title: Evaluation of a subchronic (13-week) oral toxicity study, preceded by an in utero exposure phase, with arachidonic acid oil derived from Mortierella alpina in rats.
abstract: Arachidonic acid oil (ARA-oil) derived from the fungus Mortierella alpina for use in infant nutrition was tested in a subchronic (13-week) oral toxicity study in rats, preceded by an in utero exposure phase. The ARA-oil was administered as admixture to the rodent diet at dose levels of 3000 ppm, 15,000 ppm and 75,000 ppm. An additional high-dose group received 75,000 ppm ARA-oil in combination with 55,000 ppm fish oil containing docosahexaenoic acid (DHA), at a ratio of ARA to DHA, comparable to the ratio in mother's milk of 2:1. The total levels of fat in each diet were kept constant by adding the appropriate amounts of corn oil. A concurrent control group received 130,000 ppm corn oil in the diet. An additional carrier control group was fed unsupplemented rodent diet. Administration of the test substances from 4 weeks prior to mating, throughout mating, gestation, lactation of parental (F(0)) animals and weaning of the F(1) pups did not affect fertility or reproductive performance, nor the general condition of pups, viability, sex ratio or number of pups. Pup weight gain in the ARA/DHA-oil group was lower than the controls administered equal amounts of corn oil. In the subsequent subchronic study survival, clinical signs, body weight gain and food consumption were not adversely affected by the test substances. Ophthalmoscopic examination did not reveal any treatment-related changes. There were no treatment-related effects observed up to dietary test substance concentrations of 15,000 ppm. The following statistically significant differences were found in the ARA high-dose group and /or in the ARA/DHA group compared to the corn oil control group: decreased alkaline phosphatase activity, decreases in cholesterol, triglycerides and phospholipids concentrations, increased creatinine and urea concentrations. Furthermore, these groups showed increased adrenal, spleen and liver weights. The incidence of hepatocellular vacuolation was increased in females of the ARA high-dose group and the ARA/DHA group. Oil droplets were observed in the mesenteric lymph nodes and in the intestinal villi in the ARA high-dose group and the ARA/DHA group. In addition, lipogranulomas were observed in the mesenteric lymph nodes in these groups. The observed changes in the high-dose groups may be effects of the high intake of high-fat levels, rather than specific effects of the ARA-oil. The no-observed-effect level in this study was placed at 15,000 ppm ARA-oil. This level is equivalent to approximately 970mg ARA-oil/kg body weight/day.
authors.affiliation: DSM Gist, PO Box 1, 2600 MA Delft, The Netherlands.
authors.forename: R A
authors.initials: RA
authors.lastname: Hempenius
authors.forename: B A
authors.initials: BA
authors.lastname: Lina
authors.forename: R C
authors.initials: RC
authors.lastname: Haggitt
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001095:Arachidonic Acids / Q000008:administration & dosage / Q000633:toxicity*; D001835:Body Weight; D004281:Docosahexaenoic Acids / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005285:Fermentation; D005395:Fish Oils; D006801:Humans; D007225:Infant Food; D007227:Infant Nutritional Physiological Phenomena; D007231:Infant, Newborn; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D020094:Mortierella / Q000737:chemistry; D009152:Mutagenicity Tests; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D017208:Rats, Wistar; D012098:Reproduction
chemical_list: D001095:Arachidonic Acids; D005395:Fish Oils; D004281:Docosahexaenoic Acids