4-methylbenzophenone

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Remarks:

study restricted to plasma kinetics

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

2006

Materials and methods

Objective of study:

absorption

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

Deviations:

yes

Principles of method if other than guideline:

Blood plasma kinetics were determined after intravenous administartion. Concentrations of benzophenone were determined in plasma at timepoints up to 24 hours after dosing.

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Benzophenone

EC Number:

204-337-6

EC Name:

Benzophenone

Cas Number:

119-61-9

Molecular formula:

C13H10O

IUPAC Name:

benzophenone

Details on test material:

- Name of test material (as cited in study report): Benzophenone
- Substance type: aryl ketone
- Physical state: crystals
- Analytical purity: >99% (by capillary gas chromatography)
- Identity: characterized by infrared, ultraviolet/visible, nuclear magnetic resonance, and mass spectroscopy
- Lot/batch No.: 10803KG

Radiolabelling:

no

Test animals

Species:

mouse

Strain:

B6C3F1

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Taconic (Germantown, NY)
- Age at study initiation:10 to 11 weeks old at the time of the studies
- Fasting period before study: no data
- Housing: individually in polycarbonate cages on Ab-Sorb-Dri® cage litter
- Individual metabolism cages:no
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature: 69° to 75° F
- Humidity (%): 40% to 70%,
- Photoperiod (12 hrs dark / 12 hrs light):

Administration / exposure

Route of administration:

intravenous

Vehicle:

other: Emulphor®:ethanol:deionized distilled water, 10:10:80.

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: Dose formulations for intravenous injection were prepared in Emulphor®:ethanol:deionized distilled water, 10:10:80.

VEHICLE
- Justification for use and choice of vehicle (if other than water): Benzophenone had a good solubility in the vehicle Emulphor®:ethanol:deionized distilled water, 10:10:80.
- Amount of vehicle : 2 mL/kg bw


HOMOGENEITY AND STABILITY OF TEST MATERIAL:
For analysis of benzophenone concentrations, 20 μL of a 0.508 mg/mL solution of butyrophenone in acetonitrile was added as an internal standard to a 0.3 mL aliquot of thawed plasma. The samples were mixed and allowed to stand at room temperature for approximately 15 minutes. A sodium chloride solution (0.1 mL of 330 mg sodium chloride/mL water) was added and mixed, followed by the addition of 0.4 mL acetonitrile with additional mixing. After centrifugation, the supernatant was analyzed using a validated high performance liquid chromatography (HPLC) method utilizing a Waters 845 HPLC (Waters Corp., Milford, MA). A Zorbax C8 column (25 cm × 4.6 mm ID) was eluted with acetonitrile:water (1:1) at 1 mL per minute. Ultraviolet detection was used at 254 nm.

Duration and frequency of treatment / exposure:

Single intravenous administration

Doses / concentrations

Remarks:

Doses / Concentrations:
nominal dose of 15 mg

No. of animals per sex per dose / concentration:

One male and one female mouse per time point.

Control animals:

no

Positive control reference chemical:

n.a.

Details on study design:

- Dose selection rationale:
The toxicokinetic study was conducted to define the oral bioavailability of benzophenone after intravenous administartion and to establish a dose range over which plasma kinetics are linear

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption)
- Tissues and body fluids sampled: plasma
- Time and frequency of sampling:
Intravenous nominal dose 15 mg/kg bw
4, 7, 10, 15, 20, 30, 45, 60, 75, 90, 120, 150, 180 minutes after dosing

ANYLYSIS
For analysis of benzophenone concentrations, 20 μL of a 0.508 mg/mL solution of butyrophenone in acetonitrile was added as an internal standard to a 0.3 mL aliquot of thawed plasma. The samples were mixed and allowed to stand at room temperature for approximately 15 minutes. A sodium chloride solution (0.1 mL of 330 mg sodium chloride/mL water) was added and mixed, followed by the addition of 0.4 mL acetonitrile with additional mixing.
After centrifugation, the supernatant was analyzed using a validated high performance liquid chromatography (HPLC) method utilizing a Waters 845 HPLC.

Statistics:

Plasma concentration data were analyzed by noncompartmental modeling techniques using Models 200 and 201 WinNonlin®, Version 1.0 (Scientific Consulting Inc., Cary, NC). These data were also analyzed by compartmental models (WinNonlin®) written to simultaneously solve gavage and intravenous data sets.

Results and discussion

Main ADME results

Type:

absorption

Results:

For males, half-life was 26.7 min and for females 54.0 min after administration

Toxicokinetic / pharmacokinetic studies

Details on absorption:

After intravenous injection of a nominal dose of 15 mg/kg to male and female mice, benzophenone was initially rapidly cleared from plasma, followed by a slower elimination phase. As with rats, fluctuations in mean plasma benzophenone concentration were observed in mice and were most likely due to enterohepatic recirculation.

Details on distribution in tissues:

not determined

Details on excretion:

If benzophenone does undergo enterohepatic recirculation, none of the known metabolites are good candidates for the source of recirculated benzophenone. It may be explained by reduction to benzhydrol, conjugate formation, biliary excretion, deconjugation by gut flora, reabsorption, and oxidation to benzophenone.

Toxicokinetic parameters

Toxicokinetic parameters 1

Test no.:

#1

Toxicokinetic parameters:

AUC: AUC in µg min/mL: males 140; females 137

Toxicokinetic parameters 2

Test no.:

#1

Toxicokinetic parameters:

half-life 1st: males: t½ elim: 26.7 min; females 45.0 min

Toxicokinetic parameters 3

Test no.:

#1

Toxicokinetic parameters:

other: elimination rate constant males: 0.0259: females 0.0128

Metabolite characterisation studies

Metabolites identified:

not measured

Any other information on results incl. tables

For further details refer to the Tables 1 and 2 under the attached background information section

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
After intravenous injection of a nominal dose of 15 mg/kg to male and female mice, benzophenone was initially rapidly cleared from plasma, followed by a slower elimination phase. As with rats, fluctuations in mean plasma benzophenone concentration were observed in mice and were most likely due to enterohepatic recirculation. In mice, the AUCs were supralinear with respect to dose; as the dose was increased, the AUC/dose also increased. In rats, this parameter was more or less constant over the dose range. The nonlinearity in mice may be due to a first-pass effect of liver metabolism restricting the amount of benzophenone that gets into the general circulation. As the dose is increased, the first-pass metabolism becomes saturated. Mice appear to metabolize benzophenone more rapidly than rats; the doses are higher for mice, yet the half-lives and AUCs are smaller. As with rats, there were no obvious sex-related differences in noncompartmental pharmacokinetic parameter estimates for mice.

Executive summary:

A single dose of 15 mg/kg bw. of benzophenone were administered intravenously to male and female B6C3F1 mice. Concentrations of benzophenone were determined in plasma at various timepoints up to 24 hours after dosing.

Bioavailability of benzophenone in male and female mice is 50% or less. AUC/Dose, kelim, and t½ elim are dose dependent in mice, with similar dependency for males and females. There was a great deal of fluctuation in plasma benzophenone concentrations at later time points, with clear secondary and even tertiary increases in concentration at all doses tested, regardless of the route of administration. The nonlinearity in mice may be due to a first-pass effect of liver metabolism restricting the amount of benzophenone that gets into the general circulation.