Relevant background information 2.1 Toxicological studies 2.1.1 Acute toxicity 2.1.2 Short-term and long-term toxicity and carcinogenicity 184.108.40.206 gamma-Butyrolactone 220.127.116.11 gamma-Nonalactone and gamma-undecalactone 18.104.22.168 5-Ethyl-3-hydroxy-4-methyl-2(5H)-furanone 22.214.171.124 4,5-Dimethyl-3-hydroxy- 2,5-dihydrofuran-2-one 2.1.3 Genotoxicity 2.1.4 Other relevant study 3.
0248 5-Hydroxy-8-undecenoic acid 8.6/0.01 Yes No - - No safety concerns delta-lactone 0249 1,4-Dodec-6-enolactone 8.6/0.01 Yes No - - No safety concerns 0240 omega-6-Hexadecenlactone 0.10/6 Yes No - - No safety concerns 0227 4,4-Dibutyl--butyrolactone 0.10/0.14 Yes No - - No safety concerns 0244 3-Heptyldihydro-5-methyl- 0.1/0.04 Yes No - - No safety concerns 2(3H)-furanone ---- 4-Hydroxy-3-methyloctanoic 8.6/0 Yes No - - No safety concerns acid gamma-lactone 0237 6-Hydroxy-3,7-dimethyloc- 0/0.1 Yes No - - No safety concerns tanoic acid lactone 43/0 Yes No - - No safety concerns 0250 gamma-Methyldecalactone Structural class III 0246 5-Hydroxy-2-decenoic acid 0.10/12 No - - - Not evaluated2 delta-lactone 0245 5-Hydroxy-2,4-decadienoic 0.10/0.33 No - - - Not evaluated2 acid delta-lactone ---- Mixture of 5-Hydroxy-2- 2/0 No - - - Not evaluated2 decenoic acid delta-lactone, 5-Hydroxy-2-dodecenoic acid delta-lactone, and 5-Hydroxy- 2-tetradecenoic acid delta-lactone ---- 5-Hydroxy-2-dodecenoic acid 8.6/0 No - - - Not evaluated2 delta-lactone 0222 5-Ethyl-3-hydroxy-4-methyl- 6.1/13 No No No Yes No safety concerns 2(5H)-furanone 0243 4,5-Dimethyl-3-hydroxy-2,5- 0.1/2.1 No No No Yes No safety concerns dihydrofuran-2-one 1 Not applicable 2 Evaluation deferred pending consideration of other ý,-unsaturated compounds.
1.3.2 Lactones derived from linear saturated 4- or 6-hydroxycarboxylic acids Linear saturated 4- or 6-hydroxycarboxylic acids (formed from gamma- or epsilon-lactones) participate in the same pathway; however, loss of an acetyl CoA fragment produces an alpha-hydroxythioester which undergoes alpha-oxidation and alpha-decarboxylation to yield a linear carboxylic acid and eventually carbon dioxide.
Oxidation of gamma-butyrolactone to succinate by alcohol dehydrogenase and succinic semialdehyde dehydrogenase occurs primarily in the liver (Jakoby & Scott, 1959).
For the 29 lactones derived from saturated linear and branched-chain hydroxycarboxylic acids in Class I, three lactones, gamma-decalactone (1800 µg/person per day), delta-decalactone (8400 mg/person per day) and delta-dodecalactone (6800 µg/person per day) have intakes equal to or greater than the threshold of concern for Class I (1800 µg/person per day).
These NOELs provide an adequate margin of safety (>1000) for gamma-decalactone, delta-decalactone and delta-dodecalactone and, therefore, these substances would not be expected to be of safety concern.
In Europe, gamma-decalactone (8.4 mg/person per day) and delta-dodecalactone (6.8 mg/person per day) account for two-thirds of the daily per capita intake of lactones in Europe (IOFI, 1987).
126.96.36.199 gamma-Butyrolactone Groups of B6C3F1 mice (10/sex/dose level) were administered gamma-butyrolactone in corn oil by gavage at dose levels of 0, 65, 131, 262, 535 or 1050 mg/kg bw per day for 13 weeks.
Groups of F344/N rats (10/sex/dose level) were administered gamma- butyrolactone (97% pure) in corn oil by gavage at dose levels of 0, 56, 112, 225, 450 or 900 mg/kg bw per day for 13 weeks.
Groups of B6C3F1 mice (50/sex/dose level) were administered gamma-butyro-lactone in corn oil by gavage at dose levels of 0, 262 or 525 mg/kg bw per day for 2 years.
The conclusion of this study was that there was equivocal evidence of carcinogenic activity of gamma-butyrolactone in male B6C3F1 mice, based on marginally increased incidences of adrenal medulla pheochromocytomas and hyperplasia in the low-dose group.
Groups of F344/N rats (50/sex/dose level) were administered gamma- butyrolactone in corn oil by gavage at dose levels of 0, 112 or 225 mg/kg bw per day for 2 years.
In the USA, four substances, the gamma-decalactone (0.36 mg/person per day) and delta-decalactone (1.87 mg/person per day) and the gamma-dodecalactone (0.11 mg/person per day) and delta-dodecalactone (1.14 mg/person per day) account for the majority of the daily per capita intake of aliphatic lactones used as flavour ingredients (NAS, 1987).
188.8.131.52 gamma-Nonalactone and gamma-undecalactone Groups of rats (10/sex/dose level) were given a diet containing either gamma-nonalactone or gamma-undecalactone at a level of 0, 1000 or 5000 mg/kg diet for 2 years.
2.1.4 Other relevant study In a teratogenicity study, Sprague-Dawley rats were given gamma-butyrolactone at dose levels up to 500 mg/kg per day on days 6-15 of gestation.