1,3,5-triazine-2,4,6-triamine phosphate

Endpoint summary

Description of key information

There is no study available with melamine phosphate but with melamine.

 

Melamine was administered to rats in a daily diet over a period of 13 weeks. Melamine induced the formation of urinary calculi in the bladder and hyperplasia in the bladder epithelium of both sexes (NTP 1983). The effects were dose-related, with the male rats being more sensitive than females to the effects in the bladder. The NOAEL of 750 ppm for males (72 mg/kg bw/day) and 15000 ppm for females (1400 mg/kg bw/day) was considered. Later on, the US FDA has recalculated these results to a NOAEL rat,13w, oral of 63 mg/kg bw/day.

Mice were also investigated: The incidence of bladder stones was dose related as in rats, being greater in males than in females, but starting at much higher doses than in rats (NTP 1983).

In a newer subchronic study with monkeys the kidney was also the primary target organ. A NOAEL of 60 mg/kg/d was obtained, much the same as in the rat study, but it should be considered that the study is of poor reliability (Early 2013b).

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

For Read Across Justification please refer to section 13.

Reason / purpose for cross-reference:

read-across: supporting information

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across: supporting information

Reason / purpose for cross-reference:

read-across: supporting information

Key result

Dose descriptor:

NOAEL

Effect level:

72 mg/kg bw/day (actual dose received)

Sex:

male

Basis for effect level:

other: urinary bladder stones/Hyperplasia of bladder epithelium in males

Remarks on result:

other: CAS 108-78-1

Key result

Dose descriptor:

NOAEL

Effect level:

1 400 mg/kg bw/day (actual dose received)

Sex:

female

Basis for effect level:

other: other: based on the formation of urinary bladder stones and reduced body weights observed in the first study (refers to 15000 ppm)

Remarks on result:

other: CAS 108-78-1

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

1 500 ppm

System:

urinary

Organ:

bladder

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

yes

Endpoint conclusion

Dose descriptor:

NOAEL

72 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Thirteen-Week toxicity study, Klimisch 1 (Read Across)

System:

urinary

Organ:

bladder

kidney

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Mode of Action Analysis / Human Relevance Framework

The relevant trigger for the toxicity of melamine is the production of urinary tract crystals and calculi at sufficiently high doses, because of the precipitation of melamine in the urine above the solubility limit. Other toxicities observed are considered sequels of the crystals or uroliths. The main toxic effects of melamine are urinary bladder stones and hyperplasia of the transitional epithelium of the bladder in rats, in case uroliths were present. Other effects (lower body weight gain, kidney lesions) were observed at higher doses.

The relevance for humans is low, as no high enough doses has ever been observed to occur in humans to produce bladder calculi, except for the past cases of fraudulent tainting infant formulas in China.

Additional information

There is no study available for melamine phosphate but for melamine, oral studies ranging from 14-day to chronic studies, with rats and mice were reported.

 

Subchronic studies in rats:

The NTP 1983 13-weeks study with rats is selected as the key repeated dose toxicity studies, as NTP-studies are generally considered to be of high reliability. In this case there are few doubts on the high reliability, as there is an unexpected result for the crucial finding, i.e. urinary bladder stones: There was 1/10 stone in the control group, which is suspicious, as urinary bladder stones in rats are seldom. The results of the chronic study of Reno 1983, see Section 7.7 (NOAEL = 1000 ppm) and subacute study of Heck 1985 (NOAEL = 2000 ppm) are considered to be more appropriate as key studies, but the NTP 13-weeks study with rats was up to now preferred as the worst case study by the health authorities EFSA, WHO, US FDA.

 

The NTP-studies reported that the main effects of melamine are urinary bladder stones. Hyperplasia of the transitional epithelium of the bladder is detected, in case uroliths were present. These effects occurred in male rats, becoming significant at 1500 ppm in feed (equivalent to 150 mg/kg bw/day), in a dose dependent way. 1/10 stone in the control group and 2/10 stones in the lowest dose of 750 ppm (72 mg/kg/d) were observed. The difference between control and lowest dose is not statistically significant. Other effects (lower body weight gain, kidney lesions) were observed only at ca. 10 times higher doses and above. The NOAEL13weeks, reported by NTP, is 72 mg/kg bw/day, based on urinary stones in male rats (The US FDA has calculated from the same results of the NTP-study a NOELrat,13w,oral of 63 mg/kg bw/day. No data as to how FDA arrived to the result are available). Hard et al. 2009 re-evaluated the histological specimen of the kidneys and detected additional lesions, but only at the highest dose level.

 

Chronic studies in rats:

A long-term NOAEL of 2250 ppm, corresponding to ca. 126 mg melamine/kg bw/day, was derived from the NTP 1983 2-years study for male rats, see section 7.7. Interestingly enough, the 5 bladder stones detected in 10 animals in the 13-weeks study at 1500 ppm were not anymore detected at the even higher dose of 2250 ppm at the end of the 2-years study, as only 1 rat out of 50 dosed rats had a bladder stone. A regression of bladder stones occurs with time, even at ongoing dosing. Hard et al. 2009 re-evaluated the histological specimen of the kidneys and detected retrograde nephropathy in 7 out of 50 rats in the low dose group (2250 ppm), turning the NOAEL of 2250 ppm into a LOAEL. 

 

A chronic study with rats and with doses at the lower end of the NTP-study was performed by Reno 1985, see Section 7.7. The NOAEL was 1000 ppm for male and 2000 ppm for female rats.

 

Subacute studies in rats:

- The NOAEL of the NTP 1983 14-days study with rats is 417 mg/kg bw/d.

 

NOAELs in relation to the exposure duration for rats are:

14 days: 417 mg/kg bw/day

28 days. 240 mg/kg bw/day

13 weeks: 72 respectively 63 mg/kg bw/day

2 years: LOAEL = 126 mg/kg bw/day

 

The LOAEL_rat, 2 years, oral of 126 mg/kg bw/day was taken as - worst case - basis for the calculation of the long-term DNEL of melamine phosphate.

Based on the differences in molecular weight (MW of melamine phosphate = 224.1 g/mol) and the fact that melamine represents the toxicologically relevant part of the compound, this LOAEL could be adapted to 224.28 mg/kg bw/d. It is expected that the formation of crystals in the urinary tract start at higher doses of melamine phosphate compared to melamine alone. However, the LOAEL for melamine is taken forward for DNEL calculation for precautionary reasons, giving a high margin of safety.

Mice: Mice were also investigated by NTP 1983. The incidence of bladder stones was dose related as in rats, being greater in males than in females, starting at much higher doses of 12000 mg/kg feed.

Monkey: In a subchronic study with monkeys (Early 2013), the kidneys were again the primary target organ. A NOAEL of 60 mg/kg/d was derived, much the same as in the rat study. The study has a poor reliability.

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No. 1272/2008:

Based on the data available, melamine phosphate is not classified for repeated dose toxicity under Regulation (EC) No.1272/2008 (CLP)