Mequinol

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Concerning PMP toxicokinetics, only in vivo data on animals or in vitro data on human cells are available.

Absorption and distribution:

i.p. and i.v. route: After a single i.p. and i.v. administration in mice, PMP is rapidly absorbed into the circulation and is distributed throughout the total body water. The bioavailability of PMP given by i.p. injection is 104% (Holden et al., 1984).

 

Dermal route: in a in vitro test on human skin, the absorption rate of PMP through dermatomed human skin is relatively low and was found to be 0.33 ± 0.10mg/cm2/hr, giving a corresponding permeability constant of 9.39±3.10(x 10-3) cm/hr (Guerin et al., 2005).

 

Metabolism:

In rabbits, 24 hours after an oral single exposure (gavage), PMP is mainly excreted as its conjugates with glucuronic and sulphuric acid and an appreciable proportion of the dose was methylated to quinol (Bray et al., 1955).

 

Excretion:

 i.p. and i.v. route: In the case of i.v. delivery of PMP to the mice, non linear elimination was seen at above 25 mg/kg b.w. for females and at 100 and 150 mg/kg b.w for males. Clearance of PMP is most probably by metabolism. Indeed, the results concerning excretion of radiolabel indicate that free PMP is not detected in either urine or faeces. 96.5 % of the radioactivity were accounted for by 48 hours and 86% were present in the urine (Holden et al., 1984).

Discussion on bioaccumulation potential result:

Two metabolism studies are available with reliability 2 according to Klimisch criteria:

- In the first one (Holden et al. 1984), 4-hydroxyanisole (PMP) was administrated to mice in a single application by intraveinous injection or intraperitoneal route:

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 intraveinous 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 intraperitoneal injection was 104%. There was no significant difference between the half-life of the substance given intraperitoneal and intraveinous routes.

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.

- In the second one (Bray et al. 1955), PMP was administered to rabbits in single method of exposure: by gavage at dose of 0.7g per rabbit in water once. Although PMP is mainly excreted as conjugates of p-methoxyphenol an appreciable proportion of a dose is demethylated to quinol.

This metabolism study in the rabbit is classified acceptable and does not satisfy the guideline requirement for a metabolism study (OPPTS 870.7485); OECD 417 in rabbits, because:

- no data concerning the animals (species, sex, housing, feeding...)

- and only one dose was administrated

Based on these 2 studies, the conclusion is that there is no bioaccumulation potential of PMP in the conditions of these tests, and that PMP is largely excreted as conjugates of p-methoxyphenol and as small part as quinol.

Two other studies of Bray et al. (1952) are referenced, of reliability 3, which give information on the conjugation of PMP with glucuronic acid and with sulphuric acid.

The mean velocity constants are the following;

Kg = 0.54 hr-1 for glucuronide conjugation in the rabbit

The rate of glucuronide formation is proportional to the body level of the phenol.

Kg = 0.54 hr-1 for sulphate conjugation in the rabbit

In the fasting rabbit the rate of ethereal sulphate formation is independent of the amount of PMP present above a certain body level, but  the simultaneous administration of sodium sulphite, which is converted to  sulphate in-vivo, 

changes the kinetics of the process to those of a  first-order reaction.