1,3,5-triazine-2,4,6(1H,3H,5H)-trione, trisodium salt

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

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

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The analogue CAS nº 36549-48-1 monosodium salt of cyanuric acid, monohydrate, shares the same functional group with the substance CAS nº 3047-33-4 trisodium cyanurate and the results can be extrapolated to trisodium cyanurate.

Cross-reference

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

other: read-across

Title:

Unnamed

Year:

2010

Materials and methods

Principles of method if other than guideline:

Read-across approach from a study report (using the methods outlined by EU Method B.36) on the analogue CAS nº 36549-48-1 monosodium salt of cyanuric acid, monohydrate.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Sodium cynaurate monohydrate

IUPAC Name:

Sodium cynaurate monohydrate

Constituent 2

Reference substance name:

36549-48-1

Cas Number:

36549-48-1

IUPAC Name:

36549-48-1

Details on test material:

- Name of test material (as cited in study report): monosodium salt of cyanuric acid, monohydrate
- Molecular formula (if other than submission substance): C3H3N3O3.H2O.Na
- Molecular weight (if other than submission substance): 170.08
- Smiles notation (if other than submission substance): Na].O.O=C1NC(=O)NC(=O)N1
- InChl (if other than submission substance):
InChI=1/C3H3N3O3.Na.H2O/c7-1-4-2(8)6-3(9)5-1;;/h(H3,4,5,6,7,8,9);;1H2
- Structural formula attached as image file (if other than submission substance): see Fig.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Sodium cyanurate was totally absorbed after administration at 5 mg/kg p.o but absorption after administration at 500 mg/kg p.o was highly variable ranging from less than 10% of the dose to total absorption with an average of around 50% of the dose absorbed. After repeated administration of the compound at 5 mg/kg p.o absorption of the final 14C-labeled dose was marginally reduced. Absorption was determined by comparison of the urinary recovery of the compound after i.v and p.o administration, and by comparison of the areas under the 0-8 hr blood concentration-time curves after i.v and p.o administration.

Details on distribution in tissues:

The concentrations of sodium cyanurate equivalents in tissues at the time of animal sacrifice were less than the limits of sensitivity for the assay for all treatment regimens.

Details on excretion:

After iv or oral administration at 5 mg/kg sodium cyanurate compound equivalents were primarily excreted via the urinary route during the first 12 h with only marginal excretion occurring after 24 h. The percentage of dose excreted in the urine was similar after either route of administration. Recovery of sodium cyanurate equivalents in the feces was negligible ie 2% of the dose or less except for three of the multiple dose animals in which 6-13% was recovered via the fecal route. The total percentage of the 5 mg/kg dose recovered in the urine and feces of both sexes varied from 80 to 100%. Similar total recoveries were observed after oral adminitsration of the compound at 500 mg/kg. However, the percentage excreted in the urine after the higher dose varied from as low as 14% to a maximum of 73%. Urinary excretion of compound equivalents occurred primarily during the first 24 h after dosing, with only marginal excretion occurring after 48 h. There were no differences between the urinary excretion patterns of males and females.

Metabolite characterisation studies

Metabolites identified:

no

Details on metabolites:

Only parent compound was found in urine indicating that metabloism of sodium cyanurate did not occur or was minimal.

Any other information on results incl. tables

Sodium cyanurate was rapidly absorbed, with peak blood levels 1-3 hours post dose and a single elimination half life of 1.5-2 h.  Absorption was probably rate limiting, thus tmax was later and the terminal half-life was longer in high dose animals.

Sodium cyanurate was completely absorbed following administration at 5mg/kg to dogs, but absorption was highly variable at the 500 mg/kg dose level, averaging ~ 50%.  The absorbed compound was rapidly and almost quantitatively eliminated in the urine.

Metabolism, if it occurred at all, is negligible.

There is no evidence for bioaccumulation of the compound and there are no major changes in the disposition or metabolism of sodium cyanurate following repeated administration.

Based on the experimental results obtained with the analogue monosodium salt of cyanuric acid, monohydrate (there is no evidence for bioaccumulation of the compound and there are no major changes in the disposition or metabolism of sodium cyanurate following repeated administration) the read-across approach is applied and the same results can be extrapolated for trisodium cyanurate, under test conditions.

As indicated in the European Chemical Agency Practical Guide 6 “How to report read –across and categories”, the structural grouping was realized using “OECD QSAR APPLICATION TOOL BOX” version 1.1.0.(see attachment).

 

Table 1: Data Matrix, Analogue Approach.

CAS Number		36549-48-1	3047-33-4
CHEMICAL NAME		Analogue 3 Sodium cyanurate monohydrate	Trisodium cyanurate
PHYSICO-CHEMICAL DATA
Melting Point		No data	Estimated data: 260.74ºC
Boiling Point		No data	Estimated data: 603.07ºC
Density		No data	Experimental results: 2.09g/mL
Vapour Pressure		No data	Estimated data: 1.62E-013 mm Hg at 25ºC
Partition Coefficient (log Kow)		No data	Estimated data: -2.06
Water solubility		No data	Estimated data: 1E+006 mg/L at 25 ºC
ENVIRONMENTAL FATE and PATHWAY
Aerobic Biodegradation		No data	Read-across from Cyanuric acid: Normally it degrades very slowly under aerobic conditions.  Nevertheless, it can be readily degraded aerobically under nitrogen-limited conditions, but only by a number of microorganisms in certain conditions.
Anaerobic Biodegradation		No data	Read-across from Cyanuric acid: Ready biodegradability
ENVIRONMENTAL TOXICITY
Acute Toxicity to Fish		No data	Read-across from Cyanuric acid: 96 h-LC50 > 1510 mg/L
Acute Toxicity to Aquatic Invertebrates		No data	Read-across from Cyanuric acid: 48 h-LC50 > 1510 mg/L
Toxicity to Aquatic Plants		Experimental data:   72h-EbC50= 2700 mg/L, basis for effect: biomass 96h-EbC50 > 5000 mg/L, basis for effect: biomass 72h- ErC50 > 5000 mg/L, basis for effect: growth rate 96h- ErC50 > 5000 mg/L, basis for effect: growth rate 72h- NOEC = 1250 mg/L, basis for effect: growth rate 96h- NOEC = 5000 mg/L, basis for effect: growth rate	Read-across from Cyanuric acid: 96 h-EC50=1075 mg/L (basis for effect: in vivo chlorophyll) 96 h-EC50=989.6 mg/L (basis for effect: cell number)   Read-across from Sodium cyanurate: 72h-EC50 > 128.2 mg/L Read-across from Sodium cyanurate monohydrate:   72h-EbC50= 3095.7 mg/L, basis for effect: biomass 96h-EbC50 > 5708.4 mg/L, basis for effect: biomass 72h- ErC50 > 5708.4 mg/L, basis for effect: growth rate 96h- ErC50 > 5708.4 mg/L, basis for effect: growth rate 72h- NOEC = 1433.1 mg/L, basis for effect: growth rate 96h- NOEC = 5708.4 mg/L, basis for effect: growth rate
MAMMALIAN TOXICITY
Acute Oral		No data	Read-across from Cyanuric acid: LD50 > 7554.42 mg/kg bw
Acute Inhalation		No data	Read-across from Cyanuric acid: LC50 > 7.93 mg/L
Acute Dermal		No data	Read-across from Cyanuric acid: LD50 > 7554.42 mg/kg bw
Repeated Dose		Repeated dose toxicity: oral: Key study: mouse, 13 weeks: NOAEL = 5375 ppm  LOAEL < 5375 ppm Key study: rat, 104 weeks: NOAELca. 154 mg/kg bw/day, male NOAEL ca. 266 mg/kg bw/day, female LOAEL ca. 371 mg/kg bw/day, male LOAEL ca. 634 mg/kg bw/day, female	Read-across from Cyanuric acid:   NOAEL ca 349 mg/kg bw/day male NOAEL ca. 1380.9 mg/kg bw/day female Read-across from Sodium cyanurate:   LOAEL > 5128.8 ppm NOAEL = 5128.8 ppm Read-across from Sodium cyanurate:   NOAELca. 1952.8 mg/kg bw/day,male NOAELca. 2028.4 mg/kg bw/day, female Read-across from Sodium cyanurate monohydrate:   NOAEL = 6162.5 ppm  LOAEL < 6162.5 ppm Read-across from Sodium cyanurate monohydrate:   NOAELca. 176.5 mg/kg bw/day, male NOAEL ca. 304.9 mg/kg bw/day, female LOAEL ca. 425.3 mg/kg bw/day, male LOAEL ca. 726.8 mg/kg bw/day, female
Genetic Toxicity in vitro	-         Gene mutation in bacteria	Key study:  Salmonella, with and without metabolic activation, genotoxicity negative, no citotoxicity	Read-across from Sodium cyanurate: Negative   Read-across from Sodium cyanurate monohydrate: Negative
	-         Mammalian gene mutation	No data	Read-across from Sodium cyanurate: Negative
	Chromosomal aberration	No data	Read-across from Sodium cyanurate: Negative
Genetic Toxicity in vivo		No data	Read-across from Sodium cyanurate: Negative
Carcinogenicity		Key study: Rat, 104 weeks NOAEL ca. 154 mg/kg bw/day, male NOAEL ca. 266 mg/kg bw/day, female	Read-across from Sodium cyanurate: NOAEL ca. 1520  mg/kg bw/day, male NOAEL ca. 1580 mg/kg bw/day, female Read-across from Sodium cyanurate monohydrate: NOAEL ca. 176.5 mg/kg bw/day, male NOAEL ca. 304.9 mg/kg bw/day, female
Reproductive Toxicity		No data	Read-across from Sodium cyanurate:   NOAEL:   P male ca.  602.6 mg/kg bw/day P female  ca. 1218 mg/kg bw/day F1 male  ca. 641.1 mg/kg bw/day F1 female  ca. 1166.8 mg/kg bw/day F2 male  ca. 243.6 mg/kg bw/day F2 female  ca. 1243.7 mg/kg bw/day

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
There is no evidence for bioaccumulation of the compound and there are no major changes in the disposition or metabolism of sodium cyanurate following repeated administration.
The same result can be extrapolated for trisodium cyanurate.

Executive summary:

Based on the experimental results obtained with the analogue monosodium salt of cyanuric acid, monohydrate (there is no evidence for bioaccumulation of the compound and there are no major changes in the disposition or metabolism of sodium cyanurate following repeated administration) the read-across approach is applied and the same results can be extrapolated for trisodium cyanurate, under test conditions.