Allantoin

Endpoint summary

Description of key information

Allantoin is a colorless crystalline powder that is soluble in water at approximately 0.6%.  In sum, for all species tested, absorption is as much as 16% of dermal dose, and 0.2% to 1.5% for dosing by other routes. Distribution is predominantly limited to blood and urine, and metabolism is via the purine metabolic cascade. Excretion of orally dosed Allantoin is approximately 30% of the absorbed dose in rats and humans and 75% of the absorbed dose in canines. Excretion of intravenously or subcutaneously dosed Allantoin approaches quantitative levels regardless of species. 

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - dermal (%):

16

Additional information

Allantoin, (2,5-Dioxo-4-imidazolidinyl) urea or 5-Ureidohydantoin, is a colorless crystalline powder that is soluble in water at approximately 0.6%. It is endogenous in many mammals and some plants. In most mammals, it is the product of uric acid oxidation by purine catabolism. Potential exposure routes include dermal, oral, inhalation and intravenous, with dermal and oral predominating. Toxicokinetics of Allantoin are reasonably well studied..

Absorption

Absorption of Allantoin is route and vehicle dependent. Dermal absorption was as much as 16%, other routes resulted in absorption in range of 0.2% to 1.5% of the administered dose. No irritation or corrosivity was observed in the dermis of exposed test animals using a standard protocol.

Dermal

In a study of limited reliability due to the small number of human test subjects (n=6), Allantoin (1%) doses were prepared in both hydrophilic gel and oil/water emulsion vehicles. The doses (0.5 g) also contained 5000 I.U. heparin, 1% onion bulb extract, 20% azulan and 5% ethanolic extract of Anthodium chamomillae. The excess dose was quantitatively removed from the test subject’s skin after 5 min. Allantoin absorption from the hydrophilic gel vehicle was 5% after 3 hr., and 6.9% after 6 hr. Similarly, absorption was 13% at 3 hr. and 15.4% at 6 hr. for the oil/water emulsion. No evidence of skin irritation or corrosion was reported.

Oral

In a study of limited reliability due to minimal reporting of methodology information and limited number of test subjects (n=1 per dose level), canines were dosed orally with Allantoin in capsules and in solution at 386 mg, 392 mg, 436 mg, 500 mg, 517 mg, 571 mg, 1440 mg and 1500 mg. Absorption was determined by measurement of blood levels of Allantoin, which were uniformly in the range of 1.2 mg to 2.0 mg.

Intravenous

In a study of limited reliability due to minimal reporting of methodology information and limited number of test subjects (n=1 per dose level), canines were dosed intravenously with a 0.6% solution of Allantoin for a delivered dose of 600 mg. Absorption was determined by measuring blood levels of Allantoin after 10 min., 50 min., 30 min., 70 min., 110 min., 2.5 hr., 3 hr., 3.5 hr., 4 hr. and 5 hr. Absorption reached a maximum of 9.5 mg 10 min. after administration of dose, then fell to 2.5 mg at 50 min followed by gradual decrease to baseline after 5 hr.

Inhalation

No inhalation absorption data are available.

Distribution

Because Allantoin is rapidly absorbed and excreted, distribution in tissues and fluids other than blood and urine has not been extensively studied. Allantoin distribution in blood and urine is discussed more fully in the context of absorption and excretion. However, distribution has been evaluated in the rumen of sheep and in the fetus of pregnant rhesus monkeys, further supporting the rapid absorption and excretion of Allantoin.

A reliable study (score 2) investigated the distribution of Allantoin in sheep. Test animals were dosed with 28 µCi of 4,5-14C labeled Allantoin and 15 mg unlabelled Allantoin in 10 mL isotonic saline via jugular cannula. Approximately 80% of the 14C Allantoin was recovered in the urine during the 12 hr. immediately post injection. This rose to 94% after 4 days. 14C Allantoin passed through the blood bicarbonate pool, suggesting that Allantoin is degraded in the gastrointestinal tract. A small amount of 14C Allantoin (4 % of the net flux of allantoin through the blood pool) was apparently degraded to form bicarbonate-C in the rumen and postruminally as determined by examination of rumen contents sampled via cannula.

A study of indeterminant reliability tested the transfer of Allantoin from fetus to dam in rhesus monkeys. The fetus was surgically catheterized (femoral artery and vein) in utero, and the maternal aorta and vena cava were similarly catheterized. 14C Allantoin was infused into the fetal femoral artery. Testing of blood from the fetus and dam indicated little exchange of 14C.

Metabolism

Extensive literature reports that exogenous Allantoin is rapidly absorbed and excreted. Most mammals process purines to Allantoin yielding stable endogenous levels of Allantoin in both blood and urine. Purine catabolism yields hypoxanthine, which is converted to uric acid then xanthine by xanthine oxidase. Uric acid is converted to Allantoin by urate oxidase, followed by Allantoin excretion. Humans and some non-human primates do not possess urate oxidase, so in those species, uric acid is excreted directly.

Excretion

Allantoin, whether from exogenous dosing, or from endogenous sources related to the purine metabolic cascade, is rapidly and completely excreted. Extensive literature supports this conclusion, including several studies reported herein. In general, excretion of orally dosed Allantoin is species dependent, approximately 30% of the absorbed dose in rats and humans and 75% of the absorbed dose in canines. Excretion of intravenously or subcutaneously dosed Allantoin approaches quantitative levels regardless of species.

In a study of limited reliability due to the small number of human test subjects (n= 2 to 4), aqueous solutions of Allantoin were administered orally to the test subjects in two dosing schemes: (1) a single dose of 1000 ppm, and (2) four doses of 1500 mg at 2 hr. intervals. Similarly, test subjects were dosed intravenously at 50 mg, 75 mg, 100 mg and 240 mg in a Ringer’s solution vehicle, and subcutaneously at 50 mg, also in a Ringer’s solution vehicle. Absorbed dose recoveries were 19% - 34% for the oral route, 72% - 98% for the intravenous route, and 73% - 81% for the subcutaneous route.

In a study of limited reliability due to minimal reporting of methodology information and limited number of test subjects (n=1 per dose level), canines were dosed orally with Allantoin in capsules and in solution at 386 mg, 392 mg, 436 mg, 500 mg, 517 mg, 571 mg, 1440 mg and 1500 mg. Urinary recovery was in the 67% - 80% (absorbed dose) range. In a similar study, canines were dosed intravenously with a 0.6% solution of Allantoin for a delivered dose of 600 mg. Urinary recovery amounted to 98% of the absorbed dose. Another study involving intravenous dosing of canines with Allantoin (200 mg delivered) yielded similar results (88% - 92% recovery).

In a study of limited reliability due to minimal reporting of methodology information, rats (n=20) were dosed by gavage at an unreported dose level. Remarkable, however, is the fact that reported recoveries of absorbed dose (29% - 39%) were similar to those seen in human test subjects (19% - 34%).