Sodium periodate

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

3 July 2012 to 24 August 2012

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

A GLP study conducted to sound scientific principles with a sufficient level of detail to assess the quality of the submitted data. Some of the analytical techniques employed were not conclusive.

Objective of study:

other: Gastric hydrolysis

Qualifier:

equivalent or similar to guideline

Guideline:

other: Guideline 111 (Hydrolysis as a Function of pH)

Qualifier:

equivalent or similar to guideline

Guideline:

other: EU Method C.7 (Degradation: Abiotic Degradation: Hydrolysis as a Function of pH)

Principles of method if other than guideline:

Gastric hydrolysis of the test material was investigated using a procedure based on EU Method C.7 and OECD 111. During the study, the test material was dissolved in either Fasted State Simulated Gastric Fluid (FaSSGF), or Fed State Simulated Gastric Fluid (FeSSGF), in the dark at body temperature. The concentration of the test material was determined as a function of time. Furthermore, the quantities, and nature of the decomposition products, was investigated.

GLP compliance:

yes (incl. QA statement)

Radiolabelling:

no

Details on exposure:

PREPARATION OF SOLUTIONS
Sample solutions were prepared in stoppered glass flasks at a nominal concentration of 5.0 g/L in the two test media (pre-warmed to 38 °C). The test solutions were split into individual vessels for each data point. The solutions were shielded from light whilst maintained at the test temperature. The sample solutions were maintained at 38.0 ± 0.5 °C for a period of at least 0.75 hours.

Dose / conc.:

5 other: g/L (nominal conc.)

Type:

other: Gastric hydrolysis

Results:

the test material quickly degraded in both the fasted and fed state simulated gastric simulations solutions. The half-life of the test material in fasted and fed state simulated gastric fluids was significantly less than 1 hour 38.0 ± 0.5 °C

Key result

Test no.:

#1

Toxicokinetic parameters:

half-life 1st: < 1 hour at 28 ± 0.5 °C

Metabolites identified:

no

- Definitive Test

The test material concentrations at the given time points are given in the following table:

Fasted state
Time (hours)	conc (g/L) NaIO4		% NaIO4 of "weighed-out" conc.
	A	B	A	B
0	0.075	0.153	1.5	3.1
0.75	<0.005	0.014	<0.1	0.3
Fed state
Time (hours)	conc (g/L) NaIO4		% NaIO4 of "weighed-out" conc.
	A	B	A	B
0	<0.005	<0.005	<0.1	<0.1
0.75	<0.005	<0.005	<0.1	<0.1

The above results indicate that the test material was quickly degraded in both the fasted and fed state simulated gastric fluids.

Furthermore, a scientific review of the titration method used indicated that it measures the potential of the (remaining) oxidising species in the solution to convert potassium iodide into iodine, which is then titrated to the end point with the arsenate titrant. The problem with this is that the oxidising potential includes periodate (oxidation state: +7) and its degradation (reduction) product iodate (oxidation state: +5), as both species will oxidise iodide to iodine. Thus, all of the periodate will have been reduced to iodate when the oxidation potential had diminished by (7 - 5) / 7, i.e. 29 %. Consequently, as the initial and 0.75 to 1.5 hours time point samples indicated essentially no oxidising potential remaining, it is clear that all of the periodate had been reduced to (at least) iodate almost instantaneously on contact with the two test media.

Consequently, it was concluded that the half-life of the test material in both fasted and fed state simulated gastric fluids was significantly less than 1 hour at 38 °C.

- Additional Tests

Part A): On addition of the hydrochloric acid, the solution became yellow in colour. After addition of at least 15 mL of 0.05M potassium iodate titrant, the solution was still yellow in color. More importantly, the chloroform layer remained colourless throughout. An aliquot of each gastric fluid treated as the samples gave similar results, i.e. the chloroform layer remained colourless throughout the titrations. However, on adding the hydrochloric acid, the solutions did not become yellow in colour. This test was undertaken to assess whether iodine or an iodide salt had formed in the test solutions. The observations indicated a negative result.

Part B): On addition of the potassium iodide, the fasted state sample became brown in colour, whereas, the fed state supernatant turned yellow/brown in colour. This test was undertaken to assess whether there was an oxidising component in the test solutions to oxidise iodide to iodine, e.g. iodate or periodate. The result indicated there may be such a component although further test work would be required.

Part C): After addition of the silver nitrate solution, the fasted state sample became white in colour; however, after a few minutes, a precipitate formed at the bottom of the beaker and the sample had turned grey in colour with a few grey specks present. A 5 g/L potassium iodide solution treated similarly turned from a clear solution to a milky white/yellow solution. Furthermore, after approximately 30 minutes standing, the fasted state sample had become a purple coloured solution with a precipitate at the bottom of the beaker; the fed state sample had become a brown solution with large amounts of a silver coloured precipitate present; and the potassium iodide control sample had become a lime green coloured, milky opaque solution. This test was undertaken to assess whether iodide could be identified in the solutions by the presence of a yellow silver iodide precipitate, with silver (grey deposits) also being a common component. It was clear the test results were ambiguous and no clear conclusion could be drawn.

Validation

Definitive Test: The linearity of the detector response with respect to concentration was assessed over the concentration range of 1.01 x 10³ to 7.58 x 10³ mg/L. This was satisfactory with a correlation coefficient (r) of 1.000 being obtained.

Conclusions:

Interpretation of results: Periodate rapidly transforms to iodate in the stomach
Under the conditions of the study, the test material quickly degraded in both the fasted and fed state simulated gastric simulations solutions. The half-life of the test material in fasted and fed state simulated gastric fluids was determined to be significantly less than 1 hour at 38.0 ± 0.5 °C.
The definitive analytical technique used to determine the test material concentration of the initial and final reaction solutions was satisfactory in confirming the reduction of the periodate ion in both solutions.
Additional analytical techniques employed were not conclusive in proving the presence of iodate, iodide or iodine in the reacted test solutions. However, as there was essentially zero oxidising potential remaining in the degraded solutions, as well as no visible evidence of purple coloured elemental iodine in these solutions, it was considered that the periodate had been reduced all of the way down to iodide. This, however, could not be proved by the analytical techniques on hand.

Executive summary:

Gastric hydrolysis of the test material was investigated using a procedure based on EU Method C.7 and OECD 111. During the study, the test material was dissolved in either Fasted State Simulated Gastric Fluid (FaSSGF), or Fed State Simulated Gastric Fluid (FeSSGF), in the dark at body temperature. The concentration of the test material was determined as a function of time. Furthermore, the quantities, and nature of the decomposition products, was investigated.

Under the conditions of the study, the test material quickly degraded in both the fasted and fed state simulated gastric simulations solutions. The half-life of the test material in fasted and fed state simulated gastric fluids was determined to be significantly less than 1 hour at 38.0 ± 0.5 °C.

The definitive analytical technique used to determine the test material concentration of the initial and final reaction solutions was satisfactory in confirming the reduction of the periodate ion in both solutions.

Additional analytical techniques employed were not conclusive in proving the presence of iodate, iodide or iodine in the reacted test solutions. However, as there was essentially zero oxidising potential remaining in the degraded solutions, as well as no visible evidence of purple coloured elemental iodine in these solutions, it was considered that the periodate had been reduced all of the way down to iodide. This, however, could not be proved by the analytical techniques on hand.

Alternative analytical techniques would therefore be required to analyse the nature of the complex solutions. However, this was outside of the scope of the current study.

Reference 2

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

Not reported

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Objective of study:

other: gastric hydrolysis

Qualifier:

equivalent or similar to guideline

Guideline:

other: EU Method C.7 (Degradation: Abiotic Degradation: Hydrolysis as a Function of pH)

Principles of method if other than guideline:

Gastric hydrolysis of the test material was investigated using a procedure based on EU Method C.7. During the study, the test material was dissolved in either Fasted State Simulated Gastric Fluid (FaSSGF), or Fed State Simulated Gastric Fluid (FeSSGF), at body temperature. The concentration of the test material, and known decomposition products, were determined at 0.5, 1, 2, 4, 6 and 24 hours. The procedure was repeated using the reference substance, potassium iodate, with incubation periods of 1, 2, 4, and 6 hours.

GLP compliance:

no

Radiolabelling:

no

Details on exposure:

PREPARATION TEST SOLUTION
- Test Material Solution: A weight of 5.1592 g of test material was dissolved in deionised water & diluted quantitatively to 100 mL using an ‘A’ grade volumetric. 20 mL aliquots were used each containing 0.9142g IO4.

Preparation of the Reference Solution
- Potassium Iodate Solution: A weight of 5.0304 g of Potassium Iodate (100 % w/w) was dissolved in 100mL of deionised water & diluted quantitatively to 100mL using an ‘A’ grade volumetric flask. 20 mL aliquots were used containing 0.8223g IO3.

The test solution and the reference solution were prepared to contain the same amount of iodine.

Dose / conc.:

0.914 other: g

Remarks:

20 mL aliquots were used each containing 0.9142 g of iodate

Type:

other: Gastric hydrolysis

Results:

periodate rapidly transforms to iodate in the stomach

Metabolites identified:

no

Quantitative analysis

Tables 1 to 4 show the concentrations of the iodine based substances over a period of 24 hours when sodium periodate and potassium iodate were reacted with FaSSGF and FeSSGF solutions. These data have been used to calculate the degree of periodate and iodate conversion in each solution – see Table 5

Sodium periodate contains the Na+ and IO4- ions with the periodate ion containing iodine in its +7 oxidation state. It is a strong oxidising agent and reaction with organic materials is known to result in conversion of the periodate ion to iodate (IO3 -, Iodine oxidation state +5), iodine (I2,- Iodine oxidation state 0) or iodine (I-, Iodine oxidation state -1) depending upon the degree of reduction.

 Table 1: Reaction of Sodium Periodate with Fasted State Simulated Gastric Fluid (FaSSGF)

Time (Hours)	gpl IO4	gpl IO3	gpl I2/I	pH at 20°C	mV at 38°C (ΔmV)	Total I Raw kcps
Periodate solution	0.914	ND	ND	4.3
0 (Initial)	Not measured	ND	ND	1.4	460	0
0.5	ND	0.835	ND	1.4	695 (235)	0.482
1	ND	0.838	ND	1.4	696 (1)	0.481
2	ND	0.838	ND	1.4	698 (2)	0.482
4	ND	0.838	ND	1.4	695 (-3)	0.481
6	ND	0.838	ND	1.4	691 (-4)	0.482
24	ND	0.838	ND	1.4	690 (-1)	0.482
ND = None detected.

 

 Table 2: Reaction of Sodium Periodate with Fed State Simulated Gastric Fluid (FeSSGF)

Time (Hours)	gpl IO4	gpl IO3	gpl I2/I	pH at 20 °C	mV at 38 °C (ΔmV)	Total I Raw kcps
Periodate solution	0.914	ND	ND	4.3
0 (Initial)	Not measured	ND	ND	5.0	278	0
0.5	ND	0.837	ND	5.0	361 (83)	0.479
1	ND	0.838	ND	5.0	374 (13)	0.478
2	ND	0.838	ND	5.0	372 (-2)	0.477
4	ND	0.838	ND	5.0	373 (1)	0.478
6	ND	0.838	ND	5.0	380 (7)	0.478
24	ND	0.838	ND	5.0	378 (-2)	0.478
ND = None detected

 

Table 3: Reaction of Potassium Iodate with Fasted State Simulated Gastric Fluid (FaSSGF)

Time (Hours)	gpl IO4	gpl IO3	gpl I2/I	pH at 20 °C	mV at 38 °C (ΔmV)	Total I Raw kcps
Iodate solution	ND	0.822	ND	5.9
0 (Initial)	ND	Not measured	ND	1.3	520	0
0.5	ND	0.822	ND	1.3	715 (195)	0.482
1	ND	0.822	ND	1.3	712 (-3)	0.483
2	ND	0.822	ND	1.3	715 (3)	0.483
4	ND	0.822	ND	1.3	722 (7)	0.483
6	ND	0.822	ND	1.3	719 (-3)	0.482
24	ND	0.822	ND	1.2	712 (7)	0.482
ND = None detected

 

Table 4: Reaction of Potassium Iodate with Fed State Simulated Gastric Fluid (FeSSGF).

Time (Hours)	gpl IO4	gpl IO3	gpl I2/I	pH at 20 °C	mV at 38 °C (ΔmV)	Total I Raw kcps
Iodate solution	ND	0.822	ND	5.9
0 (Initial)	ND	Not measured	ND	5.0	349	0
0.5	ND	0.822	ND	5.0	364 (15)	0.471
1	ND	0.822	ND	5.0	364 (0)	0.470
2	ND	0.822	ND	5.0	370 (6)	0.470
4	ND	0.822	ND	5.0	366 (-4)	0.472
6	ND	0.822	ND	5.0	372 (6)	0.471
24	ND	0.822	ND	5.0	378 (6)	0.470
ND = None detected

 

Table 5: Degree of periodate and iodate conversion

	Sodium Periodate				Potassium Iodate
	FaSSGF		FeSSGF		FaSSGF		FeSSGF
Time (Hours)	% IO4	% IO3	% IO4	% IO3	% IO4	% IO3	% IO4	% IO3
0	100.00	<0.01	100.00	<0.01	<0.01	100.0	<0.01	100.0
0.5	<0.01	99.6	<0.01	99.9	<0.01	100.0	<0.01	100.0
1	<0.01	100.0	<0.01	100.0	<0.01	100.0	<0.01	100.0
2	<0.01	100.0	<0.01	100.0	<0.01	100.0	<0.01	100.0
4	<0.01	100.0	<0.01	100.0	<0.01	100.0	<0.01	100.0
6	<0.01	100.0	<0.01	100.0	<0.01	100.0	<0.01	100.0
24	<0.01	100.0	<0.01	100.0	<0.01	100.0	<0.01	100.0
<0.01 % = limit of detection of the test The molecular weights & conversion factors used were as follows: Sodium periodate (NaIO4): 213.892 Potassium Iodate (KIO3): 214.001 Periodate (IO4): 190.902 Iodate (IO3): 174.902 Periodate to Iodate (IO4>> IO3): 0.91619

 

Qualitative analysis 

Tables 6 and 7 identify the main components of the precipitated reactions products detected by X-ray Diffraction analysis.

The XRD spectrum of each precipitate sample was compared against a library of known spectra which included the test reagents and known degradation products.

Silver iodate was a main peak detected along with silver chloride and silver which are by-products of the precipitation process. Other unidentifiable peaks were detected which may originate from the organic components of the simulant solutions.

Fasted State Simulated Gastric Fluid (FaSSGF)

Table 6: Reaction time

Phase	1 hour	2 hours	4 hours	6 hours
NaIO4	ND	ND	ND	ND
NaIO3	ND	ND	ND	ND
NaI	ND	ND	ND	ND
AgIO4	ND	ND	ND	ND
AgIO3	Positive	Positive	Positive	Positive
AgI	ND	ND	ND	ND
Pepsin	ND	ND	ND	ND
NaCl	ND	ND	ND	ND
NaOH	ND	ND	ND	ND
AgCl	Positive	Positive	Positive	Positive
AgO	ND	ND	ND	ND
Ag2O	ND	ND	ND	ND
Ag	ND	ND	Positive	Positive
Unidentified	Balance	Balance	Balance	Balance
Positive = significant peaks identified in the spectra ND = None detected Balance = unidentified peaks

  

Fed State Simulated Gastric Fluid (FeSSGF)

Table 7: Reaction time

Phase	1 hour	2 hours	4 hours	6 hours
NaIO4	ND	ND	ND	ND
NaIO3	ND	ND	ND	ND
NaI	ND	ND	ND	ND
AgIO4	ND	ND	ND	ND
AgIO3	Positive	Positive	Positive	Positive
AgI	ND	ND	ND	ND
NaCl	ND	ND	ND	ND
NaOH	ND	ND	ND	ND
AgCl	Positive	Positive	Positive	Positive
AgO	ND	ND	ND	ND
Ag2O	ND	ND	ND	ND
Ag	ND	ND	ND	ND
Unidentified	Balance	Balance	Balance	Balance
Positive = significant peaks identified in the spectra ND = None detected Balance = unidentified peaks

 

Both stomach simulant solutions used in the study contain organic materials. The Fasted State simulated gastric solution (FaSSGF) consisted of an acidic solution of the enzyme pepsin, which is a very large biological molecule.The Fed State simulated gastric solution (FeSSGF) consistedmainly of milk, which is acolloidal dispersion of fat globules and proteins in an aqueous solution of lactose, minerals, and other minor constituents.Consequently it was anticipated that reaction of periodate with the simulant solutions would result in its reduction to one of the lower oxidation states of iodine. In the case of pepsin-containing solutions previous literature has confirmed periodate reacts with pepsin rapidly.

 

Quantitative analysis 

For both types of simulant solutions the test results from the quantitative analysis clearly show periodate undergoes reduction to iodate very rapidly but was not reduced further under the test conditions to the lower oxidation states (iodine or iodide) over the 24 hour time period covered by the study.

The pH, redox potential and total iodine content of the reaction solutions were monitored. The pH did not change which was not surprising given the two media were either very acidic or buffered. The total iodine measured by XRF was performed to confirm that there were no significant iodine losses during the reaction stage. A sealed reaction vessel was used and only briefly opened to remove aliquots for chemical analysis.

The redox potential of both media changed immediately as soon as the sodium periodate was added - 235 mV for the pepsin based medium and 83 mV for the milk based medium. This was thought to signal the reaction between the constituents. Unfortunately, it was not possible to measure the rate of reaction over a time period of less than half an hour.

No effort was made to identify other non-iodine based degradation products because of the complexity of the ingredients.

A reference sample of potassium iodate was tested to compare with the periodate sample and there was no evidence that this underwent any form of reduction to lower iodine oxidation states.

This would appear to confirm that the Iodine +5 (iodate) is the lowest oxidation state that will be produced in the prescribed test conditions.

The iodate reference sample also produced a change of 95 mV when it was added to the pepsin based medium even though it did not appear to have undergone chemical conversion to the other iodine based substances being measured. It is known that in acid solution iodate forms iodic acid which may account for the change. The addition to the buffered milk medium showed much less of a change (15 mV).

 

Qualitative analysis

XRD analysis confirmed that periodate had completely reduced to iodate over a period of 1 hour. Residual silver and silver chlorides originating from the test reagents were also detected. Given the organic content of the simulant solutions it was not possible to identify the organic degradation components shown on the XRD spectra.

The test involved an organic solvent wash to remove degradation products such as proteins from the test solutions before iodine salt precipitation. Duplication of the test with and without the solvent proved there was no interference from the test reagents. 

Conclusions:

Interpretation of results: Periodate rapidly transforms to iodate in the stomach
The results of the study indicate that periodate reduces to iodate in both fasted and fed state gastric simulation solutions. The quantitative analysis shows the reaction proceeds very rapidly in less than 0.5 hours during which the conversion to iodate is essentially complete. There was no quantitative evidence that iodate was reduced to other iodine based substances under test conditions over the 24 hour period of measurement though there was some qualitative evidence suggestive of further reduction .

Executive summary:

Gastric hydrolysis of the test material was investigated using a procedure based on EU Method C.7. During the study the test material was dissolved in either Fasted State Simulated Gastric Fluid (FaSSGF), or Fed State Simulated Gastric Fluid (FeSSGF), at body temperature. The concentration of the test material, and known decomposition products, were determined at 0.5, 1, 2, 4, 6 and 24 hours. The procedure was repeated using the reference substance, potassium iodate, with incubation periods of 1, 2, 4, and 6 hours.

The test work confirmed that sodium periodate reacts with both types of simulated gastric fluids. The reaction occurs rapidly and in both cases is completed within half an hour. The periodate (IO4-) undergoes a chemical reaction to form iodate (IO3-). However, no further reaction was identified, specifically to other iodine based substances such as iodine or iodide, over the 24 hour monitoring period. A reference sample of iodate was also tested and showed the same behaviour confirming the rapid reduction to iodate.

The test work confirms that the toxicological effects of iodate in the human body need to be considered when assessing the effects of periodate exposure.

Reference 3

Endpoint:

basic toxicokinetics

Type of information:

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

Adequacy of study:

weight of evidence

Study period:

Not reported

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Remarks:

This article is an abridged version of a report commissioned to ICCIDD by the World Health Organization in which the metabolism and kinetics of iodate are evaluated. There is limited detail on the experimental methods on which the evaluation is based; however, overall the range of studies documented substantiates the conclusions drawn. The evaluation on iodate is considered to be relevant to the registration substance based on the fact that periodate rapidly transforms to iodate in the body following exposure by ingestion.

Objective of study:

distribution

excretion

metabolism

Principles of method if other than guideline:

Data from a range of studies, investigating the metabolism and kinetics of iodate, were evaluated in a peer reviewed article.

GLP compliance:

not specified

Radiolabelling:

yes

Remarks:

[128]-I was used in a number of the reported studies

Type:

metabolism

Results:

Iodate is quantitatively reduced to iodide by nonenzymatic reactions, and thus becomes available to the body as iodide.

Details on distribution in tissues:

Experiments, using [128]-I have shown that after intravenous injection of 750 mg of iodate (an excessive iodine dose in this species) the rat thyroid gland accumulated radioactivity, albeit at a slower rate than when the [128]-I was injected in the form of iodide. In rats and rabbits given much smaller, physiological doses (0.750 to 1.0 mg of iodine) orally or intraperitoneally, the tracer was equally available to the thyroid, whether originating from iodate or iodide. Tissue distribution of radio iodine in liver, kidney, brain, heart, muscle, small intestine, stomach, testes, submaxillary gland, skin, hair, and thyroid was identical from iodide and from iodate. After iodate injection, radioactivity in tissues (as well as in urine) was exclusively in the form of iodide. Large doses of iodate (1.4 to 15 mg iodine per kilogram) blocked the thyroidal uptake of injected labelled iodide in rats, again suggesting that iodine from iodate is available to the thyroid. When added to animal feed, iodate increases the iodine content of eggs and milk, respectively.

In humans, isotopic iodine from iodate is available to the thyroid when given orally, but the bioavailability was about 10 % lower than that of iodide.

Details on excretion:

When dogs were fed a dose of 200 mg/kg of potassium iodate in the form of gelatine capsules, their urine contained iodide as well as iodate.

Transformation

Iodate may undergo several redox reactions, of which the major one may be writtem as:

IO3- + 6 H+ + 6 e-  →  I-  + 3 H2O

As outlined in the above equation, iodate oxidises to iodate. the standard redox potential of 1.085 V decreases to 0.672 V at pH 7, and to 0.648 V at the physiological pH of 7.4.

Kinetics of Transformation

Thyroid slices incubated in vitro took up radio iodine from iodate, albeit at a slightly slower rate than from iodide. The radio iodine accumulating in the slices was all in the form of iodide. Iodate was partly transformed into iodide already in the incubation medium. After injection of large doses of iodate into rats, iodate in blood was quantitatively reduced to iodide within 40 minutes. After intravenous administration of intermediate iodate doses to rabbits (1000 mg of iodine) and rats (95 mg of iodine) transformation in the blood into iodide was complete in less than 1 minute. When high retinotoxic doses (30 mg/kg) were injected intravenously into rabbits, iodate disappeared from the circulation and was transformed into iodide with a half life of 14 minutes. In vitro, whole blood as well as extracts of liver, kidney, and brain reduced 84 to 99 % of added iodate to iodide within 1 minute, while washed red cells and serum were clearly less efficient, confirming other experiments that used longer incubation times. The reduction of iodate has been shown to be a non-enzymatic process and depends on the availability of sulfhydryl groups, e.g. in glutathione. Furthermore, this reaction is inhibited by N-ethyl-maleimide, a recognised glutathione- depleting agent.

Conclusions:

Interpretation of results: Iodate is quantitatively reduced to iodide
The article concludes that iodate is quantitatively reduced to iodide by non-enzymatic reactions, and thus becomes available to the body as iodide. Therefore, except perhaps for the gastrointestinal mucosa, exposure of tissues to iodate might be minimal.

Executive summary:

Data from a range of studies, investigating the metabolism and kinetics of iodate, were evaluated in the peer reviewed article.

The article concludes that iodate is quantitatively reduced to iodide by non-enzymatic reactions, and thus becomes available to the body as iodide. Therefore, except perhaps for the gastrointestinal mucosa, exposure of tissues to iodate might be minimal.

Reference 4

Endpoint:

basic toxicokinetics in vivo

Type of information:

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

Adequacy of study:

weight of evidence

Study period:

Not reported

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Remarks:

Publication outlining studies investigating the conversion of iodate to iodide in rats. The publication contains a sufficient level of detail to assess the quality of the relevant results.

Objective of study:

absorption

distribution

excretion

Principles of method if other than guideline:

Studies to investigate the conversion of iodate to iodide in rats in vivo.

GLP compliance:

no

Radiolabelling:

yes

Remarks:

[131]-I was used in the various studies

Species:

rat

Strain:

Sprague-Dawley

Sex:

not specified

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: Adult
- Diet: modified McCollum diet (containing aproximately 0.2 µg iodine per g)

Prior to study initiation, a number of animals had been made hypothyroid by the feeding og 0.05 % propyl thiouracil in the diet for 30 days.

Route of administration:

other: oral (gavage), intraperitoneal and intravenous

Details on exposure:

PREPARATION OF [131]-I
1 mL of a solution containing 10 µg of iodide, 25 µL of 1 % sodium acetate-10 % acetic acid, and the desired amount of [131]-I was mixed with 10 µL of Br2 in a centrifuge tube. After a few minutes, the coloured supernatant was withdrawn from the excess Br2 with a capillary pipette and transferred to a small flask. Two small Carborundum boiling chips were added and the contents of the flask were carefully brought to boiling in a hood over a micro gas burner. The excess Br2 was completely eliminated after 1 to 2 min of boiling, and the reaction mixture was diluted to 10 mL with 0.067 M phosphate buffer, pH 7.8. The final pH of the resulting radioiodate solution was approximately 7. Carrier potassium iodate was added to provide the concentrations indicated in the various experiments.
The identity of the radioiodate was established by ascending paper chromatography. The purity of the radioiodate was determined by butanol-ethanol-NH4OH chromatography.

Duration and frequency of treatment / exposure:

Animals recieved a sinlge administration.

Dose / conc.:

0.002 other: µmole

Remarks:

Thyroid uptake investigations, oral administration (radioiodate and radioiodide)

Dose / conc.:

0.2 other: µmole

Remarks:

Thyroid uptake investigations, oral administration (radioiodate and radioiodide)

Dose / conc.:

0.002 other: µmole

Remarks:

Thyroid uptake investigations, intraperitoneal administration (radioiodate and radioiodide)

Dose / conc.:

0.8 other: µmole

Remarks:

Thyroid uptake investigations, intraperitoneal administration (radioiodate and radioiodide)

Dose / conc.:

0.003 other: µmole

Remarks:

Absorption investigations, oral dose (radioiodate, radioiodide)

Dose / conc.:

0.25 other: µmole

Remarks:

Absorption investigations, oral dose (radioiodate, radioiodide)

Dose / conc.:

1.25 other: mµmoles

Remarks:

Distribution investigation, intravenous injection (radioiodate, radioiodide)

Dose / conc.:

4 other: mµmoles

Remarks:

Excretion investigation, intravenous injection (radioiodate, radioiodide)

Dose / conc.:

0.75 other: µmole

Remarks:

Determination of in Vivo Transformation of Iodate to Iodide, intravenous dose radioiodate

No. of animals per sex per dose / concentration:

- Thyroid uptake investigations
Oral administration: 6 animals dosed 0.002 µmole; 4 animals dosed 0.2 µmole (radioiodate and radioiodide)
Intraperitoneal administration: 6 animals dosed 0.002 µmole; 4 animals dosed 0.8 µmole (radioiodate and radioiodide)

- Absorption investigation
Four rats were dosed 0.003 or 0.25 µmole of radioiodate or radioiodide

- Distribution investigation
3 animals dosed (radioiodate and radioiodide)

- Excretion investigation:
4 animals dosed (radioiodate and radioiodide)

- Determination of in Vivo Transformation of Iodate to Iodide
2 animals (1 normal rat and 1 hypothyroid rat)

Control animals:

no

Details on absorption:

Iodate iodine was just as readily absorbed from the gastrointestinal tract as was iodide. No significant differences between the two groups could be observed 2 to 3 hours after administration of the radioactive compounds.
This was true both for normal rats and for rats that had been made hypothyroid by the feeding of 0.05 % propyl thiouracil in the diet for 30 days. Presumably, under the conditions used here radioiodate was very rapidly converted to radioiodide in the gastrointestinal tract, since it has been reported that iodate as such is not absorbed by the isolated small intestine. Preliminary experiments of with everted sacs of rat small intestine also confirmed the inability of iodate to move across the gut wall.

Details on distribution in tissues:

No essential differences were observed between the radioiodate- and the radioiodide- injected groups.

Details on excretion:

[131]-I measurements, made after a 48-hour collection period, showed no significant differences between the two groups.
No radioiodate was detected in urine after its administration to rats.

Details on metabolites:

Iodate was almost immediately reduced to iodide following its intravenous administration to rats.

Thyroid Uptake of [131]-I after Administration of Radioiodate or Radioiodide

Iodate iodine was just as readily available to the thyroids of rats as was iodide, following oral or intraperitoneal injection. This was true both for injections of 0.25 µg (0.002 µmole) or 25 µg (0.2 µmole) of iodine.

The distribution of the [131]-I among the various iodinated amino acids of the thyroid was the same for both radioiodate- and radioiodide-injected rats.

Table 1: Thyroid Uptake of [131]-I after Administration of Radioiodate or Radioiodide

Form of administration	Oral administration			Intraperitoneal administration
	Dose (µmole)	Interval (hours)	Uptake in thyriod	Dose (µmole)	Interval (hours)	Uptake in thyriod
iodide	0.002	4	6.05 ± 0.68	0.002	4	12.1 ± 0.33
iodate	0.002	4	9.1 ± 2.2	0.002	4	11.5 ± 0.37
iodide	0.2	2	1.8 ± 0.19	0.8	4	1.6 ± 0.25
iodate	0.2	2	2.5 ± 0.23	0.8	4	1.4 ± 0.12

Conclusions:

Interpretation of results: Iodate was almost immediately reduced to iodide
Iodate was almost immediately reduced to iodide following its intravenous administration to rats. Even when it is given in relatively large doses, reduction was complete within 2 to 3 min. Following oral administration also, radioiodate is so rapidly transformed to radioiodide that 2-hour thyroid [131]-I uptakes in rats that received radioiodate by stomach tube were not significantly different from those of rats that received radioiodide by the same route.

Executive summary:

Various investigations on rats were reported. The investigations evaluated the absorption, distribution and excretion of [131]-I following administration of radioiodate or radioiodide to rats. Under the conditions of the investigations iodate was almost immediately reduced to iodide following its intravenous administration to rats. Even when it is given in relatively large doses, reduction was complete within 2 to 3 min. Following oral administration also, radioiodate is so rapidly transformed to radioiodide that 2-hour thyroid [131]-I uptakes in rats that received radioiodate by stomach tube were not significantly different from those of rats that received radioiodide by the same route.

Reference 5

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

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

Adequacy of study:

weight of evidence

Study period:

not reported

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Remarks:

Publication outlining studies investigating the conversion of iodate to iodide in a series of in vitro tests. The publication contains a sufficient level of detail to assess the quality of the relevant results.

Objective of study:

other: uptake of iodate and iodide by thyroid slices (see attached file)

Principles of method if other than guideline:

Studies to investigate the conversion of iodate to iodide in vitro

GLP compliance:

no

Radiolabelling:

yes

Remarks:

[131]-I was used in the various studies

Details on exposure:

PREPARATION OF [131]-I
1 mL of a solution containing 10 µg of iodide, 25 µL of 1 % sodium acetate-10 % acetic acid, and the desired amount of [131]-I was mixed with 10 µL of Br2 in a centrifuge tube. After a few minutes, the coloured supernatant was withdrawn from the excess Br2 with a capillary pipette and transferred to a small flask. Two small Carborundum boiling chips were added and the contents of the flask were carefully brought to boiling in a hood over a micro gas burner. The excess Br2 was completely eliminated after 1 to 2 min of boiling, and the reaction mixture was diluted to 10 mL with 0.067 M phosphate buffer, pH 7.8. The final pH of the resulting radioiodate solution was approximately 7. Carrier potassium iodate was added to provide the concentrations indicated in the various experiments.
The identity of the radioiodate was established by ascending paper chromatography. The purity of the radioiodate was determined by butanol-ethanol-NH4OH chromatography.

Uptake of Radioiodate or Radioiodide by Thyroid Slices

Thyroid slice experiments were performed to determine whether iodate can be concentrated by thyroid tissue. When thyroid slices were incubated in Krebs-Ringer-bicarbonate medium containing either radioiodate or radioiodide, the initial rate of uptake of [131]-I was greater in the case of radioiodide. However, after 90 minutes of incubation there was very little difference between the samples with respect to either total uptake or [131]-I distribution. In the thyroid slices exposed to radioiodate, no evidence could be obtained that iodate as such was concentrated by the tissue. The results suggest that iodate-[131]-I was converted to iodide-[131]-I before it was concentrated.

 

Rate of Conversion of Iodate to Iodide by Blood in Vitro

When radioiodate (4 x 10^-5 M) was incubated in vitro at 37 °C with whole blood, all the radioiodate was converted to iodide within 3 minutes. Plasma was not nearly as effective as whole blood, reducing only about 24 % of the radioiodate in 15 minutes. Even when the concentration of radioiodate was raised to 8.3 x 10^-4 M (105 µg of iodine per mL), complete reduction to iodide occurred within 2 minutes in rat whole blood. Washed, resuspended red cells were about equally as effective as whole blood in reducing iodate. Blood that had been heated to 65 °C for 10 minutes still retained its high capacity for reducing iodate, suggesting that an enzymatic reaction was not involved. When the concentration of radioiodate was raised to 3.3 X 10^-3 M (420 µg of iodine per mL), the rate of reduction by whole blood was slowed, and approximately 15 % of the iodate remained unchanged after 15 minutes of incubation.

 

Reduction of Iodate by Various Reducing Agents at pH 7.3

The sulfhydryl-containing compounds, cysteine, thioglycolate, and reduced glutathione, readily reduced iodate at pH 7.3. However, the reducing compounds 1-methyl-2-mercaptoimidazole, ascorbic acid, sulfite, and thiourea did not react with iodate at this pH. The biological reducing agents, DPNH and TPNH, did not reduce iodate at pH 7.4. On the other hand, extracts prepared from 0.15 % NaCl-perfused rat liver, kidney, or brain readily reduced iodate at pH 7.1 to 7.4, as did human whole blood and resuspended, washed red cells.

 

Effect of pH on Reaction between Iodate and I-Methyl-d-Mercaptoimidaxole

The reaction between 1-methyl-2-mercaptoimidazole and iodate was pH-dependent. Above pH 5 no reaction occurred, but at pH 2.3 iodate was almost completely reduced to iodide in 30 minutes at room temperature. In other experiments it was shown that ergothioneine, which was ineffective at pH 7.3, readily reduced iodate at pH 3.7.

 

Effect of Iodate on GSH Level of Red Cells

Incubation of red cell suspensions with iodate quickly reduced the GSH level. These results indicate that the GSH in red cells is readily available for reaction with iodate. It should be recognized, however, that the concentration of iodate used here (5 X 10^-4 M) was relatively high. It is unlikely that iodate administered to animals only in amounts necessary to provide the daily requirement of iodine would have any detectable effect on the reduced glutathione level of red blood cells.

Conclusions:

Whole blood, resuspended washed red cells, and various tissue extracts reduced iodate to iodide very rapidly in vitro. However, plasma was much less effective than whole blood in reducing iodate. Iodate was rapidly reduced by glutathione at pH 7.4, but not by a number of other biological reducing agents.
Because red cells and most tissues contain a fairly high concentration of GSH, it might appear that GSH is the active agent in blood and tissues responsible for reducing iodate. However, the iodate-reducing capacity of red cells and of tissue extracts far exceeded their potential GSH content, and it was suggested that -SH groups in hemoglobin and in other proteins may also be oxidised by iodate. Results of incubations carried out at 0° C suggest that iodate reduction in blood is not enzymatic, at least for iodate levels below 1 x 10^-3 M.

Executive summary:

Studies were conducted to investigate the conversion of iodate to iodide in rats in vitro.

Under the conditions of the study whole blood, resuspended washed red cells, and various tissue extracts reduced iodate to iodide very rapidly in vitro. However, plasma was much less effective than whole blood in reducing iodate. Iodate was rapidly reduced by glutathione at pH 7.4, but not by a number of other biological reducing agents. Because red cells and most tissues contain a fairly high concentration of GSH, it might appear that GSH is the active agent in blood and tissues responsible for reducing iodate. However, the iodate-reducing capacity of red cells and of tissue extracts far exceeded their potential GSH content, and it was suggested that -SH groups in haemoglobin and in other proteins may also be oxidised by iodate. Results of incubations carried out at 0 °C suggest that iodate reduction in blood is not enzymatic, at least for iodate levels below 1 x 10^-3 M

Description of key information

Sodium periodate is an inorganic salt, which in its pure form exists as a white crystalline powder. Information is utilised from the physical chemical properties and existing toxicology studies on similar compounds, to infer as far as possible, the potential toxicokinetics of the compound.

In the two available gastric hydrolysis studies, the substance was found to react with simulated gastric fluids. The reaction occurs rapidly and is completed within half an hour. The periodate (IO4-) undergoes a chemical reaction to form iodate (IO3-). However, no further reaction was identified. The available data confirm that the toxicological effects of iodate in the human body need to be considered when assessing the effects of periodate.

Sodium periodate is reactive, an oxidising agent, and is seen to be caustic to skin in-vitro. The periodate ion is rapidly reduced in biological media to form iodate and iodide. These are forms of iodine that are an essential component of diet, are used as fortification of foodstuffs in certain parts of the world, and (at low concentrations of periodate relevant to a NOAEL) are well-absorbed by the oral route. An oral absorption value of 100 % is assumed. There is some indication of dermal absorption from topical use of iodine compounds, but in the absence of specific data a default value of 25 % for dermal absorption, and of 100 % for inhalation absorption, is assumed for risk assessment.

Absorbed iodate or iodide will be incorporated into thyroid hormones and tissue physiology in a process that is well-understood.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

25

Absorption rate - inhalation (%):

100

Additional information

Gastric hydrolysis of the test material was investigated using a procedure based on EU Method C.7 and OECD 111. During the study, the test material was dissolved in either Fasted State Simulated Gastric Fluid (FaSSGF), or Fed State Simulated Gastric Fluid (FeSSGF), in the dark at body temperature. The concentration of the test material was determined as a function of time. Furthermore, the quantities, and nature of the decomposition products, were investigated.

Under the conditions of the study, the test material quickly degraded in both the fasted and fed state simulated gastric simulations solutions. The half-life of the test material in fasted and fed state simulated gastric fluids was determined to be significantly less than 1 hour at 38.0 ± 0.5 °C.

The definitive analytical technique used to determine the test material concentration of the initial and final reaction solutions was satisfactory in confirming the reduction of the periodate ion in both solutions.

Additional analytical techniques employed were not conclusive in proving the presence of iodate, iodide or iodine in the reacted test solutions. However, as there was essentially zero oxidising potential remaining in the degraded solutions, as well as no visible evidence of purple coloured elemental iodine in these solutions, it was considered that the periodate had been reduced all of the way down to iodide. This, however, could not be proved by the analytical techniques on hand.

Alternative analytical techniques would therefore be required to analyse the nature of the complex solutions. However, this was outside of the scope of the current study.

 

A further study was therefore conducted, the aim of which was to:

- verify that sodium periodate undergoes a chemical reaction within two types of solution which are designed to simulate the contents of the human stomach in its ‘fasted’ and ‘fed’ stated

- to determine how quickly the reaction proceeds and if it goes to completion

- to identify the nature of the iodine-based decomposition products.

The study was conducted using a procedure based on EU Method C.7. During the study the test material was dissolved in either Fasted State Simulated Gastric Fluid (FaSSGF), or Fed State Simulated Gastric Fluid (FeSSGF), at body temperature. The concentration of the test material, and known decomposition products, were determined at 0.5, 1, 2, 4, 6 and 24 hours. The procedure was repeated using the reference substance, potassium iodate, with incubation periods of 1, 2, 4, and 6 hours.

The test work confirmed that sodium periodate reacts with both types of simulated gastric fluids. The reaction occurs rapidly and in both cases is completed within half an hour. The periodate (IO4-) undergoes a chemical reaction to form iodate (IO3-). However, no further reaction was identified, specifically to other iodine based substances such as iodine or iodide, over the 24 hour monitoring period. A reference sample of iodate was also tested and showed the same behaviour confirming the rapid reduction to iodate.

 

This report supports the previous test study and confirms that the toxicological effects of iodate in the human body also need to be considered when assessing the effects of periodate.

Data from a range of studies, investigating the metabolism and kinetics of iodate, were evaluated in a peer reviewed article. The article concludes that iodate is quantitatively reduced to iodide by non-enzymatic reactions, and thus becomes available to the body as iodide. Therefore, except perhaps for the gastrointestinal mucosa, exposure of tissues to iodate might be minimal.

An additional study was also considered which investigated evaluated the absorption, distribution and excretion of [131]-I following administration of radioiodate or radioiodide to rats. Under the conditions of the investigations iodate was almost immediately reduced to iodide following its intravenous administration to rats. Even when it is given in relatively large doses, reduction was complete within 2 to 3 min. Following oral administration also, radioiodate is so rapidly transformed to radioiodide that 2-hour thyroid [131]-I uptakes in rats that received radioiodate by stomach tube were not significantly different from those of rats that received radioiodide by the same route. The study also included in vitro studies to investigate the mechanism of the conversion of iodate to iodide in rats in vitro. Under the conditions of the study whole blood, resuspended washed red cells, and various tissue extracts reduced iodate to iodide very rapidly in vitro. However, plasma was much less effective than whole blood in reducing iodate. Iodate was rapidly reduced by glutathione at pH 7.4, but not by a number of other biological reducing agents. Because red cells and most tissues contain a fairly high concentration of GSH, it might appear that GSH is the active agent in blood and tissues responsible for reducing iodate. However, the iodate-reducing capacity of red cells and of tissue extracts far exceeded their potential GSH content, and it was suggested that -SH groups in haemoglobin and in other proteins may also be oxidised by iodate. Results of incubations carried out at 0 °C suggest that iodate reduction in blood is not enzymatic, at least for iodate levels below 1 x 10^-3 M

In accordance with the principles for assessing data quality as defined in Klimisch et al (1997), the gastric hydrolysis studies were assigned a reliability score of 2. The studies were reported to a high standard, and the methodology was designed in basic compliance with the standardised testing guidelines to investigate hydrolysis as a function of pH. The published data were also assigned a reliability score of 2, although the investigation of the metabolism and kinetics of iodate was presented is an abridged version of a report commissioned to ICCIDD by the World Health Organization. The second published study was performed in line with good scientific principles and was reported in sufficient detail in order to assess the accuracy of the conclusions drawn.

TOXICOKINETIC EVALUATION

Physicochemical properties

Sodium periodate has a molecular weight of 214 g/mol and is readily soluble in water (80-93 g/L). It meets criteria as an oxidising agent, so is reactive in biological media.

Absorption

Oral absorption

Sodium periodate dissociates in water, forming the periodate ion. Periodate is demonstrated to be rapidly reduced in gastric fluid, forming iodate which is then further reduced in tissues via non-enzymatic processes to iodide. Iodine, available as iodate or iodide, is an essential physiological requirement and is readily absorbed (see Bürgi 2001; EFSA 2006). At dose levels relevant to determination of a NOAEL, complete absorption may be anticipated; therefore for risk assessment purposes an oral absorption value of 100 % is applied.

Dermal absorption

No data is available to estimate dermal absorption. The MW (214) and pKa (-1) suggest dermal absorption to be of concern. High concentrations of periodate are caustic and will react chemically with components of the skin. At lower concentrations relevant to a NOAEL periodate may degrade (primarily to iodate) and be available for absorption; EFSA (2006) indicates iodine from topical disinfectant products to be absorbed dermally. The skin however exercises a barrier function and is unlikely to be completely permeable. 

For the purposes of risk assessment therefore, estimation of mammalian dermal absorption is made in accordance with principles adopted by the EFSA guidance on estimating dermal absorption of pesticide active substances (EFSA, 2012). On this basis, dermal absorption is estimated at 25 % for the substance at non-corrosive concentrations.

 

Inhalation absorption

For any material subject to inhalation, absorption is considered to be 100 %.

 

Distribution, Metabolism and Elimination

The distribution and metabolism of iodide (the downstream product of periodate) is well-documented (Bürgi 2001; EFSA 2006). The majority of iodide is taken up by the thyroid and used in synthesis of the thyroid hormones. There is also some distribution of iodide to other tissues. It is very likely that periodate will be rapidly transformed under biological conditions to iodate and iodide, and the same tissue distributions will occur. The thyroid has a storage function and will retain iodine; thyroid hormones are also strongly protein-bound in circulation, promoting persistence. The process is subject to feedback control and does not indicate potential for bioaccumulation. Bürgi (2001) identifies an ocular toxicity for iodate which is not seen for iodide, suggesting the transformation from iodate to iodide may not be complete at high doses. Iodide not taken up into tissues is readily eliminated in urine (EFSA 2006) and the same may be anticipated for iodate.

 

Conclusion

For the purposes of human risk assessment oral absorption of the substance is estimated at 100 %, inhalation absorption is estimated at 100 % and dermal absorption is estimated at 25 %.