Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2012-2013
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP-study in accordance with OECD guideline

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Report Date:
2013

Materials and methods

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

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder
Details on test material:
Batch No.: 110526S
Expiry date: 26.05.2013
Purity: 99.24% (taken as 100%)
Instructions for storage: Room temperature, tighly closed container, cool, dry, only in original container
State of material: crystalline, damp, not dusty
Colour: white
Odour: odourless

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
Strain: Rat Wistar SPF Charles River Germany D- 97633 Sulzfeld- Facility,
Species: Rattus norvegicus ssp.alba
- Age at study initiation:8-9 weeks
- Weight at study initiation:180g-230g

Environmental conditions were monitored and recorded continuously over the study. The temperature in the animal room was in-between 20°C and 24°C and the relative humidity was in-between 40% and 70% . A 12/12h light/dark cycle was set.

During the study, the study rats were housed in TECHNIPLAST cages Type 2145 F. The cages measured 480 x 265x 210 mm (floor area 940 cm2). As bedding, sterilized sawdust was used. Two and three animals were housed per cage, respectively.

Diet and water:
For feeding, a standard pelleted diet from Bonagro a.s. CZ10174, Czech Republic was used.
Drinking water from the public water supply was offered in water bottels ad libitum. Water bottels were changed daily.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
administration volume: 10 ml/kg bw.
maximum administration volume: 100 ml/kg bw.
Duration and frequency of treatment / exposure:
single administration
Doses / concentrations
Remarks:
Doses / Concentrations:
800 and 1600 mg/kg bw
No. of animals per sex per dose:

Group Number of animals Substance Concentration Time of sample taking Volume (ml)
1 Blood (1m;1f)
Serum (4 m; 4 f)
Urine (4 m; 4 f) ASC plus 1600mg.kg-1 3h 10ml/kg bw.
2 Blood (1m;1f)
Serum (4 m; 4 f)
Urine (4 m; 4 f) ASC plus 1600mg.kg-1 6h 10ml/kg bw.
3 Blood (1m;1f)
Serum (4 m; 4 f)
Urine (4 m; 4 f) ASC plus 1600mg.kg-1 12h 10ml/kg bw.
4 Blood (1m;1f)
Serum (4 m; 4 f)
Urine (4 m; 4 f) ASC plus 1600mg.kg-1 24h 10ml/kg b.w.
5 Urine (3 m; 3 f)
Faeces (3 m; 3 f) ASC plus 1600mg.kg-1 3h, 6h, 12h, 24h, 168 h 10ml/kg bw.
6 Urine (3 m; 3 f)
Faeces (3 m; 3 f) ASC plus 800mg.kg-1 3h, 6h, 12h, 24h, 168 h 10ml/kg b.w.
Control animals:
no
Positive control:
no
Details on dosing and sampling:
- Method for identification: HPLC with UV-VIS detector (column: HAMILTON PRP-1,250x4.1 mm 5µm)
Relevant parameters: Limits of detection, Limit of quantification, Uncertainties, Linearity, Precision/Repeatability.
Statistics:
mean, standard deviation, recovery

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Group Name of animals Laboratory number Dosage of ASC plus in mg.kg-1 Time of sample taking Assay of ASC plus in mg.kg-1
1 ♂1-4 13-001876 1600 3h 18.6
2 ♂5-8 13-001874 1600 6h 1.28
3 ♂9-12 13-001872 1600 12h 0.90
4 ♂13-16 13-001870 1600 24h <0.10

Group Name of animals Laboratorynumber Dosage of ASC plus in mg.kg-1 Time of sample taking Assay of ASC plus in mg.kg-1
1 ♀17-20 13-001877 1600 3h 11.8
2 ♀21-24 13-001875 1600 6h 0.22
3 ♀25-28 13-001873 1600 12h 0.82
4 ♀29-32 13-001871 1600 24h <0.10

Annotation: the samples were weighted, therefore the results are given as mg x kg-1.
Details on excretion:
The concentrations of ASC plus in the feces are relatively low. This could be a result of either a rapid degradation in the intestine or a nearly comlete resorption into the body.
The urine concentrations of ASC plus show that relevant amounts of the test article are resorped into the body and excreted via urine in unchanged form.
As only samples and not the complete excretion of urine or feces were taken, a mass bilance from the present data is not possible.
The data from the urine and feces samples are not very consistent. Due to the sampling conditions a cross-contamination cannot be completely excluded. As consequence from the physiological processes forming feces and urine the highest concentrations occur 6 to 12 hours after administration. Even after 168 h traces of the test article can be found.

Metabolite characterisation studies

Metabolites identified:
not measured
Details on metabolites:
no data

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
An oral dosage of 1600 mg ASC plus/kg bw was administered to male and female Wistar rats by stomach tube in 10 ml water/kg bw. Blood, serum, urine and feces were analyzed 3, 6, 12 and 24 hours after administration. Additionally examples of urine and feces were taken 168 hours after administration and 3, 6, 12, 24 and 168 h after oral administration of 800 mg ASC plus/kg bw..The most relevant data are the results of the serum analysises.
The serum levels of ASC plus showed a maximum 3 h after administration. Within 24 hours these levels fall beneath the limit of quantitation. Therefore ASC plus has no potential for bioaccumulation.
The data from the urine and the feces are not very consistent. The concentrations of ASC plus showed that relevant amounts of the test article are resorbed into the body and excreted via urine in unchanged form.
Executive summary:

It was possible to establish an analytical method for the determination of ASC Plus in biological fluids.

An oral dosage of 1600 mg ASC plus/kg bw. was administered to male and female Wistar rats by stomach tube in 10 ml water/kg bw. Blood, serum, urine and feces were analyzed 3, 6, 12 and 24 hours after administration. Additionally examples of urine and feces were taken 168 hours after administration and 3, 6, 12, 24 and 168 h after a oral administration of 800 mg ASC plus/kg bw. The most relevant data are the results of the serum analysis.

The serum levels of ASC plus showed a maximum 3 h after administration. Within 24 hours these levels fall beneath the limit of quantitation.

The concentrations of ASC plus in the feces were relatively low. The urine concentrations of ASC plus showed that relevant amounts of the test article are excreted via urine as unchanged substance.

From the present data one can assume that ASC plus is resorped easily after oral administration. Relevant amounts of an oral dosage are excreted unchanged via urine.