Ethylenediaminetetra(methylenephosphonic acid): genotoxicity, biodistribution, and subchronic and chronic toxicity in rats.
Ethylenediaminetetra(methylenephosphonic acid), EDITEMPA, was tested for oral toxicity in rats in a 13-wk feeding study (at doses of 0, 5, 50 and 500 mg/kg/day) and in a chronic feeding study (at doses of 0, 4, 20 and 100 mg/kg/day). EDITEMPA was also tested for genotoxicity in the Ames, mouse lymphoma, unscheduled DNA synthesis, and in vivo cytogenetics assays. Additionally, absorption, distribution and excretion (ADE) studies were conducted following administration of [14C]EDITEMPA to rats by gavage and via the feed and drinking-water. The principal finding in the 13-wk study was mild anaemia in male and female rats given 500 mg/kg/day, which was resolved during a 9-wk recovery period. In the chronic study, there was no substantial evidence of any treatment-related toxicity or carcinogenicity. Differences in survival of control and treated females (noted late in the study) were interpreted to represent unusually good survival in controls; however, a compound-related increase in mortality could not be completely ruled out. Tests for genotoxicity were all negative. ADE studies revealed that [14C]EDITEMPA was poorly absorbed from the gastro-intestinal tract and that most of the absorbed dose was rapidly excreted by the kidneys or sequestered in bone. The gavage route of administration led to four- to six-fold increases in bone EDITEMPA levels as compared with administration in the feed and drinking-water, respectively. These results suggest that no significant toxicity or carcinogenicity concerns arise from EDITEMPA when it is administered in the feed at the concentrations tested. Reversible anaemia was seen only at very high doses and was interpreted as being secondary to EDITEMPA's ability to interfere with iron absorption and utilization. Localization of EDITEMPA in bone indicated a high degree of affinity for mineralizing tissues, consistent with its chelating properties. There was, however, no effect on bone resorption or mineralization. A comparison of human drinking-water levels of 3500 ppm EDITEMPA (based on a no-effect level of 100 mg/kg/day in rats) with the estimated worst-case exposure in humans of 0.01 ppm suggested a safety margin greater than 1 x 10(5).
Calvin
G
G
Procter & Gamble Company, Cincinnati, OH 45239-8707.
Long
P H
PH
Stitzel
K A
KA
Anderson
R L
RL
Balmbra
R R
RR
Bruce
R D
RD
Bhatt
A
A
Miller
P M
PM
Broadmeadow
A
A
D000284:Administration, Oral; D000740:Anemia / Q000139:chemically induced; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001842:Bone and Bones / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D005243:Feces / Q000032:analysis; D005260:Female; D007668:Kidney / Q000378:metabolism; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D009152:Mutagenicity Tests; D009374:Neoplasms, Experimental / Q000139:chemically induced; D009943:Organophosphorus Compounds / Q000493:pharmacokinetics / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D011919:Rats, Inbred Strains; D014018:Tissue Distribution
D009943:Organophosphorus Compounds; C018940:(ethylenedinitrilo)-tetramethylenephosphonic acid; D004247:DNA