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Description of key information

Short description of key information on bioaccumulation potential result: 
After i.p. injection allyl glycidyl ether (AGE) was partly metabolised by epoxidation or hydrolysis to diglycidyl ether, 1-allyloxy-2,3-dihydroxypropane and/or 2,3-dihydroxypropyl glycidyl ether.
Short description of key information on absorption rate:
Allyl Glycidyl Ether (AGE), without metabolic activation, directly react with N-terminal valine (AGEVal).

Key value for chemical safety assessment

Additional information

Metabolism of the double bond of AGE leading to formation of the reactive epoxides I and III was investigated in mice administered by i.p. injection or by skin application (Perez 2000). Hemoglobin adducts were determined using the modified Edman method with gas chromatography: tandem mass spectrometry (GC/MS-MS) for adduct detection. Adducts of I or III with N-terminal valine, diOHPrGEVal, were demonstrated in mice administered AGE by i.p. injection, which were one to five times higher than those of AGEVal previously found in mice after identical treatment with the compound. The levels of AGEVal in the mice treated with AGE by skin application varied between individual animals and were considerably lower than those found in mice treated by i.p. injection. diOHPrGEVal was not detected in animals treated by skin application (detection limit 20 pmol/g globin) and, therefore, the levels were probably lower than those of AGEVal. These observations may be explained by different disposition of AGE following i.p. injection or skin application. Probably formation of I and III mainly occurs in the liver. A more extensive formation of I and III following i.p. injection of AGE is in accordance with a first path effect in the liver. After penetration through the skin, a larger fraction of the compound is systemically distributed.

Discussion on bioaccumulation potential result:

In a metabolism study (Pérez HL and Osterman-Golkar S, 2000), male mice (n=9) were administered a single intraperitoneal injection (i.p.) of 4 mg/mouse AGE diluted in tricaprylin. Adducts to N-terminal valine in haemoglobin were analysed. The adduct N-(2-hydroxy-3-(2,3-dihydroxy)propyloxy)propylvaline (diOHPrGEVal) was demonstrated to be present at 1600-5600 pmol/g globin in mice. This adduct can be formed after P450-catalysed epoxidation or epoxide hydrolase-catalysed hydrolysis of AGE. Also adduct formation from allyl glycidyl ether directly with N-terminal valine (AGEVal) was found at 1600 pmol/g globin. The study shows that after i.p. injection allyl glycidyl ether was partly metabolised by epoxidation and/or hydrolysis to diglycidyl ether, 1-allyloxy-2,3-dihydroxypropane and/or 2,3-dihydroxypropyl glycidyl ether.

In another study (Pérez et al., 1997), groups of 3 mice each were administered with AGE, 0, 2 and 4 mg/mouse, by i.p. injection diluted in tricaprylin. The animals were sacrificed 24 h after injection and blood was collected in heparinised tubes. Four mice were administered AGE (4 mg/mouse) at the same conditions as the other mice and blood was collected after 21 days. Hemoglobin adducts were assessed in the blood samples using the N-alkyl Edman method. A linear relation between administered amount of the chemical and adduct formation in the dose range studied (0, 2 and 4 mg/mouse) was observed. The adduct levels were similar 24 h and 21 days after exposure. The result indicates that adducts are chemically stable and that the exposure had no influence on the turnover of erythrocytes (the life span of erythrocytes in the mouse is about 40 days) or a stability of the hemoglobin molecule itself. In the same study, erythrocytes isolated from mouse, or human whole blood were treated with AGE at 37° C in-vitro, and the adduct levels were determined. It was found that the rate constants for the reaction of AGE with N-terminal valine residues in haemoglobin were similar in mouse and human erythrocytes.

Discussion on absorption rate:

In the same metabolism study as discussed above in chapter 7.1.1 (Pérez HL and Osterman-Golkar S, 2000), male mice (n=11) were administered 4 mg/mouse of AGE dissolved in acetone, by skin application. Adducts to N-terminal valine in haemoglobin were analysed. The level of AGEVal (AGE reacted with N-terminal valine) was about 20 pmol/g globin. The other adducts were below the detection limit.