title: Effects of miglyol 812 on rats after 4 weeks of gavage as compared with methylcellulose/tween 80.
abstract: Miglyol 812 is a medium-chain triglyceride used in toxicology studies as an excipient to improve test compound solubility/absorption. As part of a larger toxicology study, 15 Wistar Han IGS rats/sex/group were dosed by oral gavage for 4 weeks with 10 mL kg(-1) day(-1) of 100% Miglyol 812 or 0.5% methylcellulose/0.1% Tween 80 in water (MC-T) followed by 4 weeks without treatment to evaluate the potential effects of this excipient in long-term toxicology studies relative to a traditional excipient such as MC-T. Clinical signs evident during the dosing phase included soft and/or mucoid stool in 12/15 males and 11/15 females treated with Miglyol 812 but in no animals treated with MC-T. Animals treated with Miglyol 812 had a 6-7% statistically significant reduction in body weight gain as compared to MC-T-treated animals. Statistically significant changes in clinical chemistry parameters as compared to MC-T included decreased blood urea nitrogen (50% and 29% in males and females, respectively), increased cholesterol (1.6-fold and 1.5-fold in males and females, respectively), decreased total protein (6% and 8% in males and females, respectively), decreased globulins (15% and 11% in males and females, respectively), and increased triglycerides (2.8-fold and 1.7-fold in males and females, respectively). Absolute and relative thymic weights decreased 28% and 24%, respectively, in males, and 18% and 17%, respectively, in females without histological alterations. Histopathology revealed increased alveolar histiocytosis with focal interstitial inflammation in lungs in 5/10 males and 7/10 females treated with Miglyol 812 compared to only 1/10 males and 1/10 females treated with MC-T. All effects were reversible during the recovery period. Results of this study indicate that 100% miglyol 812 produces reversible gastrointestinal effects and decreases in body weight gains along with changes in several serum chemistry parameters. Therefore, it should not be considered innocuous when delivered by oral gavage in long-term rodent toxicology studies.
authors.affiliation: Non-Clinical Development Safety, Hoffman-La Roche, Nutley, New Jersey 07110, USA. Rani.sellers@roche.com
authors.forename: Rani S
authors.initials: RS
authors.lastname: Sellers
authors.forename: M
authors.initials: M
authors.lastname: Antman
authors.forename: J
authors.initials: J
authors.lastname: Phillips
authors.forename: K N
authors.initials: KN
authors.lastname: Khan
authors.forename: S M
authors.initials: SM
authors.lastname: Furst
mesh_terms: D000818:Animals; D001774:Blood Chemical Analysis; D001835:Body Weight / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D005079:Excipients / Q000633:toxicity*; D005260:Female; D006651:Histocytochemistry; D008297:Male; D008747:Methylcellulose / Q000633:toxicity*; D009929:Organ Size / Q000187:drug effects; D011136:Polysorbates / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D014280:Triglycerides / Q000633:toxicity*; D016482:Urinalysis
chemical_list: D005079:Excipients; D011136:Polysorbates; D014280:Triglycerides; C433530:miglyol 810; D008747:Methylcellulose