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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well documented study conducted in compliance with GLP standards

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1995
Report Date:
1995

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 417 (Toxicokinetics)
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Source (14C): Hoffman-La Roche, New Jersey, USA
- Batch No.(14C): 19154-100-15
- Source (non-radioactive): Givaudan Corporation, Clifton, N.J., USA.
- Batch No. (non-radioactive): 1001092
- Radiochemical purity: > 98 %
- Analytical purity of non-radioactive test substance: not determined
Radiolabelling:
yes
Remarks:
14C

Test animals

Species:
rat
Strain:
other: Wistar derived RORO ( Ibm:RORO (SPF)) albino rats
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Institut fuer biologisch-medizinische Forschung, Fuellindsorf, Switzerland
- Age at study initiation: 5-7 weeks
- Weight at study initiation: 207 ± 6 g
- Individual metabolism cages: yes
- Diet: ad libitum (LAD1, Special Diet Services, Manea, UK, Batches 6562 and 6882)
- Water: ad libitum (tap water)
- Acclimation period: 7-13 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 2
- Humidity (%): 50 ± 10
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: rapeseed oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The dosing solutions were prepared the day prior to dose administration. To prepare the doses 25 and 100 mg/kg, repurified 14C BMHCA (22.2 and 25.3 mg, respectively) was mixed with non radioactive BMHCA (17.1 and 135.6 mg, respectively) and rapeseed oil (14.1 and 14.3 g, repectively) to give solutions containing 2.8 and 11.2 mg BMHCA/g formulation

- Administration volume: 2 ml
Duration and frequency of treatment / exposure:
single administration
Doses / concentrations
Remarks:
Doses / Concentrations:
25 and 100 mg/kg bw
No. of animals per sex per dose:
4
Control animals:
no
Details on study design:
TREATMENT OF ANIMALS:
- Fasting: Yes, overnight before application and for 2 hours after dose administration


Details on dosing and sampling:
PHARMACOKINETIC STUDY
- Tissues and body fluids sampled: blood (ca. 0.5 ml in to heparized tubes), plasma (generated after centrifugation of blood 14,000g)
- Time and frequency of sampling: prior to oral adminstration and at 0.5, 1, 2, 4, 6, 8, 24 and 48 h afterwards.
- Storage of samples: at -20°C until analysis was performed


Results and discussion

Toxicokinetic / pharmacokinetic studies

Toxicokinetic parameters
Toxicokinetic parameters:
other: see Table below

Metabolite characterisation studies

Metabolites identified:
not measured

Any other information on results incl. tables

Table 1: Pharmacokinetic variables of radioactivity in plasma after single dose administration of 14C BMHCA to rats

Dose administered

C max (µg equivalents/ml)

T max (h)

AUC 0-48 (µg.h/ml)

T1/2 (h)

25 mg/kg bw

14.3 ± 6.4

3.5 ± 1.9

122

8*

100 mg/kg bw

52.0 ± 15.3

1.8 ± 0.5

937

9.8**

Tmax und Cmax represent the mean of Tmax and Cmax observed for single animals. AUC was estimated up to the last time at which concentrations were above the quantification limit by the linear trapezoidal rule.

* Calculated from the log linear plots of 2 animals only because a linear terminal elimination phase could not be identified for the other two animals

** Calculated from the log linear plots of 1 animal only because a linear terminal elimination phase could not be identified for the other 3 animals

Table 2: Mean Plasma concentrations of radioactivity in rats following single doses of 14C BMHCA 25 and 100 mg/kg bw in rapeseed oil

Sample collection time (h)

25 mg/kg bw

100 mg/ kg bw

µg equivalents/ml

0.5

6.1 ± 2.2

33.9 ± 12.4

1

8.7 ± 4.3

46.9 ± 16.7

2

13.7 ± 7.3

49.5 ± 12.1

4

9.0 ± 5.1

41.6 ± 22.5

6

6.2 ± 4.1

43.5 ± 15.9

8

4.3 ± 3.4

27.4 ± 13.9

24

1.5 ± 0.5

22.6 ± 7.2

48

0.3 ± 0.03

2.8 ± 0.9

Applicant's summary and conclusion