title: Timing and route of exposure affects crystal formation in melamine and cyanuric exposed male and female rats: gavage vs. feeding.
abstract: Effects of the dosing matrix and timing on the onset of renal crystal formation were evaluated in male and non-pregnant female rats (Fisher 344) exposed to both melamine (MEL) and cyanuric acid (CYA) for 28 days. Rats were fed ground feed containing 60 ppm MEL and 60 ppm CYA, (5 mg/kg bw/day equivalent), or exposed via oral gavage to carboxymethylcellulose containing 5 mg/kg bw MEL followed by 5 mg/kg bw CYA either consecutively (<1 min apart) or delayed 45 min after MEL. Staggered gavage exposure to MEL/CYA caused extensive renal crystal formation as compared to when the two compounds were administered consecutively or in feed. Treatment related effects included reduced weight gain, feed consumption, and testicular weight and increased kidney weight, water consumption and urine output. Animals from the staggered MEL/CYA gavage exposure group became ill and were removed after 9 days of exposure. Approximately 1 week after the initiation of exposure microscopic urinalysis revealed MEL/CYA crystals in both groups of gavaged animals but not in the MEL/CYA feed treatment groups. Urinary crystals were smaller (10 μm) in animals consecutively gavaged. In contrast the urinary crystals were larger (20-40 μm) and frequently clumped in the animals in the staggered gavage group.
authors.affiliation: Center for Food Safety and Applied Nutrition, US Food and Drug Administration, Laurel, MD 20708, United States. rsprando@cfsan.fda.gov
authors.forename: Robert L
authors.initials: RL
authors.lastname: Sprando
authors.forename: Renate
authors.initials: R
authors.lastname: Reimschuessel
authors.forename: Cynthia B
authors.initials: CB
authors.lastname: Stine
authors.forename: Thomas
authors.initials: T
authors.lastname: Black
authors.forename: Nicholas
authors.initials: N
authors.lastname: Olejnik
authors.forename: Michael
authors.initials: M
authors.lastname: Scott
authors.forename: Zachary
authors.initials: Z
authors.lastname: Keltner
authors.forename: Omari
authors.initials: O
authors.lastname: Bandele
authors.forename: Martine
authors.initials: M
authors.lastname: Ferguson
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Nemser
authors.forename: Andriy
authors.initials: A
authors.lastname: Tkachenko
authors.forename: Eric
authors.initials: E
authors.lastname: Evans
authors.forename: Tina
authors.initials: T
authors.lastname: Crosby
authors.forename: Kellie
authors.initials: K
authors.lastname: Woodling
authors.forename: Lucie
authors.initials: L
authors.lastname: Loukotková
authors.forename: Gonçalo
authors.initials: G
authors.lastname: Gamboa da Costa
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001806:Blood Urea Nitrogen; D001835:Body Weight / Q000187:drug effects; D003404:Creatinine / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005260:Female; D005506:Food Contamination; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D018570:Risk Assessment; D012737:Sex Factors; D014227:Triazines / Q000633:toxicity* / Q000652:urine; D014527:Uric Acid / Q000097:blood
chemical_list: D014227:Triazines; D014527:Uric Acid; D003404:Creatinine; C004632:cyanuric acid; C011907:melamine