Registration Dossier

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

15.47 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

50

Dose descriptor starting point:

NOAEL

Value:

322.88 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

773.43 mg/m³

Explanation for the modification of the dose descriptor starting point:

The dose descriptor is corrected to account for molecular weight differences and then further corrected using the equations detailed in Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose[concentration]-response for human health. Figure R.8-2.

NOAEL (H3O4P.2Na) = NOAEL SALP*8*([Mol. Weight (H3O4P.2Na)]/[Mol. Weight (SALP)]

NOAEL (H3O4P.2Na) = 322.88*8*([142]/[1185.6]) = 309.37 mg/kg bw/day

NAEC(worker, 8 h) = ([“NOAEL(H3O4P.2Na)”]*[worker bw])/([allometric factor dog]*[respiratory volume, worker, 8 h]) = (309.37*70)/(1.4*10m³/person) = 1546.85 mg/m³

Additional factor for differences in absorption oral/inhalation = 0.5

NAEC(worker, 8 h) = 1546.85 mg/m³* 0.5 = 773.43 mg/m³

AF for dose response relationship:

1

Justification:

Dose spacing is within the 2-4 range, response at the LOAEL is minimal

AF for differences in duration of exposure:

2

Justification:

Subchronic to chronic

Justification:

No assessment factor as alloemtric aclaing was taken into account in the modification of the dose descriptor

AF for other interspecies differences:

2.5

Justification:

default value

AF for intraspecies differences:

5

Justification:

default value for workers

AF for the quality of the whole database:

2

Justification:

read-across data used

Justification:

no assessment factor required

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

JUSTIFICATION FOR READ ACROSS AND CHOICE OF DATA (applicable to worker and general population DNELs):

Read-across from sodium aluminium phosphate to sodium and potassium orthophosphates is considered suitable for the following reasons:

- All substances are similar inorganic ionic compounds. In aqueous solutions they will dissociate to their cationic and anionic forms and therefore these can be viewed as separate moieties with regards to toxicity.

- The Na⁺and K⁺cations are naturally occurring essential minerals that are highly regulated by homeostatic mechanisms. As such recommended intake values for all exist and are above the key NOAEL taken from the data and therefore no further assessment of their contribution to the toxicity of the materials is necessary.

- The Al³⁺is present in the substance tested in the studies from which the values for risk assessment are derived and therefore no further consideration of the toxicity of the aluminium cation is required as this is already taken into account.

- The phosphate moiety is not considered to differ to that from any other inorganic orthophosphate from a toxicological point of view for the purpose of risk assessment and the derivation of appropriate DNELs it is considered to be appropriate to use the most reliable data available for orthophosphates (see endpoint records and summary).

- A Maximum tolerable daily intake (MTDI) value of 70 mg/kg bw /day of phosphorus as calculated by the Joint FAO/WHO Expert Committee on Food Additives (JEFCA) is available. This can be applied to all the substances discussed as any toxicity effects noted via the oral route are not attributable to the cation but are as a result of high doses of phosphates.

- The main toxicological finding in repeated dose studies with most inorganic phosphates is nephrocalcinosis (calcification of the kidneys). It is noted by JEFCA that rats are particularly susceptible to these effects and these effects were taken into account when deriving the MTDI value.

Available data:

The derivation of the long term DNELs is proposed based on a series of tests performed with sodium aluminium phosphate. Although aluminium is known to have toxic effects, the only systemic toxicity observed in the tests performed on sodium aluminium phosphate was nephrocalcinosis observed in the renal tubes. Rats generally and particularly female rats are known to be susceptible to nephrocalcinosis when administered high doses of phosphates (typically starting at about 0.5 – 1.0 % in the diet). The addition of aluminium in the phosphate compound is unlikely to have an impact on the use of this data for the sodium or potassium phosphates as any toxicity observed is due to the phosphate content of the test material.

11 reliability 2 repeated-dose oral toxicity studies are available on sodium aluminium phosphate. The available toxicity tests have been performed on three variants of sodium aluminium phosphate referred to in the reports as Kasal, Levn-lite and Levair, these test materials have the following ratios:

Sodium aluminium phosphate ratios in the test materials:

TRADE NAME	SODIUM	ALUMINIUM	PHOSPHATE
Kasal	15	3	8
Levn-lite	1	3	8
Levair	3	2	8

All the available study reports list the doses administered to the animals in either ppm or % in feed. Where the information is available in the report (i.e. body weights and food consumption) this has been converted to mg/kg bw/day. For three studies the information was not available, one paper appears to be a duplicate of the test report, one report has been discounted as only male animals were tested at only one (Kasal I) and two (Kasal II) dose levels and one study is only conducted on female animals and no information on food consumption is provided in order to calculate an effect level. Therefore, the remaining seven studies have been used for the DNEL derivation.

Four of the seven studies are ninety-day studies in the rat, two are ninety-day studies in the dog and two are six-month studies in the dog.

Choice of dose-descriptor starting point:

The following issues are taken into account when deciding on which endpoint to base the Derived No Effect Level.

1. Nephrocalcinosis (in the form of microconcretions) were observed in the renal tubes of animals investigated in some of the tests. Rats generally and particularly female rats are known to be susceptible to nephrocalcinosis when administered high doses of phosphates (typically starting at about 0.5 – 1.0 % in the diet). Occupational exposure is unlikely to reach this level and Humans are likely to be less sensitive to calcium phosphate precipitation when compared to laboratory rats.

2. Nephrocalcinosis and/or reduced body weight gain were the only toxic effects observed in any of the available studies.

3. The ratio of sodium, aluminium and phosphate in the test material appears to be less relevant to the toxicity endpoint (N(L)OAEL) than the feed consumption, body weight and dosing levels used in the tests. In all the studies on the rat, the N(L)OAEL is the lowest dose level and is based on Nephrocalcinosis. Two of the studies performed on the dog have a N(L)OAEL at the highest dose level and two studies observed minimal nephrocalcinosis and reduced body weight at the highest dose leading to a NOAEL level at the mid dose level.

The studies where nephrocalcinosis was observed exhibited no other forms of toxicity and therefore the lowest NOAEL for deriving the an inhalation No Effect Level is taken from the ninety day and six month studies in the dog (Mastalski K, IBT J749 and Pettersen JC et al T-12969). The NOAEL used is 323 mg/kg bw/day based on reduced body weight gain at the higher dose level.

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

6.63 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

Dose descriptor starting point:

NOAEL

Value:

322.88 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

662.94 mg/m³

Explanation for the modification of the dose descriptor starting point:

The dose descriptor is corrected to account for molecular weight differences and then further corrected using the equations detailed in Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose[concentration]-response for human health. Figure R.8-2.

NOAEL (H3O4P.2Na) = NOAEL SALP*8*([Mol. Weight (H3O4P.2Na)]/[Mol. Weight (SALP)]

NOAEL (H3O4P.2Na) = 322.88*8*([142]/[1185.6]) = 309.37 mg/kg bw/day

NAEC(general pop, 24 h) = ([“NOAEL(H3O4P.Na)”]*[consumer bw])/([allometric factor dog]*[respiratory volume, consumer, 24 h]) = (309.37 *60)/(1.4*20m³/person) = 662.94 mg/m³

AF for dose response relationship:

1

Justification:

Dose spacing is within the 2-4 range, response at the LOAEL is minimal

AF for differences in duration of exposure:

2

Justification:

subchronic to chronic

Justification:

No assessment factor as alloemtric aclaing was taken into account in the modification of the dose descriptor

AF for other interspecies differences:

2.5

Justification:

Default value

AF for intraspecies differences:

10

Justification:

Default value

AF for the quality of the whole database:

2

Justification:

Modified to 2 to account for read across

Justification:

No assessment factor required

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

other toxicological threshold

Value:

70 mg/kg bw/day

DNEL derivation method:

other: see 'explanation for hazard conclusion'