Reaction mass of iron chelate of sodium salt N-[1,2 dicarboxyethyl] D,L aspartic acid and sodium chloride

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.05 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):

37.5

Dose descriptor starting point:

NOAEL

Value:

64.97 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

114.55 mg/m³

Explanation for the modification of the dose descriptor starting point:

No data available for repeated dose toxicity by inhalation route.

AF for dose response relationship:

1

AF for differences in duration of exposure:

3

Justification:

DNEL is based on sub-chronic study (61 days).

AF for interspecies differences (allometric scaling):

1

Justification:

not applicable, AF not used for inhalation route

AF for other interspecies differences:

2.5

AF for intraspecies differences:

5

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

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

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.16 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):

150

Dose descriptor starting point:

NOAEL

Value:

64.97 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

324.85 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No data available for repeated dose toxicity by dermal route.

AF for dose response relationship:

1

AF for differences in duration of exposure:

3

Justification:

DNEL is based on sub-chronic study (61 days).

AF for interspecies differences (allometric scaling):

4

Justification:

The study was conducted on rats.

AF for other interspecies differences:

2.5

AF for intraspecies differences:

5

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

The calculation of the DNELs is performed in accordance with the principles given in ECHA (2012) “Guidance of Information Requirements and Chemical Safety Assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health”.

 

Available dose descriptors:

The target substance Fe(III)IDHA is not acutely toxic by oral route of exposure because LD50 was > 2000 mg/kg bw (Szefczyk, 2007). Therefore a long-term DNEL for systemic effects is needed for oral route for general public. The substance is not toxic by dermal route of exposure (LD50 > 2000 mg/kg bw; Szefczyk, 2007) and inhalation is not relevant route of exposure due to the low vapour pressure of the substance (3.84 x E-18 Pa at 25°C). The target substance is non-volatile (in microgranulated form) and therefore no risk of irritation or sensitisation of respiratory tract exists, but the substance is classified as skin sensitiser category 1B. Therefore, no DNELs for acute/short term exposures (systemic and local effects) and for long-term exposures (local effects for both inhalation and dermal routes) need to be derived.

For the long-term exposure–systemic effects (inhalation and dermal DNEL), the NOAEL of 64.97 mg/kg bw established in the repeated dose toxicity study in rats (Appel, 2001) was used as the starting point (please see TK statement IUCLID 7.1.).

The DNELs for inhalation and dermal routes can be derived by route-to-route extrapolation applying appropriate assessment factors.

For the other non-threshold endpoints (mutagenicity, eye and skin irritation/corrosion) no DNELs can be derived because a No-Observed-Effect-Level could not be established from the relevant studies.

 

Modification of the starting point:

From all available data on the target and read-across substances it is clear that these substances exert their effects by a threshold mode of action. Thus, DNELs can be calculated for the threshold endpoints based on the most relevant dose descriptors per endpoint. DNELs are derived based on the available toxicity data for the target substance and reflecting the routes, the duration and the frequency of exposure. DNELs are derived for workers and the general population. The general population includes consumers and humans exposed via the environment (please see below).

Bioavailability (absorption):

There is no substance-specific experimental information on absorption by the oral, dermal and inhalation

routes available. The absorption rates are assessed based on the physico-chemical properties and on the

effects observed in treated animals in the available studies.

Oral absorption:

A moderate direct absorption across the gastrointestinal tract epithelium will occur when Fe(III)IDHA is applied orally. The complex Fe(III)IDHA is expected to dissociate at very high acidic conditions of stomach (pH below 2). In the upper intestines, iron cation will tend to be complexed again with free ligand IDHA because pH reaches the optimum (about 5) for complex formation. Therefore, the absorbed fraction will result from intact Fe(III)IDHA and its released components: Fe3+ ions and free IDHA. Intestinal uptake of released Fe3+ ions (after reduced to the ferrous Fe2+ state) is low, 1 to 10%, while intestinal uptake of sodium IDHA is at least 37 % comparing to 5 % of sodium EDTA. Therefore, oral absorption of intact iron IDHA chelates is expected to be somewhat higher than oral absorption of iron of EDTA complexes or free EDTA.

In conclusion, taking into account low absorption potential based on physico-chemical properties of chelate Fe(III)IDHA, its instability at low pH values, absorption of 10 % for iron and 37% for free IDHA, 50 % oral absorption (as worst-case) for Fe(III)IDHA is considered appropriate in case of hazard assessment (DNEL derivation).

 

Dermal absorption:

No significant dermal absorption is expected for the target substance. The log Pow of -7.51 is below the

optimal logPow range (0 - 4) values favourable for dermal absorption. High water solubility of 733.33 g/L points

also to a low absorption potential through the skin. The molecular weight of 323.89 g/mol indicates that a

certain potential to penetrate the skin (< 500) exists. However, in case of such a hydrophilic substance

dermal penetration is rather unlikely.

Dermal absorption is considered to be negligible and equal to 10 % (worst-case) as established for

substances which meet criteria of low dermal absorption potential mentioned in ECHA guidance R7c.

(the value used for hazard assessment: DNEL derivation). Dermal absorption in rats, and in humans is assumed to be the same since no information for dermal absorption of the target substance in humans is available.

 

Inhalation absorption

Absorption by inhalation is considered to be negligible due to the low vapour pressure of 3.84 x 10-18 Pa at

25°C and that the substance is in microgranulated form with particles with aerodynamic diameter higher

than 100μm. It means that 100 % of inhaled substance (in case of dust forming) will be deposited in the upper respiratory tract, which will finally be taken up orally. Of this, 50 % will be absorbed in the GI tract and

become systemic available: 1 x 0.5 = 0.5 will be the total absorption factor for inhalation (or 50 %). Absorption by inhalation is considered to be equal in rats and in humans since no substance specific information is available.

 

 

Route-to-route extrapolation:

Oral-to-inhalation extrapolation is performed to obtain long-term inhalation NOAEC for systemic effects. The

following formula was used:

Corrected inhalatory NOAEC = oral NOAEL x (1/sRVrat) x (ABS oral-rat/ABS inh-human) x (6.7 m3/10 m3)

where sRV is the standard respiratory volume of rats during 8 hours (= 0.38 m3/kg/day); ABS-absorption and

6.7 m3and 10 m3are standard respiratory volumes for workers under normal conditions and by light activity.

Oral-to-dermal extrapolation is performed to obtain dermal NOAEL for systemic effects. The following

formula was used (as described in the Example B.5 of the Appendix R.8 -2, ECHA REACH Guidance R8):

Corrected dermal NOAEL = oral NOAEL x (ABS oral-rat/ABS derm-rat) x (ABS derm-rat/ABS derm-human)

= oral NOAEL x (ABS oral-rat/ABS derm-human).

Exposure conditions:

No modification of the starting points for exposure conditions was necessary since the systemic dose after

oral administration of the test material was already assessed in respiratory volume taken for rats during 8

h (0.38 m3). Differences in the respiratory volumes between experimental animals and humans were used

when an oral rat NOAEL from the oral repeated dose toxicity study in rats was used to assess inhalation

exposure in humans. 0.38 m3/kg/day is the standard respiratory volumes in rats during 8h exposure. 6.7

and 10 m3are standard respiratory volumes for workers under normal conditions and by light activity,

respectively.

Applying of assessment factors and calculation of DNELs:

The assessment factors have been applied to the corrected starting point to obtain the endpoint specific

DNELs. Assessment factors (AFs) correct uncertainties and variability within and between species in the

effect data.

Interspecies differences:

The species-specific default assessment factor of 4 for allometric scaling for rats was applied in the case of

employment of the oral NOAEL from the oral repeated dose toxicity study in rats, which was used to derive

the dermal long-term DNEL. No allometric scaling factor was applied when the oral NOAEL was used for

the derivation of inhalation long-term DNEL.

An assessment factor of 2.5 was applied for remaining interspecies differences in toxicodynamics between

rat and human in all cases.

Intraspecies differences:

An assessment factor of 5 was applied for workers for all endpoints and for all exposure routes.

Extrapolation of duration:An assessment factor of 3 was applied for duration of exposure (sub-chronic to chronic; the study was 61days instead of 90 days).

Quality of whole data base: A default assessment factor of 1 was used.

Issues related to dose response: An assessment factor of 1 was applied.

 

Calculation of DNELs:

Long-term exposure–systemic effects (inhalation DNEL):

The oral rat NOAEL of 64.97 mg/kg bw (In the sub-chronic oral repeated dose toxicity study (31 to 61 days of exposure) the NOAEL value was established > 11.2 mg Fe/kg bw/day (Appeal M.J. et al., 2001, publication), what corresponds with 64.97 mg Fe(III)IDHA (11.2 mg Fe x 323.98 Fe(III)IDHA /55,85 g Fe).) was converted into the inhalation NOAEL:

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

will be: 64.97 x 1/0.38 m3 (8h) x 50/50 = 170.97 mg/m3; sRV = respiratory volume rat in 8 h. Further correction:

x [sRV(human) / wRV]. This will be: 170.97 mg/m3 x [6.7 m3 (8h) / 10 m3 (8h) = 114.55 mg/m3 sRV(human)

= respiratory volume in 8 h (with a factor 4 for allometric scaling) wRV = worker respiratory volume (light

work). Next the following assessment factors were used: Interspecies: difference in BW (allometric scaling):

in this case not applicable as this has already been done at the correction in sRV; remaining differences: 2.5

(in case of systemic effects), Intraspecies worker: 5, Exposure duration: 3 (sub-chronic to chronic; please

note that study was 61 days instead of 90 days). This results in a total assessment factor of 2.5 x 5 x 3 =

37.5, so the DNEL will be: 114.55/37.5= 3.05 mg/m3.

Long-term exposure–systemic effects (dermal DNEL):

Dermal absorption is estimated to be 10% (based on the physico-chemical properties and ECHA guidance R7c); oral absorption is 50%. Corrected dermal NOAEL = oral NOAEL x [absorption (oral-rat) / absorption (dermal-human)] This will be: 64.97 x 50/10 = 324.85 mg/kg. Next the following assessment factors were used Interspecies: difference

in BW (allometric scaling): 4 and remaining differences: 2.5 (in case of systemic effects), Intraspecies

worker: 5, Exposure duration: 3 (sub-chronic to chronic). This results in a total assessment factor of 4 x 2.5

x 5 x 3 = 150, indicating that the DNEL dermal will be 324.85 / 150 = 2.16 mg/kg

 

Selected DNELs

DNEL systemic inhalation =3.05 mg/m3

DNEL systemic dermal (long-term) =2.16 mg/kg bw

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.75 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):

75

Dose descriptor starting point:

NOAEL

Value:

64.97 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

56.49 mg/m³

AF for dose response relationship:

1

AF for differences in duration of exposure:

3

Justification:

DNEL is based on sub-chronic study (61 days).

AF for interspecies differences (allometric scaling):

1

Justification:

not applicable, AF not used for inhalation route

AF for other interspecies differences:

2.5

AF for intraspecies differences:

10

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

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

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.08 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):

300

Dose descriptor starting point:

NOAEL

Value:

64.97 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

324.85 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Dermal absorption is 10%; oral absorption 50%. Corrected dermal

NOAEL = oral NOAEL x [absorption (oral-rat) / absorption (dermal-human)]. This will be: 64.97 x 50/10 = 324.85 mg/kg.

AF for dose response relationship:

1

AF for differences in duration of exposure:

3

Justification:

DNEL is based on sub-chronic study (61 days).

AF for interspecies differences (allometric scaling):

4

Justification:

rat

AF for other interspecies differences:

2.5

AF for intraspecies differences:

10

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.22 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):

300

Dose descriptor starting point:

NOAEL

Value:

64.97 mg/kg bw/day

AF for dose response relationship:

1

AF for differences in duration of exposure:

3

Justification:

DNEL is based on sb-chronic study (61 days).

AF for interspecies differences (allometric scaling):

4

Justification:

rat

AF for other interspecies differences:

2.5

AF for intraspecies differences:

10

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Route of original study:

Oral

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

The principles of the DNEL calculation for the general population are the same as already described for workers. However, there are additional considerations or deviations for:

Modification of the starting point:

Bioavailability (absorption by oral route)

The oral absorption in rats and in humans is assumed to be the same since no information for oral absorption for target chemical in rats and in humans is available.

Respiratory volumes:

No differences in the respiratory volumes under normal conditions and by light activity in humans were taken into account.

Applying of assessment factors:

A higher assessment factor of 10 (in place of 5 for workers) for intraspecies variation/differences of human

population was used.

Calculation of endpoint-specific DNEL for general population

Long-term exposure–systemic effects (inhalation DNEL):

The oral rat NOAEL of 64.97 mg/kg bw was converted into the inhalation NOAEC:

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

will be: 64.97 x 1/1.15 m3 (24h) x 50/50 = 56.49 mg/m3. sRV = respiratory volume rat in 24 h. Next the following

assessment factors were used: Interspecies: difference in BW (allometric scaling): in this case not applicable

as this has already been done at the correction in sRV; remaining differences: 2.5 (in case of systemic

effects), Intraspecies consumer: 10, Exposure duration: 3 (sub-chronic to chronic). This results in a total

assessment factor of 2.5 x 10 x 3 = 75, thus the DNEL will be: 56.49/75 = 0.75 mg/m3

Long-term exposure–systemic effects (dermal DNEL):

Dermal absorption is 10%; oral absorption 50%. Corrected dermal NOAEL = oral NOAEL x [absorption

(oral-rat) / absorption (dermal-human)]. This will be: 64.97 x 50/10 = 324.85 mg/kg. Next the following

assessment factors were used: Interspecies: difference in BW (allometric scaling): 4, remaining differences:

2.5 (in case of systemic effects), Intraspecies general population: 10, Exposure duration: 3 (sub-chronic to

chronic). This results in a total assessment factor of 4 x 2.5 x 10 x 3 = 300, indicating that the DNEL dermal

will be 324.85 / 300 = 1.08 mg/kg

Long-term exposure–systemic effects (oral DNEL):

Assuming that absorption is similar for rats and humans: NOAEL = 64.97 mg/kg bw (31/61 day study). Next the

following assessment factors were used: Interspecies: difference in BW (allometric scaling): 4, remaining

differences: 2.5 (in case of systemic effects), Intraspecies general population: 10, Exposure duration: 3

(sub-chronic to chronic). This results in a total assessment factor of 4 x 2.5 x 10 x 3 = 300, indicating that

the DNEL oral will be 64.97 / 300 = 0.22 mg/kg

 

Selected DNELs

DNEL systemic inhalation =0.75 mg/m3

DNEL systemic dermal (long-term) =1.08 mg/kg bw

DNEL systemic oral (long-term) =0.22 mg/kg bw