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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:
key study
Study period:
1987
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1987
Report Date:
1989

Materials and methods

Objective of study:
other: Absorption, distribution, metabolism and excretion
Test guideline
Qualifier:
according to
Guideline:
EPA OPP 85-1 (Metabolism and Pharmacokinetics)
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Type:
Constituent
Type:
Constituent
Type:
Constituent
Type:
Constituent
Type:
Constituent
Type:
Constituent
Details on test material:
This is formulation of 49.2% of the test substance in water.
Radiolabelling:
yes
Remarks:
14C-labelled test substance

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
Test animals:
- Source: Charles River
- Age at study initiation: 6 weeks
- Weight at study initiation: Average body weight: 268.6 g (male) and 167.0 g (female)

Administration / exposure

Details on exposure:
Preparation of dosing solutions:
Preliminary experiments: Oral gavage – single low dose
Experiment 1: Oral gavage – single low dose
Experiment 2: Dietary – repeated low dose
Experiment 3: Oral gavage – single high dose
Experiment 4: Intravenous


Vehicle:
Distilled water (Preliminary experiments and Experiments 1, 3 and 4)
Rodent diet/distilled water (Experiment 2)

Concentration in vehicle:
Preliminary experiments and Experiment 1: 1.0 mg/mL
Experiment 2: 100 ppm in diet for 14 d/1 mg/mL in water single oral dose
Experiment 3: 5.0 mg/mL
Experiment 4: 4 mg/mL


Homogeneicity and stability of the test material: Stable
Duration and frequency of treatment / exposure:
Preliminary experiments: Oral gavage – single low dose
Experiment 1: Oral gavage – single low dose
Experiment 2: Dietary – repeated low dose for 14 d
Experiment 3: Oral gavage – single high dose
Experiment 4: Intravenous
Doses / concentrations
Remarks:
Doses / Concentrations:
Preliminary experiments and Experiment 1: 10 mg/kg
Experiment 2: 100 ppm non-radiolabelled substance for 14 d, followed by 10 mg/kg radiolabelled.
Experiment 3: 50 mg/kg
Experiment 4: 10 mg/kg
No. of animals per sex per dose:
Preliminary experiments: 2 per sex per group (Total 8 animals)
Main experiments:5 per sex per group (Total 40 animals)
Control animals:
no
Details on dosing and sampling:
Pharmacokinetic study (Absorption, distribution, excretion):
- Tissues and body fluids sampled: urine, faeces, blood, plasma, cage washes
- Time and frequency of sampling: Urine, faeces and urine/feces separator washing samples were collected at the following time intervals: 0-4, 4-8, 8-12, 12-24, 24-36, 36-48, 48-72, 72-96, 96-120, 120-144 and 144-168 h.

Metabolite characterisation studies:
- Tissues, urine and faeces were collected and analysed for radioactivity and faeces were analysed by TLC, HPLC and MS for metabolites and parent compound.



Results and discussion

Preliminary studies:
A preliminary study had indicated that insignificant 14CO2 was generated.

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Percent Recovery:

Experiment 1:
Males: 5.77% urine; 98.61% faeces
Female: 6.88% urine; 91.20% faeces
Total Recovery: 104.54 ± 5.29% - males; 98.11 ± 3.25% females

Experiment 2:
Males: 4.76% urine; 95.12% faeces
Female: 5.80% urine; 97.22% faeces
Total Recovery: 100.19 ± 4.94% - males; 103.1 ± 5.18% females

Experiment 3:
Males: 7.75 % urine; 90.03% faeces
Female: 6.95% urine; 87.48% faeces
Total Recovery: 98.36 ± 2.42% - males; 94.58 ± 7.57% females

Experiment 4:
Males: 30.63% urine; 44.44% faeces
Female: 20.58% urine; 55.09% faeces
Total Recovery: 108.43 ± 5.56% - males; 111.45 ± 3.96% females

Less than 1% in tissues in all oral dosing experiments. Approximately 30-35% of the administered dose in tissues following i.v. dosing.
Details on distribution in tissues:
Residual 14C in tissues was negligible after administration of radiolabelled test substance by gavage both after single and repeated dosing, indicating low potential for bioaccumulation. After i.v. administration a higher amount of radioactivity (30−35%) was found as residue in the tissues.
Details on excretion:
About 6−8% of orally administered test substance is excreted in the urine whereas, 87−98% was found in the faeces. Since no data on bile duct-cannulated rats are available, it is not possible to conclude if this radioactivity accounts exclusively for unabsorbed test substance or not. However, the i.v. experiment showed that 20−30% was excreted in the urine and 44-55% in the faeces, suggesting that both the kidney and liver are capable of excreting test substance once absorbed and that absorption is higher than the % found in the urine after oral administration.

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
Over 50% of the faecal radioactivity was unchanged parent compound. Four major metabolites were identified, as oxidation products of the two decyl side chains to hydroxy and hydroxyketo derivatives. The only metabolism which occurred involved oxidation of the two decyl side chains to hydroxy and hydroxyketo derivatives. All were more polar and presumed less toxic than the parent compound. It is predicted that there is no major metabolite greater than 10% of the dosed radioactivity.

Applicant's summary and conclusion

Conclusions:
- Interpretation of results: no bioaccumulation potential based on study results
- Following oral administration, 14C-radiolabelled test substance was rapidly absorbed, although in very limited amount as indicated by the low blood levels attained starting from 15 min after dosing and peaking between 3 and 8 h. 87 - 99% of the orally administered 14C-radiolabelled test substance was excreted in the faeces and 5 - 8% was excreted in the urine. No bioaccumulation was noted. Test substance was found to be widely distributed in tissues following intravenous administration with approximately 45 - 55% in the faeces, 20 - 30% in the urine and 30 - 35% associated with the tissues. Further, four major metabolites were identified, formed via oxidation of the alkyl chain.
Executive summary:

A study was conducted to determine the basic toxicokinetics of the test substance according to EPA OPP 85-1, in compliance with GLP. Sprague-Dawley rats (10 animals per sex per group) were treated with radiolabelled test substance. The study was conducted in four experiments: a single low dose (10 mg/kg); a single high dose (50 mg/kg); a14-day repeated dietary exposure with non-radiolabelled test substance (100 ppm) and single low dose of radiolabelled (14C) test substance (10 mg/kg); and a single intravenous dose (10 mg/kg). Following the single doses or the last dietary dose, urine and faeces were collected for 7 days. Tissues, urine and faeces were collected and analysed for radioactivity and faeces were analysed by TLC, HPLC and MS for metabolites and parent compound. Following oral administration, radiolabelled test substance was rapidly absorbed, although in very limited amounts, consistent with its highly ionic nature. Residual 14C in tissues was negligible after administration by gavage both after single and repeated dosing, indicating low potential for bioaccumulation. After i.v. administration, a higher amount of radioactivity (30−35%) was found as residue in the tissues. Approximately6−8% of orally administered test substance was excreted in the urine whereas 87−98% was found in the faeces. Since no data on bile duct-cannulated rats are available, it was not possible to conclude if this radioactivity accounted exclusively for unabsorbed test substance or not. However, the i.v. experiment showed that 20−30% was excreted in urine and 44-55% in faeces, suggesting that both the kidney and liver were capable of excreting test substance once absorbed and that absorption was higher than the % found in the urine after oral administration. Less than 50% of the orally administered test substance was metabolised to side-chain oxidation products. In view of the limited absorption of the test substance, the four major metabolites identified may be at least have been partially formed in the gut of rats, apparently by microflora. No significant difference in metabolism between male and female rats or amongst dosing regimens was observed. Repeated dosing did not alter uptake, distribution or metabolism of the test substance (Selim, 1987).