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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
13.5 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
1
Dose descriptor starting point:
NOAEL
Value:
1.93 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
13.5 mg/m³
Explanation for the modification of the dose descriptor starting point:

To correct the route-to-route extrapolation from an oral NOAEL in humans to an inhalative NOAEC in humans the no observed effect level has to be corrected as follows:

Corrected starting point for the inhalative route for workers:

= NOAEL(oral) * (1/sRVhuman) * (ABSoral-human/ABSinh-human) * sRVhuman/wRV

= 1.93 mg/kg bw/day * (1/(6.7 m³/person / 70 kg)) * (100%/100%) * 6.7 m³ (8h) /10 m³ (8h)

= 1.93 mg/kg bw/day * (1/0.096 m³/kg bw/day) * 1 * 0.67 m³ = 13.5 mg/m³

Based on the toxicokinetic data, it can be assumed that the systemic bioavailability will be high both after oral and inhalation exposure.

(sRV = standard respiratory volum, ABSinh-human = inhalation absorption rate in humans, wRV = worker respiratory volume)

Thus, the corrected starting point for workers was 27.0 mg/m³ for inhalation.

AF for dose response relationship:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for differences in duration of exposure:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for interspecies differences (allometric scaling):
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for other interspecies differences:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for intraspecies differences:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for the quality of the whole database:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for remaining uncertainties:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
193 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
1
Dose descriptor starting point:
NOAEL
Value:
1.93 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
193 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Dermal NOAEL = oral NOAEL*ABS(oral)/ABS(dermal) = 1.93 mg/kg bw/day *(100/1) = 193 mg/kg bw/day. It is assumed that oral absorption is 100% whereas a dermal absorption rate of 1% is considered as shown in the toxikokinetic data.

AF for dose response relationship:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for differences in duration of exposure:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for interspecies differences (allometric scaling):
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for other interspecies differences:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for intraspecies differences:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for the quality of the whole database:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for remaining uncertainties:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

The DNEL derivation of dizinc pyrophosphate is on the human health effects of the counter ion zinc. Being an essential element, zinc plays an important role in many processes in the body. Although zinc deficiency can lead to notable health effects, the risk assessment for an essential element like zinc does not concern deficiencies but excess in exposure over natural background levels. The most relevant effects were observed in repeated dose toxicity studies. These effects were evaluated in latest in an OECD HPV report of a zinc category [1]. “In repeated dose toxicity studies with rats and mice, oral zinc exposure resulted in copper deficiency and pathological changes in the pancreas and the spleen as the most sensitive effects, with a NOAEL of 13.3 mg Zn2+/kg bw/day. In studies with human volunteers, women appeared to be more sensitive than men to the effects of repeated zinc supplementation. In women, supplementation at a level of 150 mg Zn2+/day (2.5 mg/kg bw/day, based on a body weight of 60 kg; LOAEL) resulted in clinical signs such as headache, nausea and gastric discomfort, and in indications for disturbance of copper homeostasis. The NOAEL in women supplemented with zinc was 50 mg Zn2+/day (0.83 mg/kg bw/day).”

To cover these uncertainties this low NOAEL for Zn2+was used to derive a DNEL which also covers these possible effects of zinc. Recalculating the effect levels to dizinc pyrophosphate in respect to the molecular weight (MW dizinc pyrophosphate = 304.76 g/mol and atomic mass Zn = 65.39) leads to the following effect levels for dizinc pyrophosphate:

NOAEL (human) = 1.93 mg/kg bw/day.

Route to route extrapolation: oral to inhalation

Since there is no dose descriptor for every exposure route, dose descriptors were converted into a correct starting point by route-to-route extrapolation based on the ECHA guidance document "Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health", November 2012. As starting point the most sensitive NOAEL found in woman was chosen for the risk assessment.

The conversion of an oral NOAEL into an inhalatory NOAEC is performed using the following equations; for workers the resulting concentration needs to be additionally corrected for the difference between basal caloric demand and caloric demand under light activity:

 

Corrected inhalatory NOAEC = oral NOAEL x 1/sRVhuman x ABSoral-human/ ABSinh-human x sRVhuman/wRV

                                            = oral NOAEL x 1/0.096m³/kg bw x 1 x 6.7 m³/10 m³

 

sRV: standard respiratory volume (6.7 m³/person, standard body weight human = 70 kg, this leads to 0.096 m³/kg bw), ABS: absorption, wRV: worker respiratory volume

 

Thus, the corrected starting point was 13.5 mg/m³.

 

In the ECHA Guidance Chapter R.8 a factor of 2 is suggested for the extrapolation from oral to inhalation absorption. On the contrary, the Technical guidance document on risk assessment in support of Commission directive 93/67/EEC, 2003 Appendix IV A and B gives a number of physico-chemical properties that normally determine oral, inhalation and dermal absorption. These parameters include molecular weight, log Kow, pKa values and for inhalation also particle size distribution, vapour pressure etc. As the absorption rate of zinc and pyrophosphate via the oral route is almost complete no factor was used for absorption differences.

 

Route to route extrapolation: oral to dermal

To convert an oral NOAEL into a dermal NOAEL, the differences in absorption between routes have to be accounted for.

As described in the TK assessment a dermal absorption rate for dizinc pyrophosphate of 1% can be assumed.

 

Corrected dermal NOAEL = oral NOAEL x ABSoral-rat/ABSdermal

                                       = oral NOAEL x 100/1

 

ABS: absorption

Thus, the corrected starting point was 193 mg/kg bw/d.

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
6.76 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
1
Dose descriptor starting point:
NOAEL
Value:
1.93 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
6.76 mg/m³
Explanation for the modification of the dose descriptor starting point:

To correct the route-to-route extrapolation from an oral NOAEL in humans to an inhalative NOAEC in humas the no observed effect level has to be corrected as follows:

Corrected starting point for the inhalative route for general population:

= NOAEL(oral) * (1/sRVhuman) * (ABSoral-human/ABSinh-human)

= 1.93 mg/kg bw/day * (1/(20 m³/person / 70 kg)) * (100%/100%)

= 1.93 mg/kg bw/day * (1/0.29 m³/kg bw/day) * 1 = 6.76 mg/m³

Based on the toxicokinetic data, it can be assumed that the systemic bioavailability will be high both after oral and inhalation exposure.

(sRV = standard respiratory volum, ABSinh-human = inhalation absorption rate in humans, wRV = worker respiratory volume)

Thus, the corrected starting point for workers was 6.76 mg/m³ for inhalation.

AF for dose response relationship:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for differences in duration of exposure:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for interspecies differences (allometric scaling):
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for other interspecies differences:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for intraspecies differences:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for the quality of the whole database:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for remaining uncertainties:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
193 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
1
Dose descriptor starting point:
NOAEL
Value:
1.93 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
193 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Dermal NOAEL = oral NOAEL*ABS(oral)/ABS(dermal) = 1.93 mg/kg bw/day *(100/1) = 193 mg/kg bw/day. It is assumed that oral absorption is 100% whereas a dermal absorption rate of 1% is considered as shown in the toxikokinetic data.

AF for dose response relationship:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for differences in duration of exposure:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for interspecies differences (allometric scaling):
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for other interspecies differences:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for intraspecies differences:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for the quality of the whole database:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for remaining uncertainties:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.93 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
1
Dose descriptor starting point:
NOAEL
Value:
1.93 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
not applicable
AF for dose response relationship:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for differences in duration of exposure:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for interspecies differences (allometric scaling):
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for other interspecies differences:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for intraspecies differences:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for the quality of the whole database:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
AF for remaining uncertainties:
1
Justification:
No AF required; NOAEL has been derived from human experience through food supplementation
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

As starting point a modified NOAEL of Zn (0.83 mg/kg bw/day) as found in the OECD HPV report [1] was used which was recalculated to dizinc pyrophosphate. The modified NOAEL of dizinc pyrophosphate is 1.93 mg/kg bw/day.

Route to route extrapolation: oral to inhalation

Since there is no dose descriptor for every exposure route, dose descriptors were converted into a correct starting point by route-to-route extrapolation based on the ECHA guidance document "Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health", November 2012. The conversion of an oral NOAEL into an inhalatory NOAEC is performed using the following equations:

 

Corrected inhalatory NOAEC = oral NOAEL x 1/sRVhuman x ABSoral-human/ ABSinh-human

                                            = 1.93 mg/kg bw/day x (1/(20 m³/person/ 70 kg)) x (100%/100%)

                                        

sRV: standard respiratory volume, ABS: absorption

 

Thus, the corrected starting point was 6.76 mg/m3.

 

In the ECHA Guidance a factor of 2 is suggested for the extrapolation from oral to inhalation absorption. On the contrary, the Technical guidance document on risk assessment in support of Commission directive 93/67/EEC, 2003 Appendix IV A and B gives a number of physico-chemical properties that normally determine oral, inhalation and dermal absorption. These parameters include molecular weight, log Kow, pKa values and for inhalation also particle size distribution, vapour pressure etc. As the absorption rate of zinc and pyrophosphate via the oral route is almost complete no factor was used for absorption differences.

 

Route to route extrapolation: oral to dermal

To convert an oral NOAEL into a dermal NOAEL, the differences in absorption between routes have to be accounted for.

The dermal absorption of dizinc pyrophosphate is relatively poor as can be expected from an anorganic molecule.

As described in the TK assessment a dermal absorption rate for dizinc pyrophosphate of 1% can be assumed.

 

Corrected dermal NOAEL = oral NOAEL x ABSoral-rat/ABSdermal

                                       = oral NOAEL x 100/1

 

ABS: absorption

Thus, the corrected starting point was 193 mg/kg bw/d.