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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.5 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):
25
Modified dose descriptor starting point:
NOAEC
Value:
88.16 mg/m³
Explanation for the modification of the dose descriptor starting point:

No inhalation study is available for Fe(Na)HBED therefore oral study conducted

with the structural analogue Fe(Na)EDDHA has been used.

AF for dose response relationship:
1
Justification:
default (clear dose response)
AF for differences in duration of exposure:
2
Justification:
sub-chronic study
AF for interspecies differences (allometric scaling):
1
Justification:
default (no allometric scaling in case of 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 for workers
AF for the quality of the whole database:
1
Justification:
good quality
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:
0.33 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
300
Modified dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Not applicable (dermal study in rats and dermal route of exposure in humans)
AF for dose response relationship:
1
Justification:
default
AF for differences in duration of exposure:
6
Justification:
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 for workers
AF for the quality of the whole database:
1
Justification:
good quality
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:
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 (2008) “Guidance of Information Requirements and Chemical Safety Assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health.”

Available dose descriptors:

For Fe(III)HBED, the following dose descriptors are available:

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

There is an acute dermal study available conducted with the target substance Fe(Na)HBED (Gruszka, 2008; Report No. OS-19/08). The substance was not acutely toxic after dermal administration to rats. A LD50 greater than 2000 mg/kg bw (OECD 401) was established in this study and is considered to be a NOAEL because no deaths and no treatment related clinical signs of systemic toxicity were noted in treated animals. The animals gained body weight, and no abnormalities were observed at necropsy. Therefore, DNEL for acute systemic effects by 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(Na)HBED is not expected to bear a significant hazard by inhalation due to its very low vapour pressure (0.000575 Pa at 20°C). Inhalation route of exposure is not relevant for humans and therefore no acute inhalation study is available. No DNEL is required.

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

The substance is not irritating to skin (Gruszka, 2008; Report No. OS-19/08) but possess skin sensitization potential (Mrzyk, 2008). 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)

There is dermal 28 -day study available, which was conducted with the structural analogue Fe(Na)EDDHA (CIBA-GEIGY, 1996; Report No. 941103). NOEL of 100 mg/kg bw was established in this study. There were slight changes in liver and in skin and increased adrenal weight was noted at the highest dose of 1000 mg/kg bw.

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 subchronic study in rats conducted with the related substance FeNaEDDHA (Novartis Crop Protection AG, 1998; Report No. 971026) by route-to-route extrapolation. NOAEL of 10 mg/kg bw was established in this study.

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 target substance Fe(Na)HBED as well as on structural analogue 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 information on absorption by the oral, dermal and inhalation routes available for the target chelate Fe(Na)HBED. The absorption rates have been assessed based on the physico-chemical properties and on the effects observed in treated animals in the available studies. Moreover, the information about oral absorption of chelating agent HBED in animal studies, presented in several publications, was also taken into account (for the detailed information on absorption please refer to section "Toxicokinetics, metabolism and distribution" of the CSR or section 7.1 of the IUCLID file).

Oral absorption:

The absorption of Fe(Na)HBED from the GI tract is considered to be low based on logPow of -1.96, high water solubility of 34,550 mg/L, and molecular weight of 463.2 as well as on the fact that the activity of chelating agent HBED administered orally to rats was low (comparing with i.p. administration) (Grady et al., 1990). However, due to the systemic effects observed in animals treated with Fe(Na)EDDHA after oral administration (NOAEL of 10 mg/kg bw), oral absorption is set to 50% and considered to be the same in animals and in humans (worst-case).

Dermal absorption:

There were slight changes in liver and in skin and increased adrenal weight was noted at the highest dose of 1000 mg/kg bw in the dermal 28 -day study available for the structural analogue Fe(Na)EDDHA. Apparently, an absorption via dermal route occurred in treated animals. However, no significant dermal absorption is expected for the target substance Fe(Na)HBED (molecular weight of 463.2, logPow of -1.96 and water solubility of 34,550 mg/L point to a very poor absorption through the skin). According to the TGD, Part I, Appendix VI (Table 3), "if water solubility is above 10,000 mg/L and the logPow value below 0 the substance may be too hydrophilic to cross the lipid rich environment of the stratum corneum". Although molecular weight of the substance is under 500, 10% dermal absorption is more appropriate for this substance due to its high hydrophilicity. 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.

Inhalation absorption:

Absorption by inhalation is considered to be negligible (vapour pressure of 0.000575 Pa at 20°C, very high water solubility of 34,550 mg/L, logPow of -1.96) 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-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 h (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 dermal 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 subchronic 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) in case of using 28 -day dermal study and assessment factor of 3 was applied in case of oral subchronic study.

Quality of whole data base:

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

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 dermal rat NOEL of 100 mg/kg bw does not need to be modified into corrected dermal NOEL since no differences in dermal absorption between animals and humans are considered (Example A.1 in ECHA Guidance R8.):
Dermal NOEL = dermal NOEL x (ABS dermal-rat/ABS dermal-human) = 100 mg/kg bw x (10%/10%) = 100 mg/kg bw.

DNEL = 100 mg/kg bw/(4 x 2.5 x 5 x 6 x 1 x 1) = 0.33 mg/kg bw. Assessment factors are: 4 – interspecies, 2.5 – remaining interspecies differences, 5 – intraspecies, 6 – study duration (sub-acute study), 1 – dose response (NOEL is used), 1 – quality of data base. The total AF amounts to 300.

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

The oral rat NOAEL of 10 mg/kg bw was converted into the inhalation NOEC:

Inhalation NOEC = oral NOEL x (1/sRVrat) x (ABS oral-rat/ABS inhal-human) x (6.7 m³/10 m³) = 10 mg/kg bw x (1/0.38 m³/kg/day) x (50%/10%) x (6.7/10) = 88.16 mg/m³

DNEL = 88.16 mg/m³/(2.5 x 5 x 2 x 1 x 1) = 3.5 mg/m³. Assessment factors are: 2.5 – remaining interspecies differences, 5 – intraspecies, 2 – study duration (sub-chronic study), 1 – dose response, 1 – quality of data base. The total AF amounts to 25.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.87 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):
50
Modified dose descriptor starting point:
NOAEC
Value:
43.5 mg/m³
Explanation for the modification of the dose descriptor starting point:

No inhalation study is available for Fe(Na)HBED therefore oral study conducted

with the structural analogue Fe(Na)EDDHA has been used.

AF for dose response relationship:
1
Justification:
default (clear dose response)
AF for differences in duration of exposure:
2
Justification:
sub-chronic study
AF for interspecies differences (allometric scaling):
1
Justification:
default (no allometric scaling in case of 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 for general population
AF for the quality of the whole database:
1
Justification:
default good quality
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:
0.17 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
600
Modified dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Not applicable (dermal study in rats and dermal route of exposure in humans)
AF for dose response relationship:
1
Justification:
default
AF for differences in duration of exposure:
6
Justification:
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 for general population
AF for the quality of the whole database:
1
Justification:
good quality
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties identified
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:
0.05 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):
200
Modified dose descriptor starting point:
NOAEL
Value:
10 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No applicable (oral study and oral route of exposure in humans)
AF for dose response relationship:
1
Justification:
default (clear dose response)
AF for differences in duration of exposure:
2
Justification:
default (sub-chronic 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 for general population
AF for the quality of the whole database:
1
Justification:
good quality
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 dermal rat NOEL of 100 mg/kg bw does not need to be modified into corrected dermal NOEL since no differences in dermal absorption between animals and humans are considered (Example A.1 in ECHA Guidance R8.):
Dermal NOEL = dermal NOEL x (ABS dermal-rat/ABS dermal-human) = 100 mg/kg bw x (10%/10%) = 100 mg/kg bw.

DNEL = 100 mg/kg bw/(4 x 2.5 x 10 x 6 x 1 x 1) = 0.17 mg/kg bw. Assessment factors are: 4 – interspecies, 2.5 – remaining interspecies differences, 10 – intraspecies, 6 – study duration (sub-acute study), 1 – dose response (NOEL is used), 1 – quality of data base. The total AF amounts to 600.

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

The oral rat NOAEL of 10 mg/kg bw was converted into the inhalation NOEC:

Inhalation NOEC = oral NOEL x (1/sRVrat) x (ABS oral-rat/ABS inhal-human) = 10 mg/kg bw x (1/1.15 m³/kg/day) x (50%/10%) = 43.5 mg/m³

DNEL = 43.5 mg/m³/(2.5 x 10 x 2 x 1 x 1) = 0.87 mg/m³. Assessment factors are: 2.5 – remaining interspecies differences, 10 – intraspecies, 2 – study duration (sub-chronic study), 1 – dose response, 1 – quality of data base. The total AF amounts to 50.

Long-term exposure – systemic effects (oral DNEL)

The oral NOAEL of 10 mg/kg bw does not need to be modified into a corrected NOAEL since no difference in oral absorption between animals and humans are considred (example A.1 in ECHA Guidance R.8):

Corrected Oral NOAEL = oral NOAEL x (ABS oral-rat/ABS oral-human) = 10 mg/kg bw x (50%/50%) = 10 mg/kg bw

DNEL = 10 mg/kg bw/(4 x 2.5 x 10 x 2 x 1 x 1) = 0.05 mg/kg bw. Assessment factors are: 4 – interspecies, 2.5 – remaining interspecies differences, 10 – intraspecies, 2 – study duration (sub-chronic study), 1 – dose response (clear dose response), 1 – quality of data base (default). The total AF amounts to 200.