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Diss Factsheets

Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: No guideline was followed but well documented scientifically defensible approach was used to conduct the study.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
2006

Materials and methods

Principles of method if other than guideline:
A single dose of benzophenone was administered by intravenous injection or gavage to male and female F344/N rats. Concentrations of benzophenone were determined in plasma at timepoints up to 24 hours after dosing. The results were analyzed to establish basic toxicokinetic parameters.
GLP compliance:
yes

Test material

Constituent 1
Chemical structure
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
- Source: Aldrich Chemical Company
- Lot. no.: 10803KG
- Purity: > 99%

Test animals

Species:
rat
Strain:
Fischer 344
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
- Housing: Individually in polycarbonate cages
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Quarentined period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24 ºC (69-75° F)
- Humidity (%): 40-70%,
- Photoperiod (hrs dark / hrs light): 12:12 hour light/dark cycle

Administration / exposure

Route of administration:
other: intravenous and oral (gavage)
Details on exposure:
Dosing volume was 2 mL/kg by intravenous injection or 5 mL/kg by gavage
Duration and frequency of treatment / exposure:
A single intravenous injection or a single gavage administration.
Doses / concentrations
Remarks:
Doses / Concentrations:
Intravenous: 2.5 mg/kg body weight
Oral: 2.5, 5, or 10 mg/kg.
No. of animals per sex per dose / concentration:
Five rats per sex and per dose.
Details on dosing and sampling:
At specified times after dosing, rats were anesthetized with a mixture of carbon dioxide and oxygen. Blood samples were collected by retroorbital puncture from five male and five female per timepoint. Generally, two samples were taken from each rat (more than 2 hours apart), one from each eye. The samples were collected into heparinized microhematocrit tubes and the plasma was separated by centrifugation at 1000 × g for 10 minutes and then stored frozen until analysis using a validated method.
The times of blood sample collection after administration was as follows:
Intravenous: 4, 7, 10, 15, 30, 60, 90, 120, 180, 240, 360, 480, 960 minutes.
Oral: 2.5, 5, 7.5, 10, 15, 30, 60, 120, 180, 360, 480, 600, 960, 1440 minutes (the last sample only at 5 and 10 mg/kg bw groups).
Statistics:
Plasma concentration data were analyzed by noncompartmental modeling techniques

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
There was a great deal of fluctuation in mean plasma benzophenone concentrations at later time points, with secondary increases observed after initial decreases at most of the doses tested, regardless of the route of administration. This variation in concentration in the terminal portion of the curve resulted in extrapolation of up to 31% of the area from the last observed time point to infinity making the accuracy of the AUC and bioavailability estimates uncertain.
Details on excretion:
Estimates of elimination rate constants and half-lives for males were similar for the intravenous and low gavage doses, with slight decreases in elimination rate constant and concomitant increases in half-lives at the two higher gavage doses. For female rats, estimates elimination rate constant and half-lives were similar for the three gavage doses. After intravenous administration to females elimination rate constants was slightly higher than after gavage administration, with a concomitant decrease in half-lives.
Toxicokinetic parametersopen allclose all
Test no.:
#1
Toxicokinetic parameters:
other: Elimination rate constant (see details below)
Test no.:
#2
Toxicokinetic parameters:
half-life 1st: (see details below)
Test no.:
#3
Toxicokinetic parameters:
AUC: (see details below)

Bioaccessibility (or Bioavailability)

Bioaccessibility (or Bioavailability) testing results:
Bioavailability after a gavage dose ranged from 1.05 to 1.39 in females, with an average value of 1.18.

Any other information on results incl. tables

 

Dose

K elim (min-1)

T ½ elim (min)

AUC (μgCmin/mL)

AUC/Dose

Bioavailability

Male

Intravenous

2.5

0.00260

268

51.9

21.1

--

Gavage

2.5

0.00280

245

32.7

17.4

0.824

Gavage

5

0.00120

594

95.6

24.9

1.18

Gavage

10

0.00140

506

208

26.7

1.27

Female

Intravenous

2.5

0.00280

247

51.6

20.6

--

Gavage

2.5

0.00120

567

53.8

28.6

1.39

Gavage

5

0.00180

395

86.8

22.7

1.10

Gavage

10

0.00140

499

166

21.6

1.05

K elim = elimination rate constant

T 1/2 elim = half-life

AUC = aera under the plasma concentration versus time curve

Applicant's summary and conclusion

Conclusions:
The plasma elimination half-life of benzophenone in rats was approximately 4 hours after intravenous injection and 8 hours after administration by gavage in corn oil.
Executive summary:

A single dose of benzophenone was administered by intravenous injection or gavage to male and female F344/N rats. Concentrations of benzophenone were determined in plasma at timepoints up to 24 hours after dosing. The results were analyzed to establish basic toxicokinetic parameters. Plasma concentrations of the parent compound were determined following oral and intravenous administration of benzophenone. The plasma concentration of benzophenone versus time plots showed secondary maxima, apparently due to enterohepatic circulation. The data were analyzed by noncompartmental modeling and indicated no consistent sex-related or exposure-related effects. There was a great deal of fluctuation in mean plasma benzophenone concentrations at later time points, with secondary increases observed after initial decreases at most of the doses tested, regardless of the route of administration. Estimates of elimination rate constants and half-lives for males were similar for the intravenous and low gavage doses, with slight decreases in elimination rate constant and concomitant increases in half-lives (k.elim ca. 0.00270/min; t1/2 ca. 255 min) at the two higher gavage doses. For female rats, estimates elimination rate constant and half-lives were similar for the three gavage doses (k.elim ca. 0.00280/min; t1/2 ca. 247 min) . After intravenous administration to females elimination rate constants was slightly higher than after gavage administration, with a concomitant decrease in half-lives. Bioavailability after a gavage dose ranged from 1.05 to 1.39 in females, with an average value of 1.18.