Adenine

Endpoint summary

Description of key information

In an in vivo repeated dose toxicity study in rat similar to OECD 407, an LD50 oral of 227 mg/kg bw was determined (LOAEL = 35 mg/kg bw/d) (reference 7.5.1 -1).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEL

35 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Klimisch Code 2

System:

urinary

Organ:

kidney

Additional information

Oral

The subacute toxic effects (36 days) of the test item (0.05, 0.10, 0.20, 0.40 0.80 and 1.6% of the diet resembling 35, 70, 130, 196, 286, and 367 mg/kg bw/d) was investigated in young male SD rats (reference 7.5.1 -1). Animals consumed normal amounts of food and water at low test item levels (0.05-0.10%). Higher levels (>0.20%) significantly reduced food consumption and increased water intake. Evidence of gross pathology in soft tissues was absent at 0.05 to 0.10% dose group. Levels greater than 0.10% produced definite pathological changes in the kidney. The kidneys were greatly enlarged and its absolute weight increased more than 2x normal. The enlarged kidneys were granular, edematous, greyish, and soft. A significant change in blood urea nitrogen occurred when the level of the test item approached 0.20%. No significant changes were found in blood uric acid at all dietary levels. Low levels did not change the hematological indices with the exception of the leukocyte count. A significant leukocytosis occured at all levels (0.05-1.6%) of adenine. An increase in systolic blood pressure but no change in EKG was noted at levels >0.20% adenine. An oral LD50 of 227 mg/kg bw/d was determined. Based on the weight gain a LOAEL of 35 mg/kg bw/d was determined.

The following paragraph cites the abtract of the publication Vishal Diwan et al. [1]:

The incidence of human chronic kidney failure with associated cardiovascular disease is increasing. Kidney damage can be induced in rats by chronic dietary adenine intake. We have used this Intervention to investigate the development of concurrent kidney and cardiovascular injury. Methods: Dose-ranging studies were undertaken on male Wistar rats by feeding with adenine (0.075%, 0.25%, 0.5% or 0.75%) for up to 16 weeks. 0.075% adenine produced minimal changes while 0.5% or 0.75% adenine produced marked kidney damage; 0.25% adenine was chosen for further studies since it produced moderate kidney and cardiovascular damage. In rats fed 0.25% adenine, renal function (blood urea nitrogen (BUN), plasma Creatinine, and their clearances; plasma uric acid; proteinuria); renal structure (collagen, apoptosis, inflammation, glomerulopathy); and protein expression of markers for oxidative stress (HO-1), fibrosis (TGF-ß, a-SMA) and inflammation (TNF-a, N F - K B p52, N F - K B p50, P L A 2 and EDI) were measured, along with cardiovascular parameters (blood pressure, left ventricular stiffness, vascular responses). Allopurinol (25 mg/kg/day, final 8 weeks only) was administered to determine the role of uric acid. Results: 0.25% adenine diet induced characteristics of human chronic kidney disease at 16 weeks including increased BUN (0.25% adenine 56.5 ± 5.4*; control 6.2 ± 0.6 mmol/L; * = p < 0.05) and plasma Creatinine (0.25% adenine 268 ± 23*; control 41.9 ± 2.8 µg/L), decreased BUN and Creatinine clearances; proteinuria; increased chronic inflammation as macrophage and myofibroblast Infiltration, increased collagen deposition, tubular atrophy, apoptosis, and TNF-αand TCF-ß expression; glomerulopathy as increased podocyte desmin expression; increased HO-1 expression; and increased plasma uric acid. Cardiovascular changes included increased ventricular fibrosis, systolic blood pressure and left ventricular stiffness, and impaired vascular responses. Allopurinol decreased plasma uric acid concentrations and reversed the adenine-induced kidney and cardiovascular changes. Conclusion: Administration of 0.25% adenine to rats induced chronic kidney and cardiovascular disease. Increased uric acid production is the most likely cause since allopurinol attenuated this damage.

Based on a conversion of the same author [2] the procentual values resemble to the following doses:

Adenine concentration in food [%]	0.075	0.25	0.5	0.75
Calculated adenine dose [mg/kg bw/day]	ca. 50	ca. 155	ca. 334	ca. 490

According to this conversion, and regarding the severity of the observed effects in the study, a NOAEL of ca. 50 mg/kg bw/day and a LOAEL of ca. 155 mg/kg bw/day can be determined. However, this study was performed in male Wistar rats, which are more susceptible to adenine-induced nephrotoxicity.

[1] Diwan V. et al., "Adenine-induced chronic kidney and cardiovascular damage in rats." Journal of pharmacological and toxicological methods, (2013 Sep-Oct) Vol. 68, No. 2, pp. 197-207

[2] Diwan V. et al., " Adenine-induced chronic kidney disease in rats", Nephrology (Carlton).2018 Jan;23(1):5-11