1) Single low dose (G1) - ca 0.49 mg/kg,
(2) repeated low dose (G2) - 0.5 mg/kg, non radiolabelled ametryn for 14 days followed by ca 0.51 mg/kg 14C labelled ametryn on 15th day
(3) Single high dose (G3) ca 194.53 mg/kg.

The number of animals in each dose group was four (total number of animals = 12). The administered radioactivity was ca 35.53 microci/kg in G1, ca 43.23 microci/kg in G2 and ca 34.51 microci/kg in G3 group of animals.
Duration and frequency of treatment / exposure:
7 days
Doses / concentrations
Doses / Concentrations:
see above
No. of animals per sex per dose / concentration:
see above
Control animals:
Positive control reference chemical:
Details on study design:
Dose selection rationale: a pre-test was performed in order to obtain an early indication of the routes of elimination in urine, faeces and tissue residue.
Details on dosing and sampling:
Total urine and faeces excretions were collected separate from each animal at 6, 24, 48, 72, 96, 120, 144 and 168 hours after the administration of the radiolabelled dose and these were assayed for radioactivity at each period. At termination (7 days) the vital tissues viz; liver, kidney, lungs, brain, testes, heart, spleen, whole blood, fat, muscle and bone were collected and assayed for the residual radioactivity.
The t1/2 (the time taken for excretion of 50% radioactivity of the administered dose) in urine and faeces has been calculated. Percentage of excretion has been determined in each of these and plotted in a graph against time to determine the total t1/2 of test substance. The proportional excretion in urine and faeces for each day and total excretion of both in each day and till end of experiment is presented.

Using specific computer programme, body weight data were analysed between the groups by Bartletts test for homogeneity using intra group Variances. When the Variances proved to be heterogeneous, the data were transformed using appropriate transformation. The data with homogeneous intra group variance were subjected to one-way Analysis of Variance (Snedecor and Cochran, 1987) followed by Dunnetts pairwise comparison (Scheffe, 1953) of treated groups.

All analysis and comparisons were evaluated at 5% (P=0.05) level of significance. Statistical significant differences (P < 0.05), indicated by the aforementioned tests were designated by the superscripts as stated below.
a+/a-: Significantly higher(a+)/lower(a-) than G1;
b+/b-: Significantly higher(b÷)/lower(b-) than G2.

Results and discussion

Preliminary studies:
The results of pre-study showed that there were no toxic signs in the animals of low dose. In animal of the high dose, there was slight dyspnoea accompanied by lethargy and dullness for 2 days. Faeces were not passed by this animal in first 24 hours and it had low urine output with minimal increase in body weight in 4 days. However, these symptoms disappeared in 48 hours and the animal did not show any toxic effects after this period. In view of mild toxic effect of the administered high dose (100 mg/kg), the doses chosen for the main study were 0.5 mg/kg in low dose and 200 mg/kg in high dose animals. In the pre-study, in all animals, almost 98 per cent radioactivity was eliminated in urine and faeces in 4 days experimental period out of which nearly 95 per cent radioactivity was eliminated within 48 hours. Therefore, measurement of radioactivity in the expired air as the 14C02 was not done. As the administered dose of radioactivity was adequate to monitor its elimination in urine and faeces and it had no toxic effects, the same amount of radioactivity viz., approximately 30 to 40 microci/kg body weight of animals was administered to each animal in the low dose as well as in the high dose in the main study.

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Nearly 60% Ametryn (which appears in urine after its metabolism) is absorbed from the gastrointestinal tract. The remaining 36% radioactivity, excreted in the faeces could be either unabsorbed Ametryn (of gastrointestinal tract), or from biliary excretion (after metabolism) or both. It was not possible to conclusively determine the biliary origin of radioactivity in the faeces, because intravenous (iv) dosing of Ametryn can not be done due to its insolubility in water. However, comparisons of faecal radioactivity excretions in these three groups of animals suggest that faecal radioactivity was most probably of the unabsorbed Ametryn origin in view of the parallel between faecal mass and faecal radioactivity in these animals.
Details on distribution in tissues:
On oral administration of 14C labelled Ametryn to rats less than 2% was accounted for in the tissues.
Transfer into organs
Test no.:
Transfer type:
other: not specified
other: Blood and liver together accounted for about 2% of the residual radioactivity whereas other organs accounted for less than 0.2%.
Details on excretion:
On oral administration of 14C labelled Ametryn to rats approximately 94 - 97% radioactivity was recovered in urine and faeces in 7 days.
Toxicokinetic parameters
Test no.:
Toxicokinetic parameters:
other: Excretion half lives (t1/2) of 14C Ametryn was estimated as 25.64, 25.77 and 28.48 hour in G1, G2 and G3 group respectively.

Metabolite characterisation studies

Metabolites identified:
Details on metabolites:
not applicable

Any other information on results incl. tables

In all the three dose groups, the predominant routes of excretion were urine and faeces with relatively higher excretion in the urine. At the end of 7 days, excreted percent of administered dose was 64.51, 56.16 and 59.27 in G1, G2 and G3 respectively in urine and 33.20, 40.14 and 34.79 in G1, G2 and G3 respectively in faeces. After 24 hours, combined excreted percent of administered dose in urine plus faecal excretion was 90.98 and 88.25 in G1 and G2 respectively. However in G3 it was 39.00, 40.60 and 10.93 percent at 24, 48 and 72 hours respectively, viz, in G3, 90.53 percent radioactivity was excreted in 72 hours. However in 7 days, combined excreted percent of administered dose in urine and faeces was 97.71, 96.36 and 94.06 in G1, G2 and G3 respectively viz, there were no significant dose related differences in combined excretion of radioactivity in urine and faeces in 7 days. In the assayed tissues, the residual radioactivity was less than 0.03 percent per gm tissue excepting in whole blood in which there was slightly higher radioactivity viz, it was 0.10 percent of the administered dose per gm tissue. The percent radioactivity in all the tissues added together was approximately 1.72 to 2.02 percent of the administered dose in all the 3 groups. These results show that on oral administration of 14C labelled ametryn to rats approximately 94 - 97% radioactivity was recovered in urine and faeces in 7 days and less than 2% was accounted for in the tissues.

Applicant's summary and conclusion

Interpretation of results (migrated information): low bioaccumulation potential based on study results
The study shows that there was nearly 96% recovery of radioactivity in urine and faeces and approximately anther 2% remaining in tissues after 7 days period viz., nearly 98% of administered radioactivity was accounted for in all the three groups of animals. This study shows that on 14C ametryn administration to the animals, 96% radioactivity was excreted in urine and faeces, of the rats in the 7 day period in all the three groups.