[ethylenebis[nitrilobis(methylene)]]tetrakisphosphonic acid, calcium sodium salt

Carcinogenicity

Description of key information

Read across from a  well conducted  chronic gavage study (rel 2)  rats were administered by gavage EDTMP   (15, 50 and 333 (increased from 150 mg/kg (bw)   on day 329 of study)) for 94 -107 consecutive weeks. The results showed EDTMP to be carcinogenic  in Sprague-Dawley rats at a level of 50 mg/kg (bw) in males and  at 150/333 mg/kg (bw) females. No treatment related effects of any description were observed at the low dose (15 mg/kg (bw) in either sex. (active acid)

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion

Dose descriptor:

NOAEL

15 mg/kg bw/day

Justification for classification or non-classification

Based on the available information on sodium salt of EDTMP (CAS No 22036 -77 -7), no classification for carcinogenicity is proposed for any of the substances being registered in the EDTMP category in accordance with the current regulation (EC1272/2008). Toxicological data are conclusive in some animals (rats) at high doses but not sufficient for classification in human health hazards. Additional toxocological data and weight of evidence to justify this non-classification are reported in an enclosed document.

Additional information

Read across from a well conducted chronic gavage study (rel 2) rats were administered by gavage EDTMP (15, 50 and 333 - increased from 150 mg/kg (bw) on day 329 of study) for 94 -107 consecutive weeks. The results showed EDTMP to be carcinogenic in Sprague-Dawley rats at a level of 50 mg/kg (bw) in males and at 150/333 mg/kg (bw) females. No treatment related effects of any description were observed at the low dose (15 mg/kg (bw) in either sex. There were non neoplastic effects (metaphyseal osteosclerosis) that were considered to be treatment related at the mid and high dose female groups and high dose male group.

In a well conducted mouse study the test compound (35631) was administered by gavage to 340 B6C3F1 mice (85/sex/group) at dose levels of 15 and 75 mg/k/day for a period of at least 24 months. There was no treatment related evidence of carcinogenicity under the conditions of this study. However there were non neoplastic changes considered to be treatment related at both treatment levels for females (fibrous osteodystrophy and alkaline phosphatase) and at 75 mg/kg males based on effects seen wihth alkaline phosphatase.

In a well conducted two year oral gavage study rats were treated with a mixture of EDTMP (neutralised with sodium hydroxide)and NaF at dose levels 0, 15:1.139 NaF, 75:5.695 NaF, 150: 11.390 NaF. The development of osteoarcomas were seen in the 75:5.695 NaF and 150: 11.390 NaF dose groups.

A 2 -year chronic dietary feeding study with EDTMP (as sodium salt) reported in the paper by Calvin et al. 1988 showed no adverse effects on calcium homeostatis, bone growth or bone morphology at a nominal dosage of 100 mg/kg. bw/d. However, it is noted that in this study, the maximun dose level reported was not high as the gavage dosing that was used in the oral gavage rat study (FDRL 1985). In addition, it is likely that any intestinal absorption may have been limited by the chelating ability of EDTMP to the food within which it was dosed. Both these factors would mean that the amount of phosphonate in the body would have been lower than in the FDRL 1985 study.

Carcinogenicity: via oral route (target organ): other: bone