pentapotassium 2,2’,2’’,2’’’,2’’’’-(ethane-1,2-diylnitrilo)pentaacetate

Toxicological Summary

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:

1.5 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

2

Dose descriptor:

NOAEC

Value:

3 mg/m³

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

DNEL extrapolated from long term DNEL

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

11 720 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):

32

Dose descriptor starting point:

NOAEL

Value:

75 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

375 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

See below

AF for dose response relationship:

1

Justification:

Sufficient data available

AF for differences in duration of exposure:

2

Justification:

See below

AF for interspecies differences (allometric scaling):

4

Justification:

Conversion from a rat study to human exposure

AF for other interspecies differences:

1

Justification:

See below

AF for intraspecies differences:

4

Justification:

See below

AF for the quality of the whole database:

1

Justification:

Sufficient data available

AF for remaining uncertainties:

1

Justification:

There are remaining uncertainties

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:

low hazard (no threshold derived)

Additional information - workers

Acute Dermal exposure, systemic effects;

Due to the lack of acute systemic toxicity DNELS have not been calculated for the acute exposure (systemic).

Acute Dermal exposure, local effects

There were no local effects observed for DTPA thus no DNEL has been calculated.

Long term Dermal exposure, local effects

No study available.

Long term Dermal exposure -Systemic effects

The key study for DNEL derivation is taken as the 28 -day oral toxicity study conducted on pentasodium DTPA. The NOEL for this study (75 mg/kg bw) is in line with the supporting study carried out with pentapotassium DTPA (NOEL of 83 mg/kg bw). These values are lower than that for the developmental toxicity study and the mode of action for toxicity is considered to be consistent for the different endpoints. Therefore these NOELs are considered to be protective for both endpoints and no separate DNEL has been calculated for developmental toxicity. Therefore the starting point for the DNEL derivation is 75 mg/kg bw/day.

Justification of assessment factors

Extrapolation from Sub acute to Chronic = 2.

The rationale for this reduction from the standard factor of 6, is that the toxicity of chelants is "acute" i. e. the chelant does not persist in the body due to its rapid excretion, thus any toxicity occurs shortly after dosing and the time between dosing allows for some recovery. Therefore if toxicity is not seen after 4 weeks of dosing, it is unlikely to occur at the same dose after 8 weeks or 1 year. This is seen with other chelating agents such as EDTA where the no effect levels from the shorter studies are similar to those from longer term studies.

Allometric scaling = 4.

Conversion from a rat study to human exposure

Other inter species differences = 1.

There is no indication that the toxicity of chelating agents such as 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. The absorption of DTPA is actually lower in man than in rats, and therefore they would not be expected to be more sensitive.

Intra species differences = 4 (workers)

Much (if not all) of the toxicity of 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 4 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 4 is sufficient to cover the variation between workers with respect to nutritional status.

Total Assessment factor is 32 for Dermal

Dermal absorption of 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)

= 75*(5/0.001)

= 375000 mg/kg bw

Dermal DNEL = 375000/32

= 11720 mg/kg bw/day

Inhalation

DNEL set based on the 90-day inhalation toxicity study with Na2H2 -EDTA (see also read across document in section 13)

A 90-day inhalation study with Na2H2-EDTA according to OECD guideline No 413 is available (BASF, 2014). Animals were exposed to 0, 0.5, 3 or 15 mg/m3 Na2H2-EDTA as respirable dust aerosol. The following results were obtained:

-      A mild laryngeal inflammation was observed in females of the high-concentration group (15 mg/m3; LOAEC).

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

The NOAEC is therefore 3 mg/m3. No other target tissues than the respiratory tract have been identified. It is assumed that the local effects observed are due to chelating properties of the test 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 90-day inhalation study.Although the number of exposure days was a factor 13 higher than in the 5-day range-finding study, the local effects observed at 15 mg/m3 in the 90-day inhalation study were comparably mild compared to the 5-day range-finding study that showed more severe local effects at 30 mg/m3 (BASF, 2010).

Due to the fact that the results of the available studies show that the effects are concentration- and not time-related, a time- and activity-scaling was not performed. This is supported by the REACh 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 8-h working shift. This is addressed through the use of a factor of 0.67 (respiratory volume during 8 -h 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 instead of rest) which results in 3 mg/m3 as a point of departure (PoD) for further calculation.

This PoD is combined with a safety factor of 2 for intraspecies variation which is considered sufficiently conservative: the REACh TGD recommends a default assessment factor of 5 whereasECETOC TR 110 recommends a default assessment factor of 3 for intraspecies differences. However, for EDTA and DTPA and their salts no biotransformation, enzyme or receptor polymorphisms or other major intraspecies variabilities are expected. Furthermore, the degree and the incidence of the effects at the LOAEC were mild/low and the concentration-spacing (LOAEC to NOAEC) in the 90 -day inhalation study was high (factor 5: 15 mg/m3 versus 3 mg/m3). Therefore, an intraspecies assessment factor 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 along-term inhalation DNEL (local) of 1.5 mg/m3 (workplace).  

 

For short-term 15-min intermittent exposures an increase in the DNEL value with a factor of 2 is proposed starting from the long-term DNEL. This is in line with Reach Guidance R.8 indicating that, in the absence of experimental data, the acute DNEL can by default be set as 1-5 times the long-term DNEL. For Na2H2-EDTA, no relevant acute inhalation toxicity data are available as a single 6-h exposure at 1000 mg/m3 resulted in 30% mortality; other groups of animals were exposed for 5 days to lower concentrations. Because of high or low pH and also because of ammonium as counter ions (see below), short-term values for strong acids were searched for comparison and it appeared these are around 2-3 mg/m3. Thus the short- term inhalation DNEL value (local) was set at: 3 mg/m3 for respirable particles.

General remarks regarding the DNELs for members of the EDTA- and DTPA-category:

The EDTA-anion is considered as the toxophore and its molar amount is high in Na2H2-EDTA (>85%) as well as in other members of these categories, such as H4-EDTA, Na4-EDTA, (NH4)2-EDTA, (NH4)3-EDTA, and (NH4)4-EDTA. This also applies to DTPA, with DTPA-anion as the toxophore, for Na5-DTPA, K5-DTPA or H5-DTPA. Therefore, 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 (local, long-term inhalation, workplace) and 0.6 mg/m3 (local, long-term inhalation, general population) for respirable particles are 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 583 g/mol (K5-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 2.5 mg/m3 (K5-DTPA). The above mentioned DNELs for respirable particles derived from the inhalation study with Na2H2-EDTA (e.g. long-term inhalation, local, workplace: 1.5 mg/m3), viz. 1.5 and 0.6 mg/m3, respectively, are considered appropriately conservative, i.e. chelants with higher molecular weights deliberate lower numbers of molecules when using a lower DNEL. Also with regard to candidates with lower molecular weights (H4 -EDTA only), using the DNEL of 1.5/0.6 mg/m3 reflects that deliberation of the toxophore, EDTA-anion, is much lower for H4-EDTA compared to Na2H2-EDTA, because the solubility of H4-EDTA (400 mg/L) is approximately 300-fold lower than of

Na2H2-EDTA (108 g/L). Also for candidates having a somewhat higher complex building constant for calcium or zinc, such as K5-DTPA, a DNEL of 1.5 mg/m3 (instead of above mentioned calculated DNEL of 2.5 mg/m3 for K5-DTPA) is considered appropriately conservative, because the severity of the effects at the highest concentration (15 mg/m3 of Na2H2-EDTA) in the sub-chronic inhalation study was low.

Assessment of potential pH-effects:the local effects in the respiratory tract determined with the read-across substance Na2H2-EDTA 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 Na2H2-EDTA particles of 1.5 mg/m3 (workplace) and the short-term DNEL local effects for respirable Na2H2 -EDTA 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 and K5 -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/m3 is >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.

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:

0.6 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

5

Dose descriptor:

NOAEC

Value:

3 mg/m³

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:

5 860 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):

64

Dose descriptor starting point:

NOAEL

Value:

75 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

375 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

See below

AF for dose response relationship:

1

Justification:

Sufficient data availabale

AF for differences in duration of exposure:

2

Justification:

See below

AF for interspecies differences (allometric scaling):

4

Justification:

Conversion from a rat study to human exposure

AF for other interspecies differences:

1

Justification:

see below

AF for intraspecies differences:

8

Justification:

See below

AF for the quality of the whole database:

1

Justification:

Sufficient data available

AF for remaining uncertainties:

1

Justification:

There are no remaining uncertainties

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:

DNEL (Derived No Effect Level)

Value:

1.2 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):

64

Dose descriptor starting point:

NOAEL

Value:

75 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

See below

AF for dose response relationship:

1

Justification:

Sufficient data available

AF for differences in duration of exposure:

2

Justification:

See below

AF for interspecies differences (allometric scaling):

4

Justification:

Conversion from a rat study to human exposure

AF for other interspecies differences:

1

Justification:

See below

AF for intraspecies differences:

8

Justification:

See below

AF for the quality of the whole database:

1

Justification:

Sufficient data available

AF for remaining uncertainties:

1

Justification:

There are no reamining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)

Additional information - General Population

Acute Dermal exposure, systemic effects;

Due to the lack of acute systemic toxicity DNELs have not been calculated for the acute exposure (systemic).

Acute Dermal exposure, local effects

There were no local effects observed for DTPA thus no DNEL has been calculated.

Long term Dermal and Oral exposure -Systemic effects

The key study for DNEL derivation is taken as the 28 -day oral toxicity study conducted on pentasodium DTPA.

The NOEL for this study (75 mg/kg bw) is in line with the supporting study carried out with pentapotassium DTPA (NOEL of 83 mg/kg bw). These values are lower

than that for the developmental toxicity study and the mode of action for toxicity is considered to be consistent for the different endpoints. Therefore these NOELs are considered to be protective for both endpoints and no separate DNEL has been calculated for developmental toxicity. Therefore the starting point for the DNEL derivation is 75 mg/kg bw/day (refer to repeated dose toxicity section)

Justification of assessment factors

Extrapolation from Sub acute to Chronic = 2.

The rationale for this reduction from the standard factor of 6, is that the toxicity of chelants is "acute" i.e. the chelant does not persist in the body due to its rapid excretion, thus any toxicity occurs shortly after dosing and the time between dosing allows for some recovery. Therefore if toxicity is not seen after 4 weeks of dosing, it is unlikely to occur at the same dose after 8 weeks or 1 year. This is seen with other chelating agents such as EDTA where the no effect levels from the shorter studies are similar to those from longer term studies.

Allometric scaling = 4.

Conversion from a rat study to human exposure

Other inter species differences = 1.

There is no indication that the toxicity of chelating agents such as 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. The absorption of DTPA is actually lower in man than in rats, and therefore they would not be expected to be more sensitive.

Intra species differences = 8 (consumers)

Much of the toxicity of 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 8 is proposed for Consumer exposure. This factor 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 64 for Oral / Dermal

Dermal

Dermal absorption of 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)

= 75*(5/0.001)

= 375000 mg/kg bw

Dermal DNEL = 375000/64

Dermal DNEL = 5860 mg/kg bw/day

Oral

In assessing the toxicity of 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 DTPA in the gut will bind metals and prevent their absorption just as the absorbed DTPA 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

= 75/64

Oral DNEL = 1.2 mg/kg bw/day

Inhalation (local effects)

Inhalation exposure to DTPA-particles can almost be excluded. The concentration of DTPA in liquid consumer formulations is low (<=5%), the vapour pressure of DTPA is very low and the generation of liquid aerosols in consumer exposure scenarios is rare. However, for exposure scenarios where this might be the case 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 with Na2H2 -EDTA 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, respirable particles (combined for local and systemic effects (see above)). No higher value is proposed for short-term intermittent exposures (such as 15 min) since the target organ is the larynx, the effect is presumably highly concentration-dependent with a possible rapid onset of early symptoms. Prolonged exposure, i.e. 24 h, of consumers can reasonably be excluded.