Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
insufficient hazard data available (further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
acute toxicity
Route of original study:
By inhalation
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
insufficient hazard data available (further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.8 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):
0.5
Modified dose descriptor starting point:
NOAEL
Value:
1.4
Explanation for the modification of the dose descriptor starting point:
Extrapolation from 50 % oral bioavailability to 10 % dermal bioavailability, since no dermal study is available. Corrected dermal DNEL = 0.28 mg Fe/kg bw/day*(50 %/10 %) = 1.4 mg Fe/kg bw/day.
AF for dose response relationship:
1
Justification:
not required (NOAEL in humans)
AF for differences in duration of exposure:
1
Justification:
not required (chronic human data)
AF for interspecies differences (allometric scaling):
1
Justification:
not required (human data)
AF for other interspecies differences:
1
Justification:
not required (human data)
AF for intraspecies differences:
0.5
Justification:
default factor for workers
AF for the quality of the whole database:
1
Justification:
not required
AF for remaining uncertainties:
1
Justification:
not required
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
Dermal
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

The long-term inhalation DNEL for systemic and local effects is not assessed, since from the sole reliable repeated inhalation study (Johansson 1992) no systemic data are available. The scientific discussion is ongoing.

The acute/short term inhalation DNEL for systemic effects is not derived, since low hazard was concluded based on an ineffective concentration of 1100 mg/m³, indicating a much greater LC50 value (Robbins 1991) for Fe2(SO4)3 as reported in the US EPA (1993) Registration Eligibility Document.

The acute/short term inhalation DNEL for local effects is not derived, since low hazard was identified based on respiratory irritating properties of iron salts reported in ACGIH (1999) documentation for worker protection.

The long-term dermal DNEL for systemic effects is derived basing on the assessment of The Expert Group on Vitamins and Minerals. The Expert Group on Vitamins and Minerals has assessed in their report in 2003 the toxicity of iron in food, drinks and supplement. After a close evaluation of the available data and taking into account the toxicokinetic information they have come up with a guidance value of approximately 17 mg/day of supplementary orally taken iron (equivalent to 0.28 mg/kg bw/day for a 60 kg adult). This ”would not be expected to produce adverse effects in the majority of people. This is derived by dividing the lower end of the range found to have an effect by an uncertainty factor of 3 to allow for extrapolation from a LOAEL to a NOAEL. This is based on data referring to ferrous iron (Fe II), which is the form of iron used in supplements currently available in this country. No additional uncertainty factor is needed for inter-individual variation because the assessment is based on studies on large numbers of people. A safe upper level for total iron has not been estimated, as gastrointestinal effects are associated with iron in supplements rather than in foods.” The value of 0.28 mg/kg bw for the general population is therefore deemed a more reliable DNEL (oral, long-term, general population). As in the not-standard approach 50 % bioavailability of iron salts via the oral and 10 % via the dermal route (based on toxicokinetic considerations) is assumed and as the intraspecies variability in workers is regarded to be lower than in the general population this value is multiplied by a factor of 2 in order to derive a DNEL (dermal, long-term, workers) of 0.28*(50%/10%)* 2 = 2.8 mg/kg bw/d.

Table: DNELs for specific iron salts calculated based on iron content threshold values

Iron salt species

Factor for relative iron content

DNEL (dermal, long-term, worker) [mg/kg bw/d]

Fe

1

2.80

FeCl3

2.90

8.15

FeCl3 x 6 H2O

4.84

13.55

FeCl2

2.27

6.35

Fe2(SO4)3

3.58

10.00

FeSO4

2.72

7.60

FeSO4 x 7 H2O

4.98

13.95

FeClSO4

3.36

9

The acute/short term dermal DNEL for systemic effects is not derived, since no hazard was identified based on acute dermal toxicity, where LD50 > 2000 mg/kg bw for FeCl2 was reported in Choi (2004b) study.

The long and acute/short term dermal DNELs for local effects are not derived, since low hazard was identified based on irritating properties to skin of the soluble iron salts.

  • U.S. EPA United States Environmental Protection Agency (1993) Reregistration Eligibility Document (RED) Iron Salts. Self-published, document reference EPA-738-F-93-002, OPPTS, Washington, DC, U.S.A.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
insufficient hazard data available (further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
insufficient hazard data available (further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.4 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):
1
Modified dose descriptor starting point:
NOAEL
Value:
1.4 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Extrapolation from 50 % oral bioavailability to 10 % dermal bioavailability, since no dermal study is available. Corrected dermal DNEL = 0.28 mg Fe/kg bw/day*(50 %/10 %) = 1.4 mg Fe/kg bw/day.
AF for dose response relationship:
1
Justification:
not required (NOAEL in humans)
AF for differences in duration of exposure:
1
Justification:
not required (chronic human data)
AF for interspecies differences (allometric scaling):
1
Justification:
not required (human data)
AF for other interspecies differences:
1
Justification:
not required (human data)
AF for intraspecies differences:
1
Justification:
not required (data from general population)
AF for the quality of the whole database:
1
Justification:
not required
AF for remaining uncertainties:
1
Justification:
not required
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
Dermal
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.28 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):
1
Modified dose descriptor starting point:
NOAEL
Value:
0.28 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
no route-to-route extrapolation performed
AF for dose response relationship:
1
Justification:
not required (NOAEL in humans)
AF for differences in duration of exposure:
1
Justification:
not required (chronic human data)
AF for interspecies differences (allometric scaling):
1
Justification:
not required (human data)
AF for other interspecies differences:
1
Justification:
not required (human data)
AF for intraspecies differences:
1
Justification:
not required (human data)
AF for the quality of the whole database:
1
Justification:
not required
AF for remaining uncertainties:
1
Justification:
not required
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
20 mg/kg bw/day
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - General Population

The long-term inhalation DNEL for systemic and local effects is not assessed, since from the sole reliable repeated inhalation study (Johansson 1992) no systemic data are available. The scientific discussion is ongoing.

The acute/short term inhalation DNEL for systemic effects is not derived, since low hazard was concluded based on an ineffective concentration of 1100 mg/m³, indicating a much greater LC50 value (Robbins 1991) for Fe2(SO4)3 as reported in the US EPA (1993) Registration Eligibility Document.

The acute/short term inhalation DNEL for local effects is not derived, since low hazard was identified based on respiratory irritating properties of iron salts reported in ACGIH (1999) documentation for worker protection.

The long-term dermal and oral DNELs for systemic effects are derived basing on the assessment of The Expert Group on Vitamins and Minerals. The Expert Group on Vitamins and Minerals has assessed in their report in 2003 the toxicity of iron in food, drinks and supplement. After a close evaluation of the available data and taking into account the toxicokinetic information they have come up with a guidance value of approximately 17 mg/day of supplementary iron (equivalent to 0.28 mg/kg bw/day for a 60 kg adult). This

“would not be expected to produce adverse effects in the majority of people. This is derived by dividing the lower end of the range found to have an effect by an uncertainty factor of 3 to allow for extrapolation from a LOAEL to a NOAEL. This is based on data referring to ferrous iron (Fe II), which is the form of iron used in supplements currently available in this country. No additional uncertainty factor is needed for inter-individual variation because the assessment is based on studies on large numbers of people. A safe upper level for total iron has not been estimated, as gastrointestinal effects are associated with iron in supplements rather than in foods.”

The value of 0.28 mg/kg bw for the general population is therefore deemed a more reliable DNEL(oral, long-term, general population).

As in the not-standard approach 50 % bioavailability of iron salts via the oral and 10 % via the dermal route (based on toxicokinetic considerations) is assumed, therefore the value multiplied by 5 applies as the DNEL(dermal, long-term, general population).

Table: DNELs for specific iron salts calculated based on iron content threshold values

Iron salt species

Factor for relative iron content

DNEL(dermal, long-term, general population) [mg/kg bw/d]

DNEL(oral, long-term, general population) [mg/kg bw/d]

Fe

1

1.4

0.28

FeCl3

2.90

4.05

0.81

FeCl3 x 6 H2O

4.84

6.8

1.36

FeCl2

2.27

3.2

0.64

Fe2(SO4)3

3.58

5.00

1.00

FeSO4

2.72

3.8

0.76

FeSO4 x 7 H2O

4.98

6.95

1.39

FeClSO4

3.36

4.7

0.94

The acute/short term dermal DNEL for systemic effects is not derived, since no hazard was identified based on acute dermal toxicity, where LD50 > 2000 mg/kg bw for FeCl2 reported in Choi (2004b) study.

The long and acute/short term dermal DNELs for local effects are not derived, since low hazard was identified based on irritating properties to skin of the soluble iron salts.

The acute/short term oral DNEL for systemic effects is taken from The Expert Group on Vitamins and Minerals (EVM 2003) assessment. Here is considered that acute toxic doses apply for infants (under the age of six years) 20 mg/kg for gastrointestinal irritation, with systemic effects not occurring below 60 mg/kg bw. Therefore the lowest dose is considered as critical value for the acute/short term oral local effects in the most sensitive population group (infants).

  • U.S. EPA United States Environmental Protection Agency (1993) Reregistration Eligibility Document (RED) Iron Salts. Self-published, document reference EPA-738-F-93-002, OPPTS, Washington, DC, U.S.A.