Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2016
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Cross-reference
Reason / purpose:
reference to same study

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
2016
Report Date:
2016
Reference Type:
study report
Title:
Unnamed
Year:
2016
Report Date:
2016

Materials and methods

Objective of study:
bioaccessibility
Test guideline
Qualifier:
according to
Guideline:
other: OECD 407
Version / remarks:
examination of plasma, liver, kidney and spleenic tissue for determination of bioavailability after 28 days oral administration at limit dose
GLP compliance:
yes (incl. certificate)

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid
Details on test material:
CAS No.: 72102-84-2

Test animals

Species:
rat
Strain:
Wistar
Details on species / strain selection:
Reason for the selection: The rat is a frequently used laboratory animal, and there is comprehensive experience with this animal species. Moreover, the rat has been proposed as a suitable animal species by the OECD and the EPA for this type of study.
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services GmbH, Sulzfeld, Germany
- Age at study initiation: 33 +/- 1 days
- Fasting period before study: over night
- Housing: 5 per cage
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 7 days

DETAILS OF FOOD AND WATER QUALITY:

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70%
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
The test substance was applied as a suspension. To prepare this suspension, the appropriate amount of test substance was weighed out depending on the desired concentration. Then, drinking water was filled up to the desired volume, subsequently mixed by a magnetic stirrer. During administration of the test substance, preparations were kept homogeneous by stirring with a magnetic stirrer. The test-substance preparations were produced once a week.
Duration and frequency of treatment / exposure:
28 days, daily
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Positive control:
not applicable
Details on dosing and sampling:
BIOAVAILABILITY
The plasma samples taken on study day 21 as well as all fresh tissue samples (liver, kidney, spleen) taken on the day of necropsy were transferred to the Analytical Chemistry Laboratory of Experimental Toxicology and Ecology of BASF SE, 67056 Ludwigshafen, Germany, and frozen at about -80°C until analysis for potential analytical determination of the parent compound in these tissued.
The analyses were carried out as a separate study at Analytical Biochemical Laboratory (ABL), Assen, The Netherlands, under the responsibility of a Study Director of this test facility.

Results and discussion

Bioaccessibility

Bioaccessibility testing results:
The test item and internal standard were found to be stable during sample collection, sample handling, sample processing, and after repeated freezing and thawing. In addition, the method shows no analytical carry-over.
 
No residues of the applied test substance could be detected in rat plasma samples. However, small amounts could be detected in
·        liver tissue of 4 individual animals ranging from 0.94 to 11.1 ng/mg tissue,
·        spleen tissue of 3 individual animals ranging from 0.98 to 7.91 ng/mg tissue,
·        kidney tissue of 6 individual animals ranging from 1.23 to 15.3 ng/mg tissue.
 
Thus, it could be concluded that the test item is bioavailable.

Any other information on results incl. tables

Orange discolored feces were observed in all animals of test group 1 (1000 mg/kg bw/d) from study day 1 onwards until the end of the administration period. No other findings occurred in animals of test groups 1 (1000 mg/kg bw/d).

Applicant's summary and conclusion

Executive summary:

In the course of another sub-acute study (OECD 407, GLP), the test itemwas administered orally by gavage to groups of 10 male Wistar rats at dose levels of 0 mg/kg body weight/day (mg/kg bw/d, test group 0) and 1000 mg/kg bw/d (test group 1) over a period of 4 weeks. The study was performed to determine the bioavailability of the test substance after oral administration at limit dose.

Clinical examination revealed orange discolored feces in all animals from study day 1 onwards.

Regardingpathology, an orange discoloration of contents in the glandular stomach, jejunum and cecum was observed. The discoloration was regarded to be treatment-related and corresponded to the color of the test substance. All other findings occurred either individually or were biologically equally distributed over control and treatment group. They were considered to be incidental or spontaneous in origin and without any relation to treatment. The increase in absolute and relative liver weight (as observed in a previous study) could not be confirmed. Thus, under the conditions of the study the no observed adverse effect level (NOAEL) is below 1000 mg/kg bw/d in male Wistar rats. Trace amounts of the applied substance could be detected in liver, spleen and kidney tissue of individual animals ranging from 0.94 - 15.3 ng/mg tissue. No test item could be detected in rat plasma samples. Thus, it could be concluded that the test item was bioavailable.