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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
key study
Study period:
not specified
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: No data on GLP or guidelines but the publication contains sufficient data for interpretation of study results.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1985

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 417 (Toxicokinetics)
Deviations:
not specified
Principles of method if other than guideline:
Following oral administration, the disposition and metabolism of epichlorohydrin was examined.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Non-radiolabeled epichlorohydrin (ECH) was obtained from Shell Chemical Co., Deer Park, TX and was mixed with (2-14C-ECH) obtained from Amersham International to give a final specific activity of approximately 16.4 microCi/mg (1.52 mCi/mmol). GC/MS analysis showed this mixture to be greater than 99% chemically pure and greater than 99% radiochemically pure by radio-GLC.
Radiolabelling:
yes
Remarks:
2-14C-Epichlorohydrin

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male
Details on test animals and environmental conditions:
Animals were fasted overnight prior to dosing; then after dosing they were allowed to feed.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
Doses were 6 mg/kg (3 ml/kg of dosing solutions) by gavage of the 98% radiochemically pure material in an aqueous solution.
Duration and frequency of treatment / exposure:
Single administration
Doses / concentrations
Remarks:
Doses / Concentrations:
6 mg/kg
No. of animals per sex per dose:
5 males/dose
Control animals:
no
Positive control:
not applicable
Details on study design:
(2-14C-Epichlorohydrin) was administered as a single dose to male Fischer 344 rats by gavage. Animals were fasted overnight prior to dosing; then after dosing they were allowed to feed. Doses were 6 mg/kg (3 ml/kg of dosing solutions) by gavage of the 98% radiochemically pure material in an aqueous solution. Prior to dosing, control samples for separation and collection of excreta including expired air were collected for a 24-hour period. Following dosing the rats were placed in glass metabolism cages for 72 hours post-dosing for the separation and collection of excreta including expired air. Animals were sacrificed three days post-dosing. Tissues were collected and analyzed for radioactivity. Excreta was also analyzed for radioactivity.
Details on dosing and sampling:
Doses were 6 mg/kg (3 ml/kg of dosing solutions) by gavage of the 98% radiochemically pure material in an aqueous solution. Prior to dosing, control samples for separation and collection of excreta including expired air were collected for a 24-hour period. Following dosing the rats were placed in glass metabolism cages for 72 hours post-dosing for the separation and collection of excreta including expired air. Animals were sacrificed three days post-dosing. Tissues were collected and analyzed for radioactivity. Excreta was also analyzed for radioactivity.
Statistics:
not applicable

Results and discussion

Preliminary studies:
no preliminary studies conducted

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Absorption was rapid with ~75% of the orally administered dose excreted as CO2 or in the urine within 12 hours of administration.
Details on distribution in tissues:
Radioactivity in tissues accounted for the remainder of the administered dose. When expressed per gram of tissue, radioactivity was highest in the liver, kidney, and forestomach.
Details on excretion:
Approximately 38% of the radioactive dose was exhaled as 14CO2, 50% was excreted as metabolites of epichlorohydrin (ECH) in the urine, and 3% was present in the feces over the 3 day period. Most of which was excreted in the first 12 hour period with 30% and 46% eliminated as 14CO2 and urine, respectively.
Toxicokinetic parametersopen allclose all
Test no.:
#1
Toxicokinetic parameters:
half-life 1st: 2.16 hours
Test no.:
#1
Toxicokinetic parameters:
half-life 2nd: 17.02 hours

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
The major metabolites in the urine were identified a N-acetyl-S-(3-chloro-2-hydroxypropyl)-L-cysteine and alpha-chlorohydrin, about 36 and 4% of the administered dose, respectively. These metabolites are consistent with two initial (but different) metabolic reactions for ECH, the conjugation with glutathione and subsequent further metabolism to the N-acetyl-S-(3-chloro-2-hydroxypropyl)-L-cysteine and hydrolysis of the epoxide to produce alpha-chlorohydrin.

Any other information on results incl. tables

No exhaled ECH was detected. The urinary excretion of radioactivity was biexponential, with half-lives of 2.16 and 17.02 hr. The exhalation of CO2 was triexponential absorption and two elimination phases with half lives of 1.65 hr and 2.02 and 32.5 hr, respectively.

Thin layer chromatography of pooled urine followed by autoradiography revealed one major and at least five minor radioactive metabolites of ECH. The major metabolite was tentatively identified as N-acetyl derivative of S-(3 -chloro-2 -hydroxypropyl)-L-cysteine (ACPC). 13C NMR of this metabolite, in comparison with the synthetic ACPC, confirmed the structure of the metabolite as ACPC. Some 13C peak splitting in the different solvents suggested that both the synthetic compound and the isolated metabolite were mixtures of diastereoisomers. Direct insertion MS of this metabolite, in comparison with the synthetic compound, also confirmed this structure assignment. Scintillation counting of the metabolite obtained from a TLC of urine indicates that this metabolite was present at 36% of the administered dose.

One of the minor metabolites was identified as a-chlorohydrin (4% of the administered dose). Another of the minor metabolites was identified as S-(2,3 -dihydroxypropyl)-L-cysteine. This represented 2% of the dose. A third metabolite (2%) had a Rf similar to that of synthetic N-acetyl-S-(2,3 -dihydroxypropyl)-L-cysteine.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): low bioaccumulation potential based on study results
Approximately 38% of the radioactive dose was exhaled as 14CO2, 50% was excreted as metabolites of epichlorohydrin (ECH) in the urine, and 3% was present in the feces. Radioactivity in tissues accounted for the remainder of the administered dose. When expressed per gram of tissue, radioactivity was highest in the liver, kidney, and forestomach. The major metabolites in the urine were identified a N-acetyl-S-(3-chloro-2-hydroxypropyl)-L-cysteine and alpha-chlorohydrin, about 36 and 4% of the administered dose, respectively.
Executive summary:

A comprehensive disposition and metabolism study of epichlorohydrin (ECH) has not been previously reported. In this study, male Fischer 344 rats were dosed (6 mg/kg) orally with [2-14C]ECH (98% radiochemically pure) as an aqueous solution and killed after 3 days. Approximately 38% of the radioactive dose was exhaled as CO2. 50% was excreted as metabolites in the urine, and 3% was present in the feces. Radioactivity in tissues accounted for the remainder of the administered dose. When expressed per gram of tissue, radioactivity was highest in liver, kidney, and forestomach. The half-life of initial elimination of radioactivity in both the urine and exhaled air was about 2 hr, indicating that ECH was rapidly absorbed and metabolized. The major metabolites in the urine were identified as N-acetyl-S-(3 -chloro-2 -hydroxypropyl)-L-cysteine and a-chlorohydrin, about 36 and 4% of the administered dose, respectively. Finding these metabolites, which have not been previously reported, is consistent with the initial metabolic reactions being conjugation of the epoxide with glutathione and hydration of the epoxide.