Sodium [N-[2-[bis(carboxymethyl)amino]ethyl]-N-(2-hydroxyethyl)glycinato(4-)]ferrate(1-)

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

22 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):

10

Modified dose descriptor starting point:

NOAEC

Value:

220 mg/m³

Explanation for the modification of the dose descriptor starting point:

only possible for systemic effects

AF for dose response relationship:

1

Justification:

dose-response relationship present

AF for differences in duration of exposure:

2

Justification:

subchronic to chronic

AF for interspecies differences (allometric scaling):

1

Justification:

already in correction for inhalation volumes

AF for other interspecies differences:

1

Justification:

low absorption and not metabolized

AF for intraspecies differences:

5

Justification:

standard assessment factor

AF for the quality of the whole database:

1

Justification:

several studies on chelates and metal chelates available

AF for remaining uncertainties:

1

Justification:

not present

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

10 mg/m³

DNEL related information

DNEL derivation method:

other: expert judgement

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:

62 500 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):

40

Modified dose descriptor starting point:

NOAEL

Value:

2 500 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

only possible for systemic effects

AF for dose response relationship:

1

Justification:

dose-response relationship present

AF for differences in duration of exposure:

2

Justification:

subchronic to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

standard factor

AF for other interspecies differences:

1

Justification:

very low absorption and not metabolized

AF for intraspecies differences:

5

Justification:

standard factor

AF for the quality of the whole database:

1

Justification:

several studies on chelates and metal chelates available

AF for remaining uncertainties:

1

Justification:

not needed

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

Acute exposure, systemic and local effects;

See also section 13 for read across document. Due to the lack of acute systemic and local toxicity (oral and inhalation), DNELs have not been calculated for acute exposure (systemic and local).There were no local dermal effects observed in the in vitro skin irritation test, and dermal absorption was estimated to be very low, thus no DNEL has been calculated.

Long term exposure -Systemic effects

The key study for DNEL derivation is taken as the extended OECD 422 oral toxicity study conducted on DTPA-FeHNa. In this study male rats were treated for at least 13 weeks and female rats for almost 14 weeks. The NOAEL for repeated exposure is similar to that for reproduction toxicity and the mode of action for toxicity is considered to be consistent for the different endpoints. Therefore this NOAEL is considered to be protective for both endpoints and no separate DNEL has been calculated for reproduction toxicity. Therefore the starting point for the DNEL derivation is 500 mg/kg bw/day (refer to sections 7.5 and 7.8)

Justification of assessment factors

Extrapolation from Subchronic to Chronic = 2

Allometric scaling (for dermal route) = 4

Remaining difference (systemic toxicity) = 1; there is no indication that the toxicity of chelating agents such as HEDTA (like EDTA and DTPA) differs significantly between animals and humans. They are absorbed poorly by both animals and man and excreted rapidly with no evidence of tissue sequestration. It is not metabolized. The absorption of DTPA is actually lower in man than in rats, and therefore they would not be expected to be more sensitive.

Intraspecies differences = 5 (workers). Much (if not all) of the toxicity of HEDTA (like EDTA and DTPA) is based upon the chelation of essential metals such as zinc. Due to the differences in nutritional status within the population, a factor of 5 is proposed for workers. This factor indicates the potential variation in the intake of essential nutrients such as zinc in the worker populations, for example, zinc intake can vary from 4 mg to 22 mg/day although in a healthy worker population the variation is likely to be far less, hence a factor of 5 is certainly sufficient to cover the variation between workers with respect to nutritional status.

Total Assessment factor is 40 for Dermal and 10 for Inhalation

Dermal

Dermal absorption of HEDTA (like EDTA and DTPA) is estimated to be 0.001% (refer to toxicokinetic section). Oral absorption is estimated to be approximately 5%.

Adjusted starting point = Oral NOEL *(oral bioavailability/dermal bioavailability)

= 500*(5/0.001)

= 2,500,000 mg/kg bw

Dermal DNEL = 2,500,000/40 = 62500 mg/kg bw/day

Inhalation of aerosol (nebulized):

For intestinal absorption a figure of 5% has been used.

For inhalation: 20% (based on studies using nebulized DTPA solutions in humans – refer to toxicokinetics section)

 

Corrected inh NOAEL = oral NOAEL x [1/sRV(rat)] x [absorption (oral-rat) / absorption (inh-human)] x [sRV(human) / wRV]

This will be: 500 x 1/0.38 m3 (8h) x 5/20 x [6.7 m3 (8h) / 10 m3 (8h) = 220 mg/m3

Application of Assessment factor of 10: Inhalation DNEL (liquid aerosol) = 220/10 = 22 mg/m3

 

Inhalation of aerosol (dust)

For intestinal absorption a figure of 5% has been used.

For inhalation absorption the following is suggested: Based on the particle size distribution, it is expected that 90% of the inhaled substance will be deposited in the upper respiratory tract, which will finally be taken up orally. Of this, only 5% will be absorbed in the gastrointestinal tract and become available systematically, i.e. 0.9 x 0.05 = 0.045. The other 10% may reach the alveoli and it is assumed that this will be absorbed completely (worst case). Therefore, the total inhalation absorption factor will be 0.045 + 0.10 = 0.145.

 

Corrected inh NOAEL = oral NOAEL x [1/sRV(rat)] x [absorption (oral-rat) / absorption (inh-human)] x [sRV(human) / wRV]

This will be: 500 x [1/0.38 m3 (8h)] x [5/14.5] x [6.7 m3 (8h) / 10 m3 (8h)] = 304 mg/m3

Application of Assessment factor of 10: Inhalation DNEL (dust) = 304/10 = 30 mg/m3

Conservatively, a dust limit of 10 mg/m3 inhalable particles is proposed as DNEL local effects for longterm exposure.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

5.5 mg/m³

Most sensitive endpoint:

effect on fertility

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

20

Modified dose descriptor starting point:

NOAEC

Value:

110 mg/m³

Explanation for the modification of the dose descriptor starting point:

only possible for local efefcts

AF for dose response relationship:

1

Justification:

dose-response relationship present

AF for differences in duration of exposure:

2

Justification:

subchronic to chronic

AF for interspecies differences (allometric scaling):

1

Justification:

already in correction for inhalation volumes

AF for other interspecies differences:

1

Justification:

low absorption and not metabolized

AF for intraspecies differences:

10

Justification:

standard factor

AF for the quality of the whole database:

1

Justification:

several studies on chelates and metal chelates available

AF for remaining uncertainties:

1

Justification:

not needed

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.5 mg/m³

DNEL related information

DNEL derivation method:

other: expert judgement

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:

31 250 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):

80

Modified dose descriptor starting point:

NOAEL

Value:

2 500 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

only possible for systemic effects

AF for dose response relationship:

1

Justification:

dose-response relationship present

AF for differences in duration of exposure:

2

Justification:

subchronic to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

standard factor

AF for other interspecies differences:

1

Justification:

very low absorption and not metabolized

AF for intraspecies differences:

10

Justification:

standard factor

AF for the quality of the whole database:

1

Justification:

several studies available for other chelates en metal chelates

AF for remaining uncertainties:

1

Justification:

not needed

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

6.25 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):

80

Modified dose descriptor starting point:

NOAEL

Value:

500 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

not needed, tested via oral route

AF for dose response relationship:

1

Justification:

dose-response relationship present

AF for differences in duration of exposure:

2

Justification:

subchronic to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

standard factor

AF for other interspecies differences:

1

Justification:

low absorption and not metabolized

AF for intraspecies differences:

10

Justification:

standard factor

AF for the quality of the whole database:

1

Justification:

several studies available on other chelates and metal chelates

AF for remaining uncertainties:

1

Justification:

not needed

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

Acute exposure, systemic and local effects;

See also read across document in section 13. Due to the lack of acute systemic and local toxicity (oral and inhalation), DNELS have not been calculated for acute exposure (systemic and local). There were no local dermal effects observed in the in vitro skin irritation test, and dermal absorption was estimated to be very low, thus no DNEL has been calculated.

Long term exposure -Systemic effects

The key study for DNEL derivation is taken as the extended OECD 422 oral toxicity study conducted on DTPA-FeHNa. In this study, male rats were treated for at least 13 weeks and female rats for almost 14 weeks. The NOAEL for this study is similar for the reproduction toxicity study and the mode of action for toxicity is considered to be consistent for the different endpoints. Therefore this NOAEL is considered to be protective for both endpoints and no separate DNEL has been calculated for reproduction toxicity. Therefore the starting point for the DNEL derivation is 500 mg/kg bw/day (refer to sections 7.5 and 7.8).

Justification of assessment factors

Extrapolation from Subchronic to Chronic = 2

Allometric scaling (for the dermal and oral route) = 4

Conversion from a rat study to human exposure; other interspecies differences (systemic effects) = 1; there is no indication that the toxicity of chelating agents such as HEDTA (like EDTA and DTPA) differs significantly between animals and humans. They are absorbed poorly by both animals and man and excreted rapidly with no evidence of tissue sequestration; they are not metabolized. The absorption of DTPA is actually lower in man than in rats, and therefore they would not be expected to be more sensitive.

Intraspecies differences = 10 (consumers). Much of the toxicity of HEDTA (like EDTA and DTPA) is based upon the chelation of essential metals such as zinc. Due to the differences in nutritional status within the population, a factor of 10 is proposed for Consumer exposure. However, this factor may be too high, as it indicates the potential variation in the intake of essential nutrients such as zinc in the worker and consumer populations, for example, zinc intake can vary from 4 mg to 22 mg/day.

Total Assessment factor is 80 for Oral / Dermal and 20 for Inhalation

Dermal

Dermal absorption of HEDTA (like EDTA and DTPA) is estimated to be 0.001% (refer to toxicokinetic section). Oral absorption is estimated to be approximately 5%.

Adjusted starting point = Oral NOEL *(oral bioavailability/dermal bioavailability)

= 500*(5/0.001)

= 2,500,000 mg/kg bw

Dermal DNEL = 2,500,000/80; Dermal DNEL = 31,250 mg/kg bw/day

Inhalation of aerosol (nebulized):

For intestinal absorption a figure of 5% has been used.

For inhalation: 20% (based on studies using nebulized DTPA solutions in humans – refer to toxicokinetics section)

Corrected inh NOAEL = oral NOAEL x [1/sRV(rat)] x [absorption (oral-rat) / absorption (inh-human)] x [sRV(human) / consRV]

This will be: 500 x [1/0.38 m3 (8h)] x [5/20] x [6.7 m3 (8h) / 20 m3 (24h)] = 110 mg/m3

Application of Assessment factor of 20: Inhalation DNEL (liquid aerosol) = 110/20 = 5.5 mg/m3

It should be understood that Inhalation DNEL is significantly over conservative for the following 2 reasons: 1) The likelihood of a consumer or member of the general population being exposed to HEDTA (like DTPA via a nebulized aerosol of DTPA inserted into the nose) is VERY unlikely, thus the degree of absorption is likely an overestimate of what would actually happen. 2) The period for which the DNEL is calculated (24h) assumes a consumer or general population would be exposed to an aerosol of DTPA for 24 hours. HEDTA is not volatile and any spray of HEDTA would settle out of the air in a short period after spraying, i.e. the HEDTA would not remain in the breathable air for long periods of time. Thus exposure via inhalation will be limited to the time periods directly following the production of an aerosol containing HEDTA.

Conservatively, a limit of 2.5 mg/m3 inhalable particles is proposed as DNEL local effects for longterm exposure (based on the worker exposure limit also divided by a factor 4).

Oral

In assessing the toxicity of HEDTA (like EDTA and DTPA) it is clear that following the oral exposure it is the whole dose rather than the fraction absorbed that is responsible for the toxicity (depletion of metals). Unabsorbed HEDTA in the gut will bind metals and prevent their absorption just as the absorbed HEDTA will bind metals in the systemic circulation and increase their excretion. Therefore it is not necessary to take into account bioavailability following an oral dose when calculating the oral DNEL.

Oral DNEL = Oral NOEL/Assessment Factor = 500/80; Oral DNEL = 6.25 mg/kg bw/day