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Basic toxicokinetics

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basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
no data
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Full details are not available, but the general test conditions are acceptable for the assessment.

Data source

Reference Type:
A study of the pharmacokinetics of 4-hydroxyanisole
Holden JL, Dewey DL, Riley PA
Bibliographic source:
Hydroxyanisole: Recent Adv Anti-Melanoma Ther (1984), 213-220. Editor(s): Riley, PA. Publisher: IRL, Oxford, UK

Materials and methods

Objective of study:
Test guideline
no guideline followed
Principles of method if other than guideline:
Test substance in 0.9% saline were injected by intraperitoneal (ip.) and intraveinous (iv.) into the tail vein in a volume of 10 mL/kg bw, of male and female mice. The mice were treated with saline solution for control group. Blood samples were collected by cardiac puncture. Concentration of the TS in plasma is measured by high pressure liquid
Urines and faeces are collected 24 and 48 hours after administration of radiolabelled TS, and analysed by scintillation counting.
GLP compliance:

Test material

Constituent 1
Reference substance name:
4-OHA (4-hydroxyanisole)
4-OHA (4-hydroxyanisole)
Constituent 2
Chemical structure
Reference substance name:
EC Number:
EC Name:
Cas Number:
Molecular formula:
Details on test material:
Name of test material: 4-OHA (4-hydroxyanisole), supplied by Koch-Light Ltd (Colnbrooks Bucks, England)
Substance type: data not available
physical state : data not available
Analytical purity: data not available
impurities: data not available
Composition of the test material: not applicable
Purity test date: data not available
lot/batch No: data not available
expiration date of the lot/batch: data not available
Radiolabelling: yes: 3H 4-OHA
radiochemical purity: data not available
specific activity: 100 µCi/mg
locations of the label: data not available
expiration data of radiochemical substance: data not available
stability under test conditions: data not available
storage condition of test material: data not available
3H 4-OHA

Test animals

Details on test animals or test system and environmental conditions:
- Species: mouse
- Strain: CBA
- Sex: male/female
- Source: Gray Laboratory of Cancer Research (UK)
- Age at study initiation: data not available
- Weight at study initiation: 30-35 g (males), 25 g (females)
- Fasting period before study: data not available
- Housing: data not available
- Individual metabolism cages: data not available
- Diet: data not available
- Water: data not available
- Acclimation period: data not available

ENVIRONMENTAL CONDITIONS (temperature, humidity, air changes, photoperiod): data not available

IN-LIFE DATES: data not available

Administration / exposure

Route of administration:
other: i.p. and i.v.
physiological saline
Duration and frequency of treatment / exposure:
single application
Doses / concentrations
Doses / Concentrations:
Males: 25, 50, 100, 150, 200 mg/kg bw
Females: 25, 100, 150, 200, 300 mg/kg bw
(doses higher than 150 mg/kg bw by iv. administration were not studied, as they approach the acute LD50)
No. of animals per sex per dose / concentration:
no data
Control animals:
not specified
Positive control reference chemical:
Details on study design:
- Dose selection rationale: no data
- Rationale for animal assignment (if not random): no data
Details on dosing and sampling:
- Tissues and body fluids sampled (delete / add / specify): urine, faeces, plasma
- Time and frequency of sampling: at 24 and 48h after administration (urine and faeces), 10 times up to 45 minutes (males) or 90 minutes (females)
(plasma concentration)
no data

Results and discussion

Toxicokinetic / pharmacokinetic studies

Toxicokinetic parametersopen allclose all
Toxicokinetic parameters:
half-life 1st:
Toxicokinetic parameters:
half-life 2nd:
Toxicokinetic parameters:
half-life 3rd:

Metabolite characterisation studies

Metabolites identified:
not measured

Any other information on results incl. tables

* Male mice:
In the case of ip. injection, the plot of log10 plasma concentration vs time is linear at all dose levels.
When mice are given i.v. injection, the rate of elimination is linear at 25 and 50 mg/kg bw, but at the higher doses the initial rate of 

elimination decreases with dose.

* Female mice:
Above 25 mg/kg bw the initial elimination rate decreases with increasing dose and the rate of elimination is not linear.

T(1/2) increases with increasing doses.
        Dose (mg/kg bw)     T(1/2) in minutes
iv.        25                        3.9 +/- 0.23
iv.       150                        5.9 +/- 0.3
ip.        25                        5.1 +/- 0.52
ip.       150                        7.8 +/- 0.66

- Parameter:  Half-life 1st:
AUC: Area under the plasma (blood) level vs. time curve from zero up to a certain measured time point (specify the time);

After ip. injection, free 4 OHA was not detected in either urine or faeces; 96.54% of the radioactivity was accounted for 48 hours. 

86% was present in the urine.

% dose excreted after ip. injection of 200 mg/kg 1 µCi 3H 4-OHA into male  CBA mice:
Time                Urinary                        Faecal
(hrs)                radioactivity                radioactivity
24                81.3 +/- 19.6                6.2 +/- 0.15
48                4.7 +/- 1.8                4.2 +/- 2.8

Applicant's summary and conclusion

No bioaccumulation potential based on study results
Executive summary:

In a metabolism study, 4-hydroxyanisole was administered to CBA mice, in a single dose application by iv. or ip. administration:

males: 25, 50, 100, 150, 200 mg/kg bw

females: 25, 100, 150, 200, 300 mg/kg bw

The results concerning the effect of dose on the pharmacokinetics of 4-OHA indicate saturable non-linear behaviour at high doses in male and female mice. The female mice were younger than the males and no direct comparison can be made between the sexes. In the case of iv.

delivery of the substance to the male mice, non linear elimination was seen at 100 and 150 mg/kg bw. Clearance of 4-OHA is most probably by metabolism.

The results concerning excretion of radio label indicate that free 4-OHA is not detected in either urine or faeces; 96.54% of the radioactivity were accounted for by 48 hours: 86% were present in the urine.

The bioavailability of 4-OHA given by ip. injection was 104%. There was no significant difference between the half-life of the substance given by ip. and iv. administration.

The volume of distribution indicates that 4-OHA is distributed throughout the total body water, and intracellular concentrations would not be expected to vary greatly from gross measurments. This study has shown that 4-OHA is rapidly absorbed into the circulation.

This metabolism study in the mouse is classified acceptable and does not satisfy the guideline requirement for a metabolism study (OPPTS 870.7485); OECD 417 in mouse.