Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Acute/short term exposure
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.5 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Acute/short term exposure
DNEL related information

Workers - Hazard for the eyes

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: 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 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 particlesis based on the following experimental results and considerations obtained for 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 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/m3in 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).

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- and activity-scaling was not performed. This is supported byREACh TGD (p.28 "Time scaling is not appropriate when the toxic effect is mainly driven by the exposure concentration (as for irritation)."). In addition, ECETOC TR 110 describes that correction for activity is not required, when the effects are concentration dependent (p. 8 "Furthermore, animals are at rest during the experimental exposure whilst for the worker light physical activity with an increased ventilation rate has to be taken into account during the 8h working shift. This is addressed through the use of a factor of 0.67 (respiratory volume during 8h at rest: 6.7 m3/person, under light activity: 10 m3/person). The factor of 0.67 does not apply to local effects driven by concentration (e.g. irritation of the respiratory tract).").Therefore, the experimental NOAEC in rats (3 mg/m³) is not corrected for an 8 h exposure in theworkplace(instead of 6 h in the experiment) or a higher breathing volume due to light activity which results in 3 mg/m³ as a point of departure (PoD) for further extrapolation.

This PoD is combined with a safety factor of 2 for intraspecies variation which is considered to be sufficiently conservative: REACh TGD recommends a default AF of 5 andECETOC TR 110 recommends a default AF of 3 for intraspecies differences. However, for EDTA and its saltsno biotransformation, enzyme or receptor polymorphisms or other major intraspecies variabilities are expected. Furthermore, degree and incidence of the effects at the LOAEL were low and the concentration-spacing (LOAEL -> NOAEL) in the 90d inhalation study was high (factor 5: 15 mg/m3-> 3 mg/m3). Therefore an intraspecies AF of 2 is considered sufficiently conservative. 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 2 is proposed.

This results in a long-term inhalation DNEL (local) of 1.5 mg/m³ (workplace) for respirable particles. 

 

For short-term intermittent exposures (such as 15 min) to inhalable particles of EDTA a short-term inhalation DNEL (local) of 3 mg/m³ (workplace) is proposed for risk assessment.

 

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 15 mg/person and day (respiratory volume light activity for worker (8h exposure) = 10 m3), i.e. some 0.21 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. Divided by an interspecies factor of 4 and an intraspecies factor of 3 (worker) 42 mg/kg bw/d results. Multiplied by the oral uptake in humans (5%) this leads to a maximum acceptable body burden for systemic effects of 2.1 mg/kg bw/d.

If it is assumed that the above mentioned daily human uptake via inhalation is based on respirable particles, i.e. 100% of the particles are inhaled and 0% are swallowed (worst case), and that subsequently the inhaled quantity is completely absorbed (100%) an internal body burden of 0.21 mg/kg bw/d results. Although this is based on worst case assumptions, this is still 10fold lower than the maximum acceptable body burden, thus the DNEL long-term local for the workplace is also protective for systemic effects.

 

Altogether, a long-term inhalation DNEL (combined for local and systemic effects) of 1.5 mg/m³ (workplace) for respirable particles or ashort-term inhalation DNEL (combined for local and systemic effects) of 3 mg/m³ (workplace) are used for risk assessment, respectively.

General Population - Hazard via inhalation route

Systemic effects

Acute/short term exposure
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.6 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.2 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Acute/short term exposure
DNEL related information

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
25 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
20
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
exposure based waiving
DNEL related information

General Population - Hazard for the eyes

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: 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 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 particlesis based on the following experimental results and considerations obtained for 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/m3in 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:

Inhalation exposure to EDTA-particles can almost be excluded. The concentration of EDTA in liquid consumer formulations is low (<=5%), the vapour pressure of EDTA is very low (1E-12 Pa) and the generation of liquid aerosols in consumer exposure scenarios is rare. However, for exposure scenarios where inhalation exposure might not be excluded completely and as a worst-case assumption, i.e. to demonstrate that even those consumer exposure scenarios would be safe, a DNEL is derived for subsequent risk assessment: 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 5 is proposed. This leads to a consumer DNEL (long-term, local) of 0.6 mg/m³ for inhalation of respirable particles(combined for local and systemic effects (see above)). For short-term intermittent exposures (such as 15 min) to inhalable particles of EDTA a short-term inhalation DNEL (combined for local and systemic effects (see above)) of 1.2 mg/m³is proposed for risk assessment.Prolonged exposure, i.e. 24 h, of consumers can reasonably be excluded.

 

 

-       Oral DNEL:

EDTA and its salts may occur in low amounts in surface water and drinking water. Furthermore, EDTA is admitted for use in food. Therefore, a systemic oral DNEL for consumers is calculated: The overall NOAEL from repeated dose toxicity studies (90 days and 2 years dietary studies in rats) was 500 mg/kg bw/d.

An allometric factor of 4 may be employed as a worst case consideration (presumably over-conservative in the light of an intestinal absorption rate of 1-5%). For the same reason, the factor 2.5 for additional differences would be unjustified. An intraspecies factor of 5 should be sufficient since there is only minimal resorption and no biotransformation. No time-extrapolation factor is necessary for life-time-exposure based on the chronic NOAEL. A total assessment factor of 20 would result from this and a chronic oral consumer DNEL of 25 mg/kg bw/d.

 

No acute oral DNEL is proposed for the uptake of higher concentration levels. Such concentrations would not occur unless in cases of accidents.

 

*****

 

General remarks regarding the DNELs for members of the EDTA-category (also including the DTPA-category; see further below):

Use of the DNELs derived from the 90d study with Na2H2EDTA for other members of the EDTA- and DTPA-category: in light of the fact that the EDTA-anion is considered as the toxophore and its molar amount is high in Na2H2EDTA (>85%) as well as in other members of these categories, such as H4-EDTA, Na4-EDTA, (NH4)2-EDTA, (NH4)3-EDTA, (NH4)4-EDTA, Na5-DTPA or H5-DTPA etc., the DNELs have not been recalculated for each member of the EDTA- or DTPA-category with regard to the respective molecular weight. The DNELs of 1.5 mg/m3 (combined for local and systemic effects, long-term inhalation, workplace) and 0.6 mg/m3 (combined for local and systemic effects, long-term inhalation, general population) for respirable particles and the respective above mentioned short-term DNELs were used for the above mentioned members of the EDTA- and DTPA-category.

Differences in molecular weight within the above mentioned members of the EDTA-category range from 292 g/mol (H4-EDTA) to 503 g/mol (Na5-DTPA), which would have resulted e.g. in long-term inhalation DNELs (local, workplace) for respirable particles corrected for molecular weight in the range of 1.3 mg/m3 (H4-EDTA) to 2.2 g/m3 (Na5-DTPA). The above mentioned DNELs for respirable particles derived from the inhalation study with Na2H2EDTA (e.g. long-term inhalation, local, workplace: 1.5 mg/m3) are considered appropriately conservative, i.e. compared to chelants with higher molecular weights lower numbers of molecules of the respective chelants are deliberated when using a lower DNEL. Also with regard to candidates with lower molecular weights (H4-EDTA only), using the DNEL of 1.5 mg/m3 reflects that deliberation of the toxophore, EDTA-anion, is much lower for H4-EDTA compared to Na2H2EDTA, because the solubility of EDTA-acid (H4-EDTA: 400 mg/L) is approximately 300-fold lower than the disodium-salt of EDTA (Na2H2EDTA: 108 g/L). Also for candidates having a somewhat higher complex building constant for calcium or zinc, such as Na5-DTPA, a DNEL of 1.5 mg/m3 (instead of above mentioned calculated DNEL of 2.2 mg/m3 for Na5-DTPA) is considered appropriately conservative, because the severity of the effects at the highest concentration (15 mg/m3 of Na2H2EDTA) in the subchronic inhalation study was low.

Assessment of potential pH-effects: the local effects in the respiratory tract determined with the read-across substance Na2H2EDTA are of similar character as effects induced by acidic or basic aerosols. It is not expected that candidates from the EDTA-category with low or high intrinsic pH-values would induce local effects of higher severity. Physiological fluids moistening the mucous membrane could buffer acidic or basic pH-values with a certain capacity and, additionally, the derived DNELs for local effects of EDTA are in the range of occupational exposure limits of e.g. strong acids, such as phosphoric acid (2 mg/m3; EU/SCOEL (STEL); 1 mg/m3 (8h TWA) (1991)), nitric acid (2.6 mg/m3; EU/SCOEL (STEL; 2001)), or hydrochloric acid (3 mg/m3; MAK (TRGS900; 2013)). Hence, the long-term DNEL local effects for respirable Na2H2EDTA particles of 1.5 mg/m3 (workplace) and the short-term DNEL local effects for inhalable Na2H2EDTA particles of 3 mg/m3(workplace) are considered to be protective also for candidates of the EDTA- and DTPA-category with lower or higher pH values, such as H4-EDTA or Na4-EDTA, or H5-DTPA, respectively. Additionally, due to the irritating potential, those substances were classified as Eye Irritating Cat 2 (H319) or Eye Irritating Cat 1 (H318) according to CLP regulation 1272/2008/EC.

 

Assessment of effects of ammonium ions:ammonium Ions that are used as counter-cations for some members of the EDTA-category could also act as toxic agents. However, inhalation DNELs (long term, workplace) of soluble ammonium salts are in the range of 11 to 970 mg/m3 (e.g. 11.2 mg/m3 (ammonium sulphate), 33.5 mg/m3 (ammonium chloride), 37.6 mg/m3 (ammonium nitrate), 369 mg/m3 (ammonium carbonate), or 911 mg/m3 (ammonium acetate) (source: EChA Homepage)). Ammonia itself has an occupational exposure limit of 14 mg/m3.

The long-term DNEL local effects for respirable EDTA- or DTPA-particles (workplace) of 1.5 mg/m3is >10-fold lower than the above mentioned threshold values for soluble ammonium salts with regard to the molar amount of ammonium ions and, thus, considered to be protective against potential effects of ammonium ions.