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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:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1987
Report Date:
1987

Materials and methods

Objective of study:
distribution
excretion
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
This study was designed to follow the elimination and distribution of the 14C-labeled test substance after oral administration in male and female rats.
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid
Details on test material:
Purity: Not reported
Radiolabelling:
yes
Remarks:
Labeled on both the phenyl and trizaine groups of the molecule

Test animals

Species:
rat
Strain:
other: Crl:CD(SD)
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: acetone:corn oil (3/7,v/v) mixture
Duration and frequency of treatment / exposure:
Animals will be maintained in individual metabolism cages for 7 days after the radioactive dose is administered or until 90+ percent of the administered dose is excreted (whichever occurs first), at which time the animals should be sacrificed.
Doses / concentrationsopen allclose all
Dose / conc.:
10 mg/kg bw (total dose)
Remarks:
No preconditioning; Each animal will receive, by gavage, one low-dose dose (10 mg) of the test substance. This dose will consist of 0.5 mg of the 14C-triazine labeled moiety and an appropriate amount of the unlabeled test substance (Group A)
Dose / conc.:
10 mg/kg bw (total dose)
Remarks:
Each animal will receive, by gavage, a daily dose of 10 mg/kg of the non-radioactive test substance for 14 consecutive days followed 24 hours later by a single 10 mg/kg gavage dose of the test substance containing 0.5 mg of the 14C-triazine labeled moiety and an appropriate amount of the unlabeled test substance (Group B)
Dose / conc.:
1 000 mg/kg bw (total dose)
Remarks:
No preconditioning; Each animal will receive, by gavage, a single high-dose (1000 mg/kg) of the test substance. This dose will consist of 0.5 mg of the 14C-triazine labeled moiety and an appropriate amount of the unlabeled test substance (Group C)
Dose / conc.:
1 000 mg/kg bw (total dose)
Remarks:
No preconditioning; Each animal will receive by gavage, one high-dose (1000 mg/kg) of the test substance. This dose will consist of 0.5 mg of the 14C-phenyl labeled moiety and an appropriate amount of the unlabeled test substance.
No. of animals per sex per dose:
Preliminary study: One male and one female rat in each group (A, B, C, and D)
Main study: Four male and four female rats in each group (A, B, C, and D)
Control animals:
no
Positive control:
No
Details on dosing and sampling:
TOXICOKINETIC / PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, faeces, expired air, blood, carcass, GI tract, whole organs, skin, muscle, fat, bone (femurs), cage washes, and residual feed
- Time and frequency of sampling: Urine, feces, and expired air at 12 and 24 hours post-dosing and at each succedlng 24-houri Interval until sacrlfice. Blood and other tissues following sacrfice of the animals
METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine and faeces
- From how many animals: 8 (samples pooled or not): Yes
- Method type(s) for identification: liquid scintillation counting (LSC)
Statistics:
The means have been compared using student's t test. Only significant differences with a "P" value less than 0.01 have been recorded.

Results and discussion

Preliminary studies:
Only very low levels of radioactivity < 0.01% were detected in the organic trapping agent (Carbosorb) surrounded by ice. Radioactivity could only be detected after 96 hours in the pre-conditioned group (Group B). Immediately after administration of the high dose (Groups C and D), the rats (male and female) appeared to breathe with difficulty and were sleepy. After about one hour female rats CF1 and DF1 were in a lethargic state, with breathing difficulties and were non responsive to external stimuli. After about three hours, the condition was about the same but female DF1 exhibited strong eye irritation with tear production. At twelve hours after administration, the condition had not changed much but, after 24 hours, all rats appeared to be normal.
Main ADME results
Type:
excretion
Results:
Groups A-C excreted > 90% of the administered radioactivity after two days. Group D excreted > 80% of the administered radioactivity after two days.

Toxicokinetic / pharmacokinetic studies

Details on excretion:
Group A (10 mg/kg of the triazine-labeled moiety): All animals excreted> 90% of the administered radioactivity after two days. The mean total recovery from males was 100.0 ± 4.7% (urine 59.3 ± 4.1%, feces 40.3 ± 5.8%) with a mean residual level of radioactivity in the body of 0.08 ± 0.04%. The corresponding recovery in females was 97.5 ± 5.3% (urine 57.3 ± 1.2%, feces 39.9 ± 5.9%) with 0.08 ± 0.03% remaining in the body. The concentration of radioactivity in all organs and tissues was below 0.1 ppm.

Group B: (Preconditioned: 10 mg/kg of the triazine-labeled moiety): All animals excreted> 90% of the administered radioactivity after two days. The mean total recovery from males was 105.9 ± 3.1% (urine 44.5 ± 3.2%, feces 61.1 ± 5.6%) with a mean residual level of radioactivity in the body of 0.05 ± 0.01%. The corresponding recovery in females was 104.0 ± 1.7% (urine 50.5 ± 2.7%, feces 53.1 ± 1.5%) with 0.07 ± 0.01% remaining in the body. The concentration of radioactivity in all organs and tissues was below 0.1 ppm.

Group C (1000 mg/kg of the triazine labeled moiety): All males excreted > 90% of the administered radioactivity after three days. All surviving female rats excreted > 80% of the administered radioactivity after three days. The mean total recovery from males was 98.8 ± 5.7% (urine 49.3 ± 5.5%, feces 48.9 ± 4.5%) with a mean total of 0.12 ± 0.07% remaining in the body. The corresponding recovery in females was 95.5 ± 2.2% (urine 52.5 ± 5.0%, feces 42.3 ± 7.1%) with 0.12 ± 0.01% remaining in the body. The concentration of radioactivity in the organs and tissues ranged from "not detectable" to about 8.8 ppm in the kidneys.

Group D (1000 mg/kg of the phenyl-labeled moiety): All male rats excreted > 90% of the administered radioactivity after three days. All surviving female rats excreted > 80% of the administered radioactivity after three days. The mean total recovery from males was 101.0 ± 4.3% (urine 51.3 ± 9.2%, feces 48.9 ± 6.7%) with a mean total of 0.04 ± 0.02% remaining in the body. The corresponding recovery in females was 93.8 ± 8.6% (urine 39.6 ± 16.3%, feces 53.5 ± 7.8%) with 0.13 ± 0.13% remaining in the body. The concentration of radioactivity in the organs and tissues ranged from "not detectable" to about 11 ppm in the fat.

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
The test substance is moderately metabolized (~ 50%) when administered orally to rats at a low- dose level (10 mg/kg), both with and without preconditioning, and at a high-dose level (1000 mg/kg). An overall similarity of male and female metabolism of the test substance was demonstrated. Two major metabolites were identified by LC/MS as the N-Demethyl and the O-Deethyl metabolite. A minor metabolite, which was found consistently in all samples analyzed, was identified as the Free Acid. A dose-dependent metabolism was observed. At the low-dose level, the N-Demethyl metabolite was the major metabolite in urine; whereas at the high-dose level, the O-Deethyl metabolite was the predominant metabolite in the urine.

Applicant's summary and conclusion

Conclusions:
Four groups of male and female rats were administered single oral gavage doses of the test substance (Group A was administered 10 mg/kg of the 14C-triazine labeled moiety without preconditioning), Group B was administered 10 mg/kg of the 14C-triazine labeled moiety with preconditioning, Group C was administered 1000 mg/kg of the 14C-triazine labeled moiety without preconditioning, and Group D was administered 1000 mg/kg of the 14C-phenyl labeled moiety without preconditioning.

The test substance is moderately metabolized (~ 50%) when administered orally to rats at a low- dose level (10 mg/kg), both with and without preconditioning, and at a high-dose level (1000 mg/kg). An overall similarity of male and female metabolism of the test substance was demonstrated. Two major metabolites were identified by LC/MS as the N-Demethyl and the O-Deethyl metabolite. A minor metabolite, which was found consistently in all samples analyzed, was identified as the Free Acid. A dose-dependent metabolism was observed. At the low-dose level, the N-Demethyl metabolite was the major metabolite in urine; whereas at the high-dose level, the O-Deethyl metabolite was the predominant metabolite in the urine.

For the low-dose groups (Groups A and B), greater than 90% of the dose was excreted within 2 days. For Group A without preconditiong, 57-59% was excreted in the urine with about 40% in the feces. The concentration of radioactivity in all organs and tissues was below 0.1 ppm. For the high-dose groups (Groups C and D), greater than 80-90% of the dose was excreted within 3 days. Males administered either the triazine or phenyl-labeled moieties, excreted similar amounts in the urine and feces while in the females administered the 14C-triazine labeled moiety, 52% of the radioactivity was found in the urine and 42% in the feces and for the females administered the phenyl-labeled moiety, 40% of the radioactivity was found in the urine and 50% in the feces. The concentration of radioactivity in the organs and tissues in Group C ranged from "not detectable" to about 8.8 ppm in the kidneys and in Group D, the concentration of radioactivity in the organs and tissues ranged from "not detectable" to about 11 ppm in the fat.
Executive summary:

Four groups of male and female rats were administered single oral gavage doses of the test substance (Group A was administered 10 mg/kg of the 14C-triazine labeled moiety without preconditioning), Group B was administered 10 mg/kg of the 14C-triazine labeled moiety with preconditioning, Group C was administered 1000 mg/kg of the 14C-triazine labeled moiety without preconditioning, and Group D was administered 1000 mg/kg of the 14C-phenyl labeled moiety without preconditioning.

All Group A animals excreted > 90% of the administered radioactivity after two days. The mean total recovery from males was 100.0 ± 4.7% (urine 59.3 ± 4.1%, feces 40.3 ± 5.8%) with a mean residual level of radioactivity in the body of 0.08 ± 0.04%. The corresponding recovery in females was 97.5 ± 5.3% (urine 57.3 ± 1.2%, feces 39.9 ± 5.9%) with 0.08 ± 0.03% remaining in the body. The concentration of radioactivity in all organs and tissues was below 0.1 ppm.

 

All Group B animals excreted> 90% of the administered radioactivity after two days. The mean total recovery from males was 105.9 ± 3.1% (urine 44.5 ± 3.2%, feces 61.1 ± 5.6%) with a mean residual level of radioactivity in the body of 0.05 ± 0.01%. The corresponding recovery in females was 104.0 ± 1.7% (urine 50.5 ± 2.7%, feces 53.1 ± 1.5%) with 0.07 ± 0.01% remaining in the body. The concentration of radioactivity in all organs and tissues was below 0.1 ppm.

 

All Group C animals excreted > 90% of the administered radioactivity after three days. All surviving female rats excreted > 80% of the administered radioactivity after three days. The mean total recovery from males was 98.8 ± 5.7% (urine 49.3 ± 5.5%, feces 48.9 ± 4.5%) with a mean total of 0.12 ± 0.07% remaining in the body. The corresponding recovery in females was 95.5 ± 2.2% (urine 52.5 ± 5.0%, feces 42.3 ± 7.1%) with 0.12 ± 0.01% remaining in the body. The concentration of radioactivity in the organs and tissues ranged from "not detectable" to about 8.8 ppm in the kidneys in rat CM2.

 

All Group D animals excreted > 80% of the administered radioactivity after three days. The mean total recovery from males was 101.0 ± 4.3% (urine 51.3 ± 9.2%, feces 48.9 ± 6.7%) with a mean total of 0.04 ± 0.02% remaining in the body. The corresponding recovery in females was 93.8 ± 8.6% (urine 39.6 ± 16.3%, feces 53.5 ± 7.8%) with 0.13 ± 0.13% remaining in the body. The concentration of radioactivity in the organs and tissues ranged from "not detectable" to about 11 ppm in the fat in rat DF5.

The test substance is moderately metabolized (~ 50%) when administered orally to rats at a low- dose level (10 mg/kg), both with and without preconditioning, and at a high-dose level (1000 mg/kg). An overall similarity of male and female metabolism of the test substance was demonstrated. Two major metabolites were identified by LC/MS as the N-Demethyl and the O-Deethyl metabolite. A minor metabolite, which was found consistently in all samples analyzed, was identified as the Free Acid. A dose-dependent metabolism was observed. At the low-dose level, the N-Demethyl metabolite was the major metabolite in urine; whereas at the high-dose level, the O-Deethyl metabolite was the predominant metabolite in the urine.