Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.8 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):
10
Dose descriptor starting point:
NOAEL
Value:
10 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
17.64 mg/m³
Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated exposure by inhalation. The recommended approach using oral data and assuming the same absorption for inhalation and oral route is used.

In order to derive a worker DNEL and under the assumption of a daily exposure period of 8 hours, the oral NO(A)EL is converted into an inhalation NO(A)EC according to the following formula:

inhalation NO(A)EC = oral NO(A)EL × 1/sRV(rat) × ABSoral(rat)/ABSinhalation(human) × sRV(human)/wRV(human)

with:

oral NO(A)EL: 10 mg/kg bw/day

sRV(rat): 0.38 m³/kg bw (8 hours) [standard respiratory volume of the rat]

ABSoral(rat)/ABSinhalation(human): 1 [ratio of oral absorption in the rat to inhalative absorption in the human]

sRV(human)/wRV(human): 6.7 m³/10 m³ [ratio of human standard respiratory volume to worker respiratory volume]

Accordingly, the oral NO(A)EL of 10 mg/kg bw/day is transformed in an inhalation NO(A)EC of 17.636 mg/m³.

AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
2
Justification:
The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point).
AF for interspecies differences (allometric scaling):
1
Justification:
Respiratory interspecies differences are fully covered by the factors used for route to route extrapolation.
AF for other interspecies differences:
1
Justification:
There is no evidence for species differences in the general mode of action or kinetics.
AF for intraspecies differences:
5
Justification:
The default value for the relatively homogenous group "worker" is used.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
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:
0.8 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):
120
Dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No route to route extrapolation is necessary since a repeated dose dermal toxicity study is available.

AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
6
Justification:
The default extrapolation factor for exposure duration is used: subacute (starting point) to chronic (end point).
AF for interspecies differences (allometric scaling):
4
Justification:
The default allometric scaling factor for the differences between rats and humans is used.
AF for other interspecies differences:
1
Justification:
Interspecies differences including toxicokinetics are fully covered by the allometric scaling.
There is no additional evidence for species differences including toxicodynamics. Therefore, no additional factor is used.
AF for intraspecies differences:
5
Justification:
The default value for the relatively homogenous group "worker" is used.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
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:
high hazard (no threshold derived)

Additional information - workers

In the assessment of Acetic acid, oxo-, sodium salt, reaction products with 2-aminoethanol and phenol, sodium hydroxide and iron trichloride (MEAHA-Fe), a read-across approach is followed based on the information available for Acetic acid, oxo-, sodium salt, reaction products with ethylenediamine and phenol, iron sodium salts (FeNa-EDDHA, CAS 84539-55-9, EC 283-044-5) and Acetic acid, oxo-, sodium salt, reaction products with cresol and ethylenediamine, iron sodium salts (FeNa-EDDHMA, CAS 84539-53-7, EC 283-041-9). The substances are structural analogues and have similar physiochemical properties. Where needed, DNEL derivation for MEAHA-Fe is therefore based on some toxicological data for EDDHA-Fe.

Acute/short-term exposure - systemic effects

According to the ECHA document "Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose[concentration]-response for human health", a DNEL for acute systemic toxicity should only be derived if an acute systemic toxicity hazard leading to classification is identified.

Referring to the available data on acute toxicity, Acetic acid, oxo-, sodium salt, reaction products with 2-aminoethanol and phenol, sodium hydroxide and iron trichloride (MEAHA-Fe) displays low acute toxicity as evidenced by LD50 values of >2000 mg/kg bw determined in rats for both the oral and the dermal route, and a LC50 value of >4200 mg/m³ determined in rats for the inhalation route. Therefore, MEAHA-Fe is not subject to classification for acute toxicity according to Regulation (EC) No 1272/2008 (as amended for the ninth time in Regulation (EC) No 2016/1179), and consequently the derivation of worker DNELs for acute/short-term exposure - systemic effects is not required.

Acute/short-term and long-term exposure - local effects

Based on the available toxicological information, MEAHA-Fe is not subject to classification for skin irritation and skin sensitisation and no worker DNEL for local effects following acute/short-term or long-term exposure is derived.

This is in line with the ECHA document "Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose[concentration]-response for human health".

Long-term exposure - systemic effects

Using a conservative approach, the NOELs determined in the repeated dose toxicity studies for the oral and dermal routes are also identified as NOAELs.

For the dermal route, the NO(A)EL of 100 mg/kg bw/day from the key subacute repeated dose dermal toxicity study with the structural analogue FeNa-EDDHA (CIBA-GEIGY Limited, 1996b) is regarded as the relevant dose descriptor for systemic effects associated with long-term exposure to MEAHA-Fe. Dermal treatment with the test item resulted in no mortality, no relevant clinical signs, no changes in food consumption, no effects on haematology and clinical chemistry parameters and no gross findings. A transient slight body weight loss was noted in females at 1000 mg/kg bw/day during the first week of treatment. There was an increase in adrenal weight in males at 1000 mg/kg bw/day. Microscopically, the skin application sites of females at 1000 mg/kg bw/day revealed epidermal hyperkeratosis associated with an increased severity of acanthosis. In 2/5 males at 1000 mg/kg bw/day centrilobular hypertrophy of hepatocytes was noted. 

For the inhalation route, the NO(A)EL of 10 mg/kg bw/day from the key subchronic oral toxicity study with the structural analogue FeNa-EDDHA (Novartis Crop Protection AG, 1998) is considered to represent the appropriate dose descriptor for systemic effects related to long-term inhalation exposure to MEAHA-Fe. 

In this study, treatment with the test item resulted in lower food intake and impaired body weight development of rats treated at 200 mg/kg bw/day. Reversible effects on the red blood cell (normochromic anaemia) and white blood cell parameters, and higher values of platelets and prothrombin activity were noted at 50 and/or 200 mg/kg bw/day. In addition, there were changes of blood chemistry and urine parameters concerning the liver and kidneys. The body weight relative heart weight was increased in males at 200 mg/kg bw/day. 

Estimation of NOAEL:

A more realistic NOAEL was estimated from the LOAEL of 50 mg/kg bw/day applying an assessment factor of 5. This method is applicable and scientifically justified for this test, as only slight adverse effects were observed at 50 mg/kg bw/day (haematology parameters - anaemia). To take the relatively large concentration gap between 5 (clear NOEL) and 50 mg/kg bw/day into account, 5 mg/kg bw/day was not taken as NOAEL, but extrapolated form the LOAEL. The guidance on information requirements and CSA, R.8 (ECHA, 2008 -2010) recommends a factor between 3 and 10 for extrapolation from LOAEL to NOAEL. An assessment factor of 5 seems to be appropriate and conservative enough for the current study as only slight effects were observed at the LOAEL of 50 mg/kg bw/day. Consequently a NOAEL of 10 mg/kg bw/day is calculated for this study and used for DNEL and PNEC(oral) derivation. 

In order to derive a worker DNEL and under the assumption of a daily exposure period of 8 hours, the oral NO(A)EL is converted into an inhalation NO(A)EC according to the following formula:

inhalation NO(A)EC = oral NO(A)EL × 1/sRV(rat) × ABSoral(rat)/ABSinhalation(human) × sRV(human)/wRV(human)

with:

oral NO(A)EL: 10 mg/kg bw/day

sRV(rat): 0.38 m³/kg bw (8 hours) [standard respiratory volume of the rat]

ABSoral(rat)/ABSinhalation(human): 1 [ratio of oral absorption in the rat to inhalative absorption in the human]

sRV(human)/wRV(human): 6.7 m³/10 m³ [ratio of human standard respiratory volume to worker respiratory volume]

Accordingly, the oral NO(A)EL of 10 mg/kg bw/day is transformed in an inhalation NO(A)EC of 17.636 mg/m³.

 

The following assessment factors are used for the derivation of worker DNELs for dermal or inhalation exposure to MEAHA-Fe:

Interspecies factor (rat to human): 4 [used for the dermal route only]

Intraspecies factor (worker): 5

Exposure duration factor: 6 (subacute to chronic) [for the dermal route], 2 (subchronic to chronic) [for the inhalation route]

Dose-response factor: 1

Quality of whole database factor: 1

  

The resulting worker DNELs are:

worker DNEL (dermal exposure) = 100 mg/kg bw/day / (4 × 5 × 6 × 1 × 1) = 100 mg/kg bw/day / 120 = 0.83 mg/kg bw/day, rounded to 0.8 mg/kg bw/day

worker DNEL (inhalation exposure) = 17.636 mg/m³ / (5 × 2 × 1 × 1) = 17.636 mg/m³ / 10 = 1.7636 mg/m³, rounded to 1.8 mg/m³

  

This is in line with the ECHA document "Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose[concentration]-response for human health".


General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
435 µg/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):
20
Dose descriptor starting point:
NOAEL
Value:
10 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
8.7 mg/m³
Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated exposure by inhalation. The recommended approach using oral data and assuming the same absorption for inhalation and oral route is used.

In order to derive a general population DNEL and under the assumption of a daily exposure period of 24 hours, the oral NO(A)EL is converted into an inhalation NO(A)EC according to the following formula:

inhalation NO(A)EC = oral NO(A)EL × 1/sRV(rat) × ABSoral(rat)/ABSinhalation(human)

with:

oral NO(A)EL: 10 mg/kg bw/day

sRV(rat): 1.15 m³/kg bw/day [standard respiratory volume of the rat]

ABSoral(rat)/ABSinhalation(human): 1 [ratio of oral absorption in the rat to inhalative absorption in the human]

Accordingly, the oral NO(A)EL of 10 mg/kg bw/day is transformed in an inhalation NO(A)EC of 8.696 mg/m³.

AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
2
Justification:
The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point).
AF for interspecies differences (allometric scaling):
1
Justification:
Respiratory interspecies differences are fully covered by the factors used for route to route extrapolation.
AF for other interspecies differences:
1
Justification:
There is no evidence for species differences in the general mode of action or kinetics.
AF for intraspecies differences:
10
Justification:
The default value for the more heterogenous group "general population" is used.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
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:
417 µg/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):
240
Dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No route to route extrapolation is necessary since a repeated dose dermal toxicity study is available.

AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
6
Justification:
The default extrapolation factor for exposure duration is used: subacute (starting point) to chronic (end point).
AF for interspecies differences (allometric scaling):
4
Justification:
The default allometric scaling factor for the differences between rats and humans is used.
AF for other interspecies differences:
1
Justification:
Interspecies differences including toxicokinetics are fully covered by the allometric scaling. There is no additional evidence for species differences including toxicodynamics. Therefore, no additional factor is used.
AF for intraspecies differences:
10
Justification:
The default value for the more heterogenous group "general population" is used.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
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:
125 µg/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):
80
Dose descriptor starting point:
NOAEL
Value:
10 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No route to route extrapolation is necessary since a repeated dose oral toxicity study is available.

AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
2
Justification:
The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point).
AF for interspecies differences (allometric scaling):
4
Justification:
The default allometric scaling factor for the differences between rats and humans is used.
AF for other interspecies differences:
1
Justification:
Interspecies differences including toxicokinetics are fully covered by the allometric scaling. There is no additional evidence for species differences including toxicodynamics. Therefore, no additional factor is used.
AF for intraspecies differences:
10
Justification:
The default value for the more heterogenous group "general population" is used.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high hazard (no threshold derived)

Additional information - General Population

In the assessment of Acetic acid, oxo-, sodium salt, reaction products with 2-aminoethanol and phenol, sodium hydroxide and iron trichloride (MEAHA-Fe), a read-across approach is followed based on the information available for Acetic acid, oxo-, sodium salt, reaction products with ethylenediamine and phenol, iron sodium salts (FeNa-EDDHA, CAS 84539-55-9, EC 283-044-5) and Acetic acid, oxo-, sodium salt, reaction products with cresol and ethylenediamine, iron sodium salts (FeNa-EDDHMA, CAS 84539-53-7, EC 283-041-9). The substances are structural analogues and have similar physiochemical properties. Where needed, DNEL derivation for MEAHA-Fe is therefore based on some toxicological data for EDDHA-Fe.

Acute/short-term exposure - systemic effects

According to the ECHA document "Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose[concentration]-response for human health", a DNEL for acute systemic toxicity should only be derived if an acute systemic toxicity hazard leading to classification is identified.

Referring to the available data on acute toxicity, MEAHA-Fe displays low acute toxicity as evidenced by LD50 values of >2000 mg/kg bw determined in rats for both the oral and the dermal route, and a LC50 value of >4200 mg/m³ determined in rats for the inhalation route. Therefore, MEAHA-Fe is not subject to classification for acute toxicity according to Regulation (EC) No 1272/2008 (as amended for the ninth time in Regulation (EC) No 2016/1179), and consequently the derivation of general population DNELs for acute/short-term exposure - systemic effects is not required.

  

Acute/short-term and long-term exposure - local effects

Based on the available toxicological information, MEAHA-Fe is not subject to classification for skin irritation and skin sensitisation and no general population DNEL for local effects following acute/short-term or long-term exposure is derived.

This is in line with the ECHA document "Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose[concentration]-response for human health".

  

Long-term exposure - systemic effects

Using a conservative approach, the NOELs determined in the repeated dose toxicity studies for the oral and dermal routes are also identified as NOAELs.

For the dermal route, the NO(A)EL of 100 mg/kg bw/day from the key subacute repeated dose dermal toxicity study with the structural analogue FeNa-EDDHA (CIBA-GEIGY Limited, 1996b) is regarded as the relevant dose descriptor for systemic effects associated with long-term exposure to MEAHA-Fe. Dermal treatment with the test item resulted in no mortality, no relevant clinical signs, no changes in food consumption, no effects on haematology and clinical chemistry parameters and no gross findings. A transient slight body weight loss was noted in females at 1000 mg/kg bw/day during the first week of treatment. There was an increase in adrenal weight in males at 1000 mg/kg bw/day. Microscopically, the skin application sites of females at 1000 mg/kg bw/day revealed epidermal hyperkeratosis associated with an increased severity of acanthosis. In 2/5 males at 1000 mg/kg bw/day centrilobular hypertrophy of hepatocytes was noted. 

For the inhalation route, the NO(A)EL of 10 mg/kg bw/day from the key subchronic oral toxicity study with the structural analogue FeNa-EDDHA (Novartis Crop Protection AG, 1998) is considered to represent the appropriate dose descriptor for systemic effects related to long-term inhalation exposure to MEAHA-Fe (for details on study see below).

In order to derive a general population DNEL and under the assumption of a daily exposure period of 24 hours, the oral NO(A)EL is converted into an inhalation NO(A)EC according to the following formula:

inhalation NO(A)EC = oral NO(A)EL × 1/sRV(rat) × ABSoral(rat)/ABSinhalation(human)

with:

oral NO(A)EL: 10 mg/kg bw/day

sRV(rat): 1.15 m³/kg bw/day [standard respiratory volume of the rat]

ABSoral(rat)/ABSinhalation(human): 1 [ratio of oral absorption in the rat to inhalative absorption in the human]

Accordingly, the oral NO(A)EL of 10 mg/kg bw/day is transformed in an inhalation NO(A)EC of 8.696 mg/m³.

 

For the oral route, the NO(A)EL of 10 mg/kg bw/day from the key subchronic oral toxicity study (Novartis Crop Protection AG, 1998) is used as the dose descriptor for systemic effects after long-term exposure to FeNaEDDHA. In this study, treatment with the test item resulted in lower food intake and impaired body weight development of rats treated at 200 mg/kg bw/day. Reversible effects on the red blood cell (normochromic anaemia) and white blood cell parameters, and higher values of platelets and prothrombin activity were noted at 50 and/or 200 mg/kg bw/day. In addition, there were changes of blood chemistry and urine parameters concerning the liver and kidneys. The body weight relative heart weight was increased in males at 200 mg/kg bw/day. 

Estimation of NOAEL:

A more realistic NOAEL was estimated from the LOAEL of 50 mg/kg bw/day applying an assessment factor of 5. This method is applicable and scientifically justified for this test, as only slight adverse effects were observed at 50 mg/kg bw/day (haematology parameters - anaemia). To take the relatively large concentration gap between 5 (clear NOEL) and 50 mg/kg bw/day into account, 5 mg/kg bw/day was not taken as NOAEL, but extrapolated form the LOAEL. The guidance on information requirements and CSA, R.8 (ECHA, 2008 -2010) recommends a factor between 3 and 10 for extrapolation from LOAEL to NOAEL. An assessment factor of 5 seems to be appropriate and conservative enough for the current study as only slight effects were observed at the LOAEL of 50 mg/kg bw/day. Consequently a NOAEL of 10 mg/kg bw/day is calculated for this study and used for DNEL and PNEC(oral) derivation.

 

The following assessment factors are used for the derivation of general population DNELs for oral, dermal or inhalation exposure to MEAHA-Fe:

Interspecies factor (rat to human): 4 [used for the oral and dermal routes only]

Intraspecies factor (general population): 10

Exposure duration factor: 6 (subacute to chronic) [for the dermal route], 2 (subchronic to chronic) [for the oral and inhalation routes]

Dose-response factor: 1

Quality of whole database factor: 1

The resulting general population DNELs are:

general population DNEL (dermal exposure) = 100 mg/kg bw/day / (4 × 10 × 6 × 1 × 1) = 100 mg/kg bw/day / 240 = 0.417 mg/kg bw/day, 416.7 µg/kg bw/day

general population DNEL (inhalation exposure) = 8.696 mg/m³ / (10 × 2 × 1 × 1) = 8 .696 mg/m³ / 20 = 0.4348 mg/m³, 435 µg/m³

general population DNEL (oral exposure) = 10 mg/kg bw/day / (4 × 10 × 2 × 1 × 1) = 10 mg/kg bw/day / 80 = 0.125 mg/kg bw/day, 125 µg/kg bw/day

  

This is in line with the ECHA document "Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose[concentration]-response for human health".