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Description of key information

ADONA (CAS 958445-44-8) is well absorbed orally, is widely distributed in the body,  is not metabolized, is rapidly excreted primarily in the urine, and is considered unlikely to bioaccumulate.

Key value for chemical safety assessment

Additional information

ADONA readily dissolves in aqueous media and dissociates to the carboxylic acid in equilibrium with the anion. Based on its pKa (< 3), the anion is expected to predominate at physiological pH. ADONA is chemically stable and non-reactive. Its logPowis 1.3.

The pharmacokinetics/toxicokinetics of ADONA has been evaluated in acute intravenous studies in mice, rats and Cynomolgus monkeys, in acute and repeat-dose oral studies in rats, and in occupationally exposed workers.

 

A key toxicokinetic study (09-107) involved oral (gavage) administration of radiolabeled test article (the 1-14C-labeled potassium salt and unlabeled ammonium salt in water) to male and female Sprague Dawley rats at a dose of approximately 9 mg/kg/day (labeled plus unlabeled salts) for 7 days followed by a 7-week washout period during which radioactivity was periodically measured in urine, feces and various organs and tissues. No metabolites were detected by QTOF-LC/MS and HPLC-FSA in urine or feces samples collected on day 6. Radioactivity was widely distributed to all organs and tissues examined with the highest levels in the blood and liver. Levels in all tissues except GI tract were higher in males than females. Organ/tissue and whole-body elimination was biphasic and paralleled elimination from blood. Following the final dose, concentrations in blood, plasma and all organs/tissues examined had declined to less than 0.01% of the cumulative dose within 1 day in females and within 4 days in males. Approximately 82% (males) and 90% (females) of the administered radioactivity was recovered in urine through study day 28. Fecal elimination accounted for about 4% (males) and 6% (females) of the administered dose. Total body burdens on day 28 were 0.25% (males) and 0.18% (females) of the administered dose. Phase 1 whole-body elimination half-lives were 0.66 days (males) and 0.12 days (females). Terminal phase whole-body elimination half-lives were 13.3 days (males) and 34.6 days (females). Based on these findings it is concluded that ADONA is well absorbed orally, is widely distributed in the body, is not metabolized, is rapidly excreted primarily in the urine, and is unlikely to bioaccumulate.

 

The second key study (EPI-0034) was performed to estimate the serum elimination half-life of ADONA in occupationally exposed workers. Three male 3M employees with potential workplace exposure to ADONA or its methyl ester volunteered to provide multiple blood samples over a 5-week period during which they had no known exposure to these substances. Blood samples were collected from each worker shortly after the last workshift and approximately 7, 21 and 28 days thereafter. Serum samples were analyzed by LC-MS/MS. Initial serum ADONA concentrations in the 3 workers ranged from 6.2 ng/ml to 18.8 ng/ml. Serum concentrations in each worker exhibited steady first-order declines over the course of the study. Calculated serum elimination half-lives were 16.8, 17.6 and 35.5 days (mean 23.3 days). This half-life in workers is similar to the whole-body terminal elimination half-life in male and female rats in the 7-day oral toxicokinetic study described above and suggests that the toxicokinetics of ADONA in humans and rats is similar.    

The studies summarized in the following paragraphs provide additional support to conclusions of the key studies described above.

Single-dose intravenous PK studies were performed in male and female mice (08-185), rats (08-033) and Cynomolgus monkeys (06-367) administered ADONA at a dose of approximately 28 mg/kg. Serum elimination half-lives (t½) for ranged from 0.9 hours in female rats to 8.1 hours in male mice, volumes of distribution (Vd) ranged from 154 ml/kg in female mice to 331 ml/kg in male monkeys, and AUCs ranged from 198 µg-h/ml in female rats to 1919 µg‑h/ml in male mice. In rats, the liver (perfused to remove blood) ADONA concentration at 24 hours postdose was much lower in females than in males but the liver-to-serum ratio in males (0.53) was about half that of females (1.14). Liver (not perfused) ADONA concentrations in male and female mice declined in parallel with serum concentrations and liver-to-serum ratios 24 hours post-dose were£1. Urinary ADONA elimination in monkeys was 50.5% (females) and 33.9% (males) of the administered dose through 96 hours postdose.

ADONA was administered at a dose of 30 mg/kg either orally or intravenously in an acute study in male and female rats (08-267). ADONA was excreted primarily (~60% in males, ~80% in females) in the urine. Fecal elimination was ~2% following IV administration and ~10% after oral administration. No fluorinated metabolites and no increase in inorganic fluoride were detected in the urine. 

In an acute oral (gavage) study (06-095) in male rats at a dose of 28 mg/kg, 84% of the dose was eliminated in the urine by 96 hours postdose.

 

In a 5-day oral study in male and female rats (06-375) at doses of 28 and 104 mg/kg/day, ADONA serum elimination following the last dose was biphasic, with the majority of the dose eliminated within the first 24 hours. Serum ADONA concentrations were somewhat higher in males than in females at 1 and 24 hours after the last dose. Liver (not perfused) concentrations were much higher in males than in females 24 hours after the last dose. Liver concentrations dropped dramatically over the week following the last dose in both males and females. Approximately one-half (52-57%) of the administered dose was eliminated in the urine by 96 hours postdose in both males and females.

In a 90-day oral study in male and female rats (07-252), plasma and liver ADONA concentrations were dose-related but were higher in males than in females at the same dose (10 mg/kg/day). Within each dose group, plasma concentrations were similar at weeks 1, 4 and 13 of the study and liver concentrations at weeks 4 and 13 were not significantly different from those at week 1. Liver-to-plasma ratios at weeks 1, 4 and 13 were less than 1 for all groups except high-dose males at week 4. No evidence for the bioaccumulation of ADONA on repeated dosing was seen in this study.