Acetic acid, oxo-, sodium salt, reaction products with ethylenediamine and hydroxybenzenesulfonic acid monosodium salt, iron sodium salts

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

23.5 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

Modified dose descriptor starting point:

NOAEC

Value:

1 763 mg/m³

Explanation for the modification of the dose descriptor starting point:

28-day oral study in rats is available (CIT, 2001, Report No. 20509 TSR) where a NOEL of 1000 mg/kg bw was established

AF for dose response relationship:

1

Justification:

default

AF for differences in duration of exposure:

6

Justification:

default (sub-acute study)

AF for interspecies differences (allometric scaling):

1

Justification:

no allometric scaling is needed for oral-to-inhalation extrapolation

AF for other interspecies differences:

2.5

Justification:

default (no substance-specific information on toxicokinetic and toxicodynamic is available)

AF for intraspecies differences:

5

Justification:

default

AF for the quality of the whole database:

1

Justification:

default (good quality of the database)

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties are 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

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.33 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

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

28-day oral study in rats is available (CIT, 2001, Report No. 20509 TSR) where a NOEL of 1000 mg/kg bw was established.

AF for dose response relationship:

1

Justification:

default

AF for differences in duration of exposure:

6

Justification:

default (sub-acute study)

AF for interspecies differences (allometric scaling):

4

Justification:

default

AF for other interspecies differences:

2.5

Justification:

default (no substance-specific information on toxicokinetic and toxicodynamic is available)

AF for intraspecies differences:

5

Justification:

default

AF for the quality of the whole database:

1

Justification:

default (good quality of the database)

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties are 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:

no hazard identified

Additional information - workers

The calculation of the DNELs is performed in accordance with the principles given in ECHA (2008) “Guidance of Information Requirements and Chemical Safety Assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health”.

Available dose descriptors:

For Fe3NaEDDHSA, the following dose descriptors are available:

Acute/short-term exposure – systemic effects (dermal DNEL):

There are three acute dermal studies available conducted with the closely related substances Fe(3K)EDDHSA (one study) and Fe(Na)EDDHA (two studies). The substances were not acutely toxic after dermal administration to rats (CIT, 2000, Report No. 20502 TAR; Hempstock, 1996, Report No. 003/082; CIBA-GEIGY, 1993, Report No. 931141). A LD50 greater than 2000 mg/kg bw (OECD Guideline 401) was established in these studies and is considered to be a NOAEL because no deaths and no clinical signs of systemic toxicity were noted in treated animals. The animals gained body weight, and no abnormalities were observed at necropsy. Therefore, a DNEL for acute systemic effects via the dermal route is unnecessary since the long-term DNEL covers sufficiently the risk of short-term exposure.

Acute/short-term exposure – systemic effects (inhalation DNEL):

Fe(3Na)EDDHSA is not expected to bear a significant hazard by inhalation due to its very low vapour pressure ( vapour pressure of the nearest analogue Fe(3K)EDDHSA is < 1E-5 Pa at 25°C). Moreover, the structural analogue Fe(Na)EDDHA did not induce mortalities and poor health condition in treated animals at the maximum attainable concentration of 4200 mg/m³ (CIBA-GEIGY, 1993, Report No. 931142). Therefore, Fe(3Na)EDDHSA is not classified for acute inhalation hazard and no DNEL is required.

Acute/short-term exposure – local effects (dermal DNEL):

The substance is not irritating to the skin (CIT, 2000, Report No. 20503 TAL; CIBA-GEIGY, 1993, Report No. 931143; Mercier, 1992, Report No. 209306) and does not possess skin sensitization potential (CIT, 2001, Report No. 20505 TSG; BASF SE, 2010, Report No. 1324900; CIBA-GEIGY, 1994, Report No. 931145). The long-term dermal DNEL for systemic effects covers sufficiently local effects.

Acute/short-term exposure – local effects (inhalation DNEL):

The substance does not bear a significant airborne hazard (and is not irritating or sensitizing to respiratory system). The long-term inhalation DNEL for systemic effects covers sufficiently local effects.

Long-term exposure – systemic effects (dermal DNEL)

Long-term systemic DNEL for the dermal route has been derived from the NOEL of 1000 mg/kg bw established in the oral 28 -day study in rats (CIT, 2001, Report No. 20509 TSR). The substance caused no treatment-related effects in any parameter tested. There is also a dermal 28 -day study conducted with another closely related substance Fe(Na)EDDHA available in which NOEL of 100 mg/kg bw was established. There were slight changes in liver and in skin and increased adrenal weight was noted at the highest dose of 1000 mg/kg bw (CIBA-GEIGY, 1996, Report No. 941103). However due to the highest structural similarity and similarity of physico-chemical properties of Fe(3K)EDDHSA with those of the target substance Fe(3Na)EDDHSA, the oral 28 -day study is considered to be more appropriate for the derivation of long-term DNEL than the dermal study (please refer to read-across statement attached in section 13 of IUCLID file). The starting point for the DNEL derivation can be obtained by conversion of oral NOAEL into dermal NOAEL (route-to-route extrapolation).

Long-term exposure – systemic effects (inhalation DNEL)

There are no long-term inhalation studies with the target substance available. The inhalation DNEL can be derived from the oral NOAEL of 1000 mg/kg bw established in the 28 -day oral study in rats (CIT, 2001, Report No. 20509 TSR) by route-to-route extrapolation.

Long-term exposure – local effects (dermal DNEL)

No long-term dermal DNEL for local effects is needed since the substance is not irritating or sensitizing to skin. Local effects are covered sufficiently by the long-term DNEL for systemic effects.

Long-term exposure – local effects (inhalation DNEL)

No long-term inhalation DNEL for local effects is needed since the substance is not irritating or sensitizing to respiratory system. Local effects are covered sufficiently by the long-term DNEL for systemic effects.

For the other non-threshold endpoints (mutagenicity, eye and skin irritation/corrosion) no DNELs can be derived because no No Observed Effect Level could be established from the relevant studies. The controlling of risk of any hazard relevant for these endpoints should be covered qualitatively introducing appropriate RMMs and OCs. Furthermore, local effects are covered sufficiently by the DNELs for systemic effects.

Modification of the starting point:

From all available data on the structurally relates substances Fe(3K)EDDHSA and Fe(Na)EDDHA for the different human health endpoints it is clear, that the substances exert their effects by a threshold mode of action. Thus, DNELs can be calculated for the different threshold endpoints based on the most relevant dose descriptors per endpoint. DNELs are derived based on the available toxicity data for the target substance, reflecting the routes, the duration and the frequency of exposure.

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. Due to the molecular weight of 641.3 g/mol and negative logPow and absence of systemic effects in the 28 -day oral study in rats, absorption by oral route is considered to be low for the target substance (for the detailed information on absorption please refer to section "Toxicokinetics, metabolism and distribution" of this CSR or section 7.1 of IUCLID file). The oral absorption is set to 10% since physico-chemical properties of the substance are not in range suggestive of absorption from the gastro-intestinal tract. The oral absorption is considered to be the same in animals and in humans (worst-case). No significant dermal absorption is expected for the substance (molecular weight of 641.3 g/mol, negative log Pow of and water solubility of 290 g/L point to a very poor absorption through the skin). According to the TGD, Part I, Appendix VI, 10% of dermal absorption should be considered in this case. Dermal absorption in rats and in humans is assumed to be the same since no information for dermal absorption of the target chemical in humans is available. Absorption by inhalation is considered to be negligible (low vapour pressure) and not to be higher than absorption by oral route. Therefore, 10% absorption is assumed for inhalation route and considered to be equal in rats and in humans since no substance specific information is available.

Route-to-route extrapolation:

Oral-to-dermal extrapolation is performed to obtain long-term dermal NOAEL for systemic effects.

The following formula was used: corrected dermal NOAEL = oral NOAEL x (ABSoral-rat/ABS dermal-human) where ABS is absorption.

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 (ABSoral-rat/ABSinh-human) x (6.7 m³/10 m³) where sRV is standard respiratory volume of rats during 8 hours (= 0.38 m³/kg/day); ABS-absorption and 6.7 m³ and 10 m³ are standard respiratory volumes for workers under normal conditions and by light activity.

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 hours (0.38m³).

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 28 -day study, which was used to derive the dermal long-term DNEL.

No allometric scaling factor was applied when the oral NOAEL from the 28 -day study 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 both cases.

Intraspecies differences:

An assessment factor of 5 was applied for workers.

Extrapolation of duration:

An assessment factor of 6 was applied for duration of exposure (subacute-to-chronic).

Quality of whole data base:

The assessment factors for uncertainties to the quality of the data base were used: 1 (GLP study is used).

Issues related to dose response:

A default assessment factor of 1 was applied when NOEL was used.

Calculation of DNELs:

Long-term exposure – systemic effects (dermal DNEL)

The oral rat NOEL of 1000 mg/kg bw was converted into the dermal NOEL:
Dermal NOEL = oral NOEL x (ABS oral-rat/ABS dermal-human) = 1000 mg/kg bw x (10%/10%) = 1000 mg/kg bw.

DNEL = 1000 mg/kg bw/(4 x 2.5 x 5 x 6 x 1 x 1) = 3.33 mg/kg bw. Assessment factors are: 4 – interspecies, 2.5 – remaining interspecies differences, 5 – intraspecies, 6 – study duration (sub-acute study), 1 – dose response, 1 – quality of data base. The total AF amounts to 300.

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

The oral rat NOEL of 1000 mg/kg bw was converted into the inhalation NOEC:

Inhalation NOEC = dermal NOEL x (1/sRVrat) x (ABS oral-rat/ABS inhal-human) x (6.7 m³/10 m³) = 1000 mg/kg bw x (1/0.38 m³/kg/day) x (10%/10%) x (6.7/10) = 1763 mg/m³

DNEL = 1763 mg/m³/(2.5 x 5 x 6 x 1 x 1) = 23.5 mg/m³. Assessment factors are: 2.5 – remaining interspecies differences, 5 – intraspecies, 6 – study duration (sub-acute study), 1 – dose response, 1 – quality of data base. The total AF amounts to 75.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

5.8 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):

150

Modified dose descriptor starting point:

NOAEC

Value:

869.6 mg/m³

Explanation for the modification of the dose descriptor starting point:

28-day oral study in rats is available (CIT, 2001; Report No. 20509 TSR) where a NOEL of 1000 mg/kg bw was established

AF for dose response relationship:

1

Justification:

default

AF for differences in duration of exposure:

6

Justification:

default (sub-acute study)

AF for interspecies differences (allometric scaling):

1

Justification:

no allometric scaling is needed for oral-to-inhalation extrapolation

AF for other interspecies differences:

2.5

Justification:

default (no substance-specific information on toxicokinetic and toxicodynamic is available)

AF for intraspecies differences:

10

Justification:

default

AF for the quality of the whole database:

1

Justification:

default (good quality of the database)

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties are 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

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.67 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):

600

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

28-day oral study in rats is available (CIT, 2001, Report No. 20509 TSR) where a NOEL of 1000 mg/kg bw was established.

AF for dose response relationship:

1

Justification:

default

AF for differences in duration of exposure:

6

Justification:

default (sub-acute study)

AF for interspecies differences (allometric scaling):

4

Justification:

default

AF for other interspecies differences:

2.5

Justification:

default (no substance-specific information on toxicokinetic and toxicodynamic is available)

AF for intraspecies differences:

10

Justification:

default

AF for the quality of the whole database:

1

Justification:

default (good quality of the database)

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties are 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:

DNEL (Derived No Effect Level)

Value:

1.67 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):

600

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Not applicable (route of exposure in animals and humans is the same)

AF for dose response relationship:

1

Justification:

default

AF for differences in duration of exposure:

6

Justification:

default (sub-acute study)

AF for interspecies differences (allometric scaling):

4

Justification:

default

AF for other interspecies differences:

2.5

Justification:

default (no substance-specific information on toxicokinetic and toxicodynamic is available)

AF for intraspecies differences:

10

Justification:

default

AF for the quality of the whole database:

1

Justification:

default (good quality of the database)

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties are identified

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

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 (dermal DNEL)

The oral rat NOEL of 1000 mg/kg bw was converted into the dermal NOEL:
Dermal NOEL = oral NOEL x (ABS oral-rat/ABS dermal-human) = 1000 mg/kg bw x (10%/10%) = 1000 mg/kg bw.

DNEL = 10000 mg/kg bw/(4 x 2.5 x 10 x 6 x 1 x 1) = 1.67 mg/kg bw. Assessment factors are: 4 – interspecies, 2.5 – remaining interspecies differences, 10 – intraspecies, 6 – study duration (sub-acute study), 1 – dose response, 1 – quality of data base. The total AF amounts to 600.

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

The oral rat NOEL of 1000 mg/kg bw was converted into the inhalation NOEC:

Inhalation NOEC = oral NOEL x (1/sRVrat) x (ABS oral-rat/ABS inhal-human) = 1000 mg/kg bw x (1/1.15 m³/kg/day) x (10%/10%) = 869.6 mg/m³

DNEL = 869.6 mg/m³/(2.5 x 10 x 6 x 1 x 1) = 5.8 mg/m³. Assessment factors are: 2.5 – remaining interspecies differences, 10 – intraspecies, 6 – study duration (sub-acute study), 1 – dose response, 1 – quality of data base. The total AF amounts to 150.

Long-term exposure – systemic effects (oral DNEL)

The oral NOAEL of 1000 mg/kg bw was not modified for differences in absorption by oral route since no substance- and route specific information is available:

DNEL = 1000 mg/kg bw/(4 x 2.5 x 10 x 6 x 1 x 1) = 1.67 mg/kg bw. Assessment factors are: 4 – interspecies, 2.5 – remaining interspecies differences, 10 – intraspecies, 6 – study duration (sub-acute study), 1 – dose response (clear dose response), 1 – quality of data base (default). The total AF amounts to 600.