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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable publication which meets basic scientific principles

Data source

Reference
Reference Type:
publication
Title:
Biotransformation of the double bond in allyl glycidyl ether to an epoxide ring. Evidence from hemoglobin adducts in mice.
Author:
Pérez HL and Osterman-Golkar S
Year:
2000
Bibliographic source:
Chemico-biological interactions 125: 17-28. Cited in OECD SIDS (SIAM 25, October 2007, Helsinki)

Materials and methods

Objective of study:
metabolism
Principles of method if other than guideline:
Nine male mice (C3H/Hej) were administered the test substance dissolved in tricaprylin, 4 mg/mouse, by intraperitoneal (i.p.) injection. Adducts to N-terminal valine in hemoglobin were analyzed using a modified Edman method for derivatization and using gas chromatography/tandem mass spectrometry for detection.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Allyl glycidyl ether (AGE)
- Analytical purity: 99%

Test animals

Species:
mouse
Strain:
C3H
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland GmbH, Sulzfeld, Germany or bred at the Arrhenius Laboratories for Natural Sciences, Stockholm, Sweden
- Average weight at study initiation: 28 g
- Diet (e.g. ad libitum): standard pellet diet
- Water (e.g. ad libitum): tap water

Administration / exposure

Route of administration:
intraperitoneal
Vehicle:
other: tricaprylin
Details on exposure:
VEHICLE
- Concentration in vehicle: 4 mg/100 µl
Duration and frequency of treatment / exposure:
single injection
Doses / concentrations
Remarks:
Doses / Concentrations:
4 mg/mouse
No. of animals per sex per dose:
9
Control animals:
yes
Details on dosing and sampling:
- The animals were sacrificed 5 or 24 h after treatment and blood was collected in heparinized tubes. The control animals were killed 5 h after exposure.
- Adducts to N-terminal valine in hemoglobin were analyzed using a modified Edman method for derivatization and using gas chromatography/tandem mass spectrometry for detection.

Results and discussion

Any other information on results incl. tables

Adducts of diglycidyl ether (I) or 2,3-dihydroxypropyl glycidyl ether (III) with N-terminal valine, N-(2-hydroxy-3-(2,3-dihydroxy)propyloxy) propylvaline (diOHPrGEVal) were demonstrated in mice administered the test substance by i.p. injection. The levels were in the 1600-5600 pmol/g globin.

Table: Hemoglobin adducts formed from AGE and its metabolites 2,3-dihydroxypropyl glycidyl ether or diglycidyl ether in mice treated with AGE.

Time after treatment (h)

AGEVal (pmol/g globin)

diOHPrGEVal (pmol/g globin) Mean (±)

5

n.d (a)

2.3 (±0.7) x 10E3 (n =3) (b)

24

1.6 x 10E3 (n =4)

n.d

24

n.d

5.0 (±0.7) x 10E3 (n =3)

24

n.d

2.2 (±0.7) x 10E3 (n =3)

5 *

n.d

<20 (n =4)

* control group; (a) not determined; (b) n denotes the number of mice;

AGE may directly, without metabolic activation, react with N-terminal valine (AGEVal). Metabolism of AGE may lead to formation of diglycidyl ether (I) by P450-catalysed epoxidation or to 1-allyloxy-2,3-dihydroxypropane (II) by epoxide hydrolase-catalysed hydrolysis. 2,3-Dihydroxypropyl glycidyl ether (III) may be formed either by hydrolysis of I or epoxydation of II. Both I and III may give the N-(2-hydroxy-3-(2,3-dihydroxy)propyloxy)propylvaline adduct. AGEVal was not detected in control mice (n =6; detection limit 2 pmol/g globin).

Applicant's summary and conclusion