[[(phosphonomethyl)imino]bis[ethylenenitrilobis(methylene)]]tetrakisphosphonic acid, potassium salt

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Additional information

The NOAEL for effects on reproductive function following oral administration of DTPMP in the rat was 294 mg/kg bw/day for males and 312 mg/kg bw/day for females (Biodynamics, 1979; Reliability 2). This is a one-generation study for both males and females (the treatment of the F0 (adult) animals began on Day 0 of gestation. The guideline requires that it start two oestrus cycles before mating, and for a two-generation study dosing should start during growth and then for two oestrus cycles). However, because there were 2 generations produced the study does go part way to addressing the 2-generation issues. No histopathological changes were apparent in reproductive tissue from male or female rats following gavage administration of 850-900 mg/kg bw /day of the sodium DTPMP for up to 90 days (CTL, 1998; Reliability 1).

The category hypothesis is that at a defined pH, a salt will behave no differently to the parent acid, at identical concentration of the particular speciated form present, and will be fully dissociated.Hence some properties for the aqueous salt can be directly read across (with suitable mass correction) to the parent acid andvice versa(see CSR for mass correction values). In the present context the effect of the alkaline metal counter-ion (sodium/potassium/calcium) will not be significant and has been extensively discussed in the public literature. In biological systems polyvalent metal ions will be present, and the phosphonate ions show very strong affinity to them.

Short description of key information:
There are no reproductive toxicity studies for the potassium salts of DTPMP, and data has been read across from the corresponding acid.



In the one-generation reproductive study (BioDynamics Inc., 1979) in which CP 66257 (DTPMP) was administered continuously via the diet to Long-Evans rats at concentrations of 300, 1000 and 3000 ppm through one complete generation. Test substance administration to the F0 generation females (20/group) was initiated at the onset of gestation and continued throughout the ensuing gestation and lactation periods. Administration then continued to the F1 generation animals (10 males and 20 females/group) through a growth period and mating, gestation and lactation period for two successive litters. In the F0 generation, no treatment-related effects in the low and mid dose groups were evident. In the high dose group, females delivered litters containing fewer live pups and more dead pups (not statistically significant). Pups also had a lower weight at birth (not statistically significant). No other treatment-related effects were observed. In the F1 generation, no treatment-related effects were evident in the low dose group. In the mid dose group, pup weight at birth was lower than control in the first litters (F2a) only. No such effects were observed in the second litters and no other treatment-related effects were observed during the remainder of the study. Gross pathological examination of five adult F1 generation males and females of the control and high dose groups did not reveal any abnormal findings. A NOAEL of 294 mg/kg bw/d for males and 312 mg/kg bw/d for females (3000 ppm) was therefore concluded.

Due to the limitations of the available data for reproduction and development, a position paper has been prepared to explain why additional testing has not been proposed for the phosphonic acids and their salts, including DTPMP and its potassium salts. This summary is attached to this endpoint summary.

Effects on developmental toxicity

Description of key information

There are no data for potassium salt of DTPMP. In a prenatal developmental toxicity screening study (Monsanto, 1982) mated female Sprague-Dawley rats (25/dose) were dosed by gavage at doses of 500, 1000, 2000 mg/kg bw/day (expressed as active acid). They were dosed on gestation days 6 to 19. Control animals were given 0.9% sodium chloride solution. On day 20 all surviving animals were sacrificed. There were no deaths. The highest dose produced marginal toxic effects in the dams, as evidenced by lower mean body weight gain between gestational days 6 and 20, and soft stools in some animals. No treatment-related lesions were detected at gross necropsy of the dams of any treatment group. There were no statistically significant treatment-related effects on postimplantation loss or fetal weight at any dose. Vertebral anomalies were observed in single fetuses in two litters of the 2000 mg/kg bw/day group and one of the 1000 mg/kg bw/day group. The incidence was not statistically significant, but the rare spontaneous occurrence of this type of malformation and the pattern of incidence was suggestive of a treatment-related effect. Review of these results for the REACH assessment concluded that the effects should not be considered adverse as they were not statistically significant and were only observed in the presence of maternal toxicity. Overall, the NOAEL for maternal toxicity was 1000 mg/kg bw/day, and for developmental toxicity was at least 2000 mg/kg bw/day (active acid). 
No teratogenic effects were observed in the one-generation reproductive toxicity study (BioDynamics Inc., 1979) and therefore the NOAEC for developmental toxicity was 3000 ppm. 
Due to the limitations of the available data for reproduction and development, a position paper has been prepared to explain why additional testing has not been proposed for the phosphonic acids and their salts, including DTPMP and its sodium salts. This summary is attached to this endpoint summary. 

Effect on developmental toxicity: via oral route

Dose descriptor:

NOAEL

2 000 mg/kg bw/day

Additional information

The available reproductive and developmental studies all support the conclusion that DTPMP and its salts do not have an adverse effect on development.

The category hypothesis is that at a defined pH, a salt will behave no differently to the parent acid, at identical concentration of the particular speciated form present, and will be fully dissociated.Hence some properties for the aqueous salt can be directly read across (with suitable mass correction) to the parent acid andvice versa(see CSR for mass correction values). In the present context the effect of the alkaline metal counter-ion (sodium/potassium/calcium) will not be significant and has been extensively discussed in the public literature. In biological systems polyvalent metal ions will be present, and the phosphonate ions show very strong affinity to them.

Justification for classification or non-classification

The available data do not suggest that potassium salts of DTPMP should be classified for adverse effects on fertility or development.