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Link to relevant study record(s)

Reference
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:
data from handbook or collection of data
Objective of study:
excretion
metabolism
Qualifier:
no guideline required
Principles of method if other than guideline:
Diphenyl Ether was injected into the rabbit. Urine was recolted and analysed to determine metabolites.
GLP compliance:
not specified
Specific details on test material used for the study:
Not Specified
Radiolabelling:
no
Species:
rabbit
Strain:
not specified
Details on species / strain selection:
Not Specified
Sex:
not specified
Details on test animals and environmental conditions:
Not Specified
Route of administration:
other: injection
Vehicle:
not specified
Details on exposure:
Not Specified
Duration and frequency of treatment / exposure:
Not Specified
No. of animals per sex per dose:
Not Specified
Control animals:
not specified
Positive control:
Not Specified
Details on study design:
Not Specified
Details on dosing and sampling:
Not Specified
Statistics:
Not Specified
Preliminary studies:
Not Specified
Details on absorption:
Not Specified
Details on distribution in tissues:
Not Specified
Details on excretion:
In the rabbit, no cleavage of the ether linkage /of phenyl ether occurs.
Metabolites identified:
yes
Details on metabolites:
The major metabolite was the p-hydroxylated ether, which is excreted both unconjugated (15%) and conjugated with glucuronic acid (63%) and sulfuric acid (12%). Another metabolite was also isolated from the rabbit urine and fairly well identified as di(p-hydroxyphenyl) ether.
Conclusions:
Diphenyl Ether, when injected into the rabbit, was excreted in the urine as p-hydroxyphenyl phenyl ether and none was excreted as the unchanged ether.
Confirmation of these observation showed that in the rabbit no cleavage of the ether linkage occurs. The major metabolite was the p-hydroxylated ether, which is excreted both unconjugated (15%) and conjugated with glucuronic acid (63%) and sulfuric acid (12%). Another metabolite was also identified as di(p-hydroxyphenyl)-ether.
Executive summary:

Diphenyl Ether, when injected into the rabbit, was excreted in the urine as p-hydroxyphenyl phenyl ether and none was excreted as the unchanged ether.

Confirmation of these observation showed that in the rabbit no cleavage of the ether linkage occurs. The major metabolite was the p-hydroxylated ether, which is excreted both unconjugated (15%) and conjugated with glucuronic acid (63%) and sulfuric acid (12%). Another metabolite was also identified as di(p-hydroxyphenyl)-ether.

Description of key information

Dermal Absorption

After semi-occlusive application to the clipped skin of rats, almost 20 % of the Diphenyl Ether dose was absorbed as measured by the amount excreted in urine. However, in a diffusion in vitro experiment, only 0.3 % (rat skin) or 0.2 % (human skin) of diphenyl ether penetrated the skin in vitro. The higher absorption in the in vivo experiment may have been caused by the vehicle (diethyl phthalate).

As indicated in basic Toxicokinetics data, due the -OH fragment, 4 -PhenoxyPhenol is more soluble in water than Diphenyl Ether. Therefore, the percentage of the dermal dose absorbed for 4 -Phenoxyphenol is expected lower than the Diphenyl Ether percentage (20%)

Toxicokinetics

In organism, metabolism is divided into two phases:

  • Phase I : enzymes introduce reactive or polar group into xenobiotics to convert lipophilic compounds into hydrophilic products that are readily excreted.
  • Phase II ; the modified compounds are conjugated to polar compounds (these reactions are catalysed by transferase enzymes such as glutathione S-transferases).

The 4-PhenoxyPhenol has a polar group in addition to Diphenyl Ether, this suggests that 4-PhenoxyPhenol is the breakdown product of Diphenyl Ether after the phase I.

The study “Basic toxicokinetics-2-Patty's-2001” confirms this point and that 4-PhenoxyPhenol are modified by the phase II and it is the principal metabolic of the Diphenyl Ether.

Key value for chemical safety assessment

Absorption rate - dermal (%):
20

Additional information