Iron orthophosphate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: - scientifically sound study - no guideline followed, non-GLP, only qualitative conclusions can be drawn

Data source

Reference

Reference Type:

publication

Title:

Biological Availability of Iron Supplements for Rats, Chicks and Humans

Author:

Pennell MD, Davies MI, Rasper J & Moztok I

Year:

1976

Bibliographic source:

The Journal of Nutrition. 106(2): 265-274

Materials and methods

Objective of study:

absorption

other: bioavailability

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Fourteen experiments were conducted on the effect of protein and carbohydrate sources in the assay diets on the relative biological values (RBV) of food grade sodium iron pyrophosphate (NaFePP) and ferric orthophosphate (FePO4) vs. ferrous sulfate (FeSO4) for rats and chicks, using the response in blood hemoglobin to graded levels of supplemental iron as the assay criterion. Two trials were made with volunteers to estimate the RBV of NaFePP and FePO4 for humans, based on the increase in plasma iron 2 hours after ingestion of 100 mg of iron of a test dose following an overnight fast.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Iron orthophosphate

EC Number:

233-149-7

EC Name:

Iron orthophosphate

Cas Number:

10045-86-0

Molecular formula:

FePO4

IUPAC Name:

iron(3+) phosphate

Details on test material:

- Name of test material (as cited in study report): ferric orthophosphate

Test animals

Species:

other: Chicks (White Plymouth Rock), Rats (Wistar) and humans

Strain:

not specified

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source:
Chicks: Woodlyn Laboratories Limited
Rats: Arbot Acres (Ontario) Limited
- Housing: Stainless steel, screen-bottom caging

Rats: 8/10 rats in individual cages
Chicks: Pens of cihcks containing 9 or 10 chicks

Administration / exposure

Route of administration:

oral: feed

Details on exposure:

In the curative procedure, the animals were made anemic using the low iron basal diets as recommended in the official AOAC method and the experimental diets were then fed for 2 weeks. In prophylactic assays, the experimental diets were fed to day-old chicks and to rats from weaning at 21 days of age.

Duration and frequency of treatment / exposure:

2 weeks

Doses / concentrations

Remarks:

Doses / Concentrations:
Three levels of the standard ferrous sulfate and of the test sample in each assay were fed at equal log increments in amounts which were estimated to give linear and parallel responses in haemoglobin when plotted against the log of the added iron. Higher levels of the test samples (120-640 mg Fe/kg diet) were required by chicks to give responses in haemoglobin which were similar to those obtained with a range of 8-32 mg Fe/kg diet furnished by ferrous sulfate.

No. of animals per sex per dose / concentration:

rats: 8 to 10
chicks: 9 to 10

Control animals:

yes

Positive control reference chemical:

ferrous sulfate was used as a control - assuming 100% bioavailability.

Results and discussion

Any other information on results incl. tables

The effect of source of protein supplement in the assay diet on the utilisation of iron from ferric orthophosphate (FePO₄) by anemic chicks and rats is shown in table 1. The RBV of iron from this sample of FePO4 for chicks was 4 (vs. ferrous sulphate=100) and the source of protein in the assay diets had no effect. The RBV for rats was 28 when the diet contained nonfat milk powder and 49 when protein source was casein. The difference in RBV due to protein supplement for rats was significant.

 

Table 1. Effect of diet on the utilisation of iron from food grade ferric orthophosphate by chicks and rats

Exp. No	Species	No. of animals	Diet no.	Source of protein	Relative biological value* (Vs. ferrous sulphate = 100)
					Mean	Fidiucial limits
13	Chicks	54	3	Casein	4	(3-6)
		54	1	Nonfat dried milk (40%)	4	(3-5)
14	Rats	60	3	Casein	49	(42-59)
		59	1	Nonfat dried milk (40%)	28^1	(20-37)

*based on haemoglobin levels after feeding of experimental diet to anemic animals for 2 weeks.

¹Difference due to protein source in diet statistically significant (P <0.05)

The results of the study on iron absorption from NaFePP (sample 1) and FePO₄by human subjects are summarized in table 6. The geometric mean absorption (% of dose) of iron from FePO₄and NaFePP were very low. The mean values for the iron absorbed from ferrous sulfate were 15-fold and 24-fold higher than from the two test sources, respectively. The two trials were made about 11 months apart and there was a marked difference in the amount of iron absorbed from ferrous sulphate by three of the volunteers (subjects JR, VP, and JAR) out of the nine individuals who participated in both trials. Nevertheless, the geometric mean absorptions of iron from the standard ferrous sulphate in these experiments were within the range of values obtained for the standard in seven other trials with human subjects.

 

Table 2. Absorption of iron from ferric orthophosphate (FePO₄) sodium iron pyrophosphate (NaFePP) and ferrous sulfate (FeSO₄) by human subjects and the relative biological value (RBV) of the iron sources

 

Identification	Sex, age	Hb blood	Iron absorption (% of dose)^1and RBV (vs. FeSO4= 100)
			Experiment 15			Experiment 16
	Years	g/100ml	%	%		%	%
1.    JR	F 24	12.6	0.83	3.72	22.3	0.90	10.73	8.4
2.    RD	F 48	13.4	0.51	4.02	12.7	0.23	3.20	7.2
3.    VP	F 49	13.6	0.45	4.07	11.1	1.67	13.75	12.1
4.    DM	F 55	14.5	0.13	1.66	7.8	0.01^2	1.43	0.7
5.    MM	F 58	12.8	0.33	1.60	20.6	0.61	1.97	30.9
6.    JAR	F 40	12.8	0.30	5.57	5.4	1.25	9.12	13.7
7.    JC	M 23	13.8	1.01	10.70	9.5	0.01^2	12.03	0.1
8.    HG	M 32	14.1	0.89	3.44	25.8	0.01^2	3.07	0.3
9.    IM	M 63	14.1	0.24	5.56	4.3	0.94	5.45	17.3
10. TG	M 29	15.4	0.01	3.09	0.3
11. AM	M 26	14.6	0.01	3.48	0.3
12. NR	F 19	11.9				0.01^2	5.66	0.2
13. DSM	M 43	13.2				1.08	5.03	21.5
14. RK	M 23	12.8				1.77	9.78	18.1
15. JP	M 24	16.2				1.07	5.85	18.3
Mean ± SEM^3			0.22 ± 1.64	3.73 ± 1.18	5.9 ± 1.3	0.23 ± 1.76^4	5.47 ± 1.22	4.3 ± 1.2

 

¹Based on increase in plasma iron 2 hours after ingestion of 100 mg iron provided by the test dose after overnight fast (single trial with each supplement) using estimates of blood volume based weight, height and sex of subjects.

²There was no detectable increase in plasma iron after ingestion of test and a value of 0.01% was arbitrarily assigned for the percentage of dose absorbed for the purpose of estimating the geometric means of percentage absorption and RBV.

³Geometric mean ± SEM. The comparison between the tests in each experiment was performed in pairs by the Students t test.

⁴Significantly different compared to iron absorption from FeSO₄(P<0.001)

 

Applicant's summary and conclusion

Conclusions:

Interpretation of results: bioaccumulation potential cannot be judged based on study results
The study concludes that food grade NaFePP and FePO4 are of little or no value in the present programs of iron enrichment of foods as their biological availability is considerably less than that of ferrous sulfate.