Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
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:
0.402 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
5
Dose descriptor:
NOAEC
Value:
2.01 mg/m³
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
1
Justification:
Due to the fact that available studies show that the effects are concentration- and not time-related, a time- and activity scaling was not performed.
AF for interspecies differences (allometric scaling):
1
Justification:
Only local effects were observed for the test substance. Thus, allometric scaling is not applied, because the effects are not dependent on metabolic rate or systemic absorption
AF for other interspecies differences:
1
Justification:
There is no evidence for species differences in the general mode of action or kinetics.
AF for intraspecies differences:
5
Justification:
Default value for workers according to ECHA REACH Guidance.
AF for the quality of the whole database:
1
Justification:
The quality of the whole database is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.804 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL extrapolated from long term DNEL

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

No DNELs are proposed for the following exposure types:

-      dermal exposure: no classification is warranted and no repeated dose effects and no CMR effects are expected from dermal exposure 

-      systemic toxicity (all routes): no systemic effects were observed which were relevant for classification; it is concluded that the local DNELs inclusively protect also from systemic toxicity.

Data from a 5 day inhalation toxicity study (range finder) and a subchronic 90 day inhalation toxicity study with the source substance disodium dihydrogen EDTA (CAS 139-33-3) are available which show a local toxicity on the larynx and the terminal bronchioles. These data allow the calculation of a long-term local DNEL for respirable EDTA-particles. The long-term inhalation DNEL (local) for respirable particles is based on the following experimental results and considerations obtained for disodium dihydrogen EDTA:

  A 5 day aerosol inhalation study (range-finder) is available:

-      The top concentration, 1000 mg/m³ (6 h/d) turned out to be fatal for some animals after 1-2 days. 

-      At 300 mg/m³ severe cell losses were observed after 5 days in the central larynx and in the terminal bronchioli in the lung.

-      30 mg/m³ caused similar effects but to a lesser extent.

A 90 day inhalation study according to OECD guideline No 413 is available. Animals received 0.5, 3 or 15 mg/m³ Na2H2EDTA as dust aerosol:

-      A mild inflammation was observed in the high-concentration group (15 mg/m³) in female animals (LOAEC).

-      No adverse effects were observed in the mid-concentration (3 mg/m³; NOAEC) and low-concentration (0.5 mg/m3) groups.

The NOAEC is 3 mg/m³. Neither systemic toxicity nor other target tissues than the respiratory tract have been identified in the course of the above mentioned studies. It is assumed that the local effects observed are due to chelating properties of the material impacted at typical critical sites. Calcium and possibly zinc may have been leached from intercellular junctions and other membranes or connective tissue with the sequel of a precipitated cell shedding, subsequent replacing activities, and metaplasia.

The local key effect is assumed to be mainly concentration-related, hence the impact of exposure time should be low at subcritical concentrations, which was confirmed by the 90d study. Although the number of exposures was factor 13 higher than in the 5d dose-range-finder study, the local effects at 15 mg/m³ in the 90d inhalation study were comparably mild compared to the 5d dose-range-finder study that showed a more severe effect at 30 mg/m³. Threshold effect is the local effect of EDTA dust in the respiratory tract (larynx).

Definition of the point of departure: Due to the fact that the results of the available studies point to the fact that the effects are concentration- and not time-related, a time-scaling was thus not performed. This is supported by REACH TGD R.8 (p.19 "Time scaling is not appropriate when the toxic effect is mainly driven by the exposure concentration (as for irritation).").

The experimental NOAEC in rats (3 mg/m³) is corrected for a higher breathing volume due to light activity which results in 2.01 mg/m³ as a point of departure (PoD) for further extrapolation. This PoD is combined with a safety factor of 5 for intraspecies variation. No interspecies factor is needed due to the inhalation route and the fast respiration rate in rats (which may even lead to a higher sensitivity of rats compared to humans). Thus an overall assessment factor of 5 is proposed.

This results in a long-term inhalation DNEL (local) of 0.402 mg/m³ (workplace) for respirable particles.  For short-term intermittent exposures (such as 15 min) to inhalable particles of EDTA no short-term inhalation DNEL (local) is proposed for risk assessment. Since no peak-exposure is expected and since the substance is only handled as liquid solution with a very low vapour pressure, the assessment of the hazard after short-term exposure is sufficiently covered by derivation of the local DNEL for long-term exposure.

Altogether, due to e.g. the different respiration rate and anatomy of rat versus human respiratory tract, it is assumed that the rat model represents a worst case model for the local effects of EDTA-dust aerosol to the larynx (=threshold effect).

Local versus systemic effects: This DNEL long-term local is equivalent to a human uptake of some 4 mg/person and day (respiratory volume light activity for worker (8h exposure) = 10 m3), i.e. some 0.057 mg/kg bw and day (70 kg bodyweight worker), respectively. It is considered to be also protective from systemic toxicity due since no other target tissue than the respiratory tract has been affected by the inhalation route (even at 150-fold higher levels than the NOAEC). No systemic effects have been observed with EDTA after oral administration in the course of a 90 days and 2 years study with NOAELs of 500 mg/kg bw/d.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
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:
0.3 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
10
Dose descriptor:
NOAEC
Value:
3 mg/m³
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
1
Justification:
Due to the fact that available studies show that the effects are concentration- and not time-related, a time- and activity scaling was not performed.
AF for interspecies differences (allometric scaling):
1
Justification:
Only local effects were observed for the test substance. Thus, allometric scaling is not applied, because the effects are not dependent on metabolic rate or systemic absorption.
AF for other interspecies differences:
1
Justification:
There is no evidence for species differences in the general mode of action or kinetics.
AF for intraspecies differences:
10
Justification:
Default value for general population according to ECHA REACH Guidance.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.6 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL extrapolated from long term DNEL
Dose descriptor starting point:
NOAEC
Value:
3 mg/m³

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
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

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - General Population

No DNELs are proposed for the following exposure types:

-      dermal exposure: no classification is warranted and no repeated dose effects and no CMR effects are expected from dermal exposure 

-      systemic toxicity (all routes): no systemic effects were observed which were relevant for classification; it is concluded that the local DNELs inclusively protect also from systemic toxicity and, hence, the DNELs proposed are to be conceived as combined DNELs.

Data from a 5d inhalation toxicity study (range finder) and a subchronic 90d inhalation toxicity study with the source substance disodium dihydrogen EDTA (CAS 139-33-3) are available which show a local toxicity on the larynx and the terminal bronchioles. These data allow the calculation of a long-term local DNEL for respirable EDTA-particles. The long-term inhalation DNEL (local) for respirable particles is based on the following experimental results and considerations obtained for disodium dihydrogen EDTA:

  A 5d aerosol inhalation study (range-finder) is available:

-      The top concentration, 1000 mg/m³ (6 h/d) turned out to be fatal for some animals after 1-2 days. 

-      At 300 mg/m³ severe cell losses were observed after 5 days in the central larynx and in the terminal bronchioli in the lung.

-      30 mg/m³ caused similar effects but to a lesser extent.

A 90d inhalation study according to OECD guideline No 413 is available. Animals received 0.5, 3 or 15 mg/m3Na2H2EDTA as dust aerosol:

-      A mild inflammation was observed in the high-concentration group (15 mg/m3) in female animals (LOAEC).

-      No adverse effects were observed in the mid-concentration (3 mg/m3; NOAEC) and low-concentration (0.5 mg/m3) groups.

  The NOAEC is 3 mg/m³. Neither systemic toxicity nor other target tissues than the respiratory tract have been identified in the course of the above mentioned studies.

 It is assumed that the local effects observed are due to chelating properties of the material impacted at typical critical sites. Calcium and possibly zinc may have been leached from intercellular junctions and other membranes or connective tissue with the sequel of a precipitated cell shedding, subsequent replacing activities, and metaplasia.

The key effect, however, is assumed to be mainly concentration-related, hence the impact of exposure time should be low at subcritical concentrations, which was confirmed by the 90d study. Although the number of exposures was factor 13 higher than in the 5d dose-range-finder study, the local effects at 15 mg/m³ in the 90d inhalation study were comparably mild compared to the 5d dose-range-finder study that showed a more severe effect at 30 mg/m³. Threshold effect is the local effect of Na2H2EDTA dust in the respiratory tract (larynx).

 

Consumer DNELs:

-       Inhalation DNEL:

The long-term inhalation DNEL (local) for consumers is calculated from the 90 days inhalation study in a similar matter as the workplace DNEL (see above). The NOAEC (3 mg/m³; 6 h/d) is not extrapolated for time and activity, but since a higher susceptibility in the general population cannot be ruled out, an assessment factor for intraspecies variability of 10 in accordance with the REACH TGD R. 8 is proposed. This leads to a consumer DNEL (long-term, local) of 0.3 mg/m³ for inhalation of respirable particles. For short-term intermittent exposures (such as 15 min) to inhalable particles of EDTA a short-term inhalation DNEL of 0.6 mg/m³ is proposed for risk assessment. Prolonged exposure, i.e. 24 h, of consumers can reasonably be excluded.  

-       Oral DNEL:

Trisodium hydrogen EDTA is classified as Acute Tox. 4, H302 according to Regulation EC No. 1272/2008 based on read-across.

No oral acute toxicity DNEL was derived. Medium hazard was selected according to table E.3-1 in the “Guidance on information requirements and chemical safety assessment Part E: Risk Characterisation (ECHA, 2016), in which Acute Tox. 3 classifications are allocated to the moderate hazard band.