Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.2 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
75
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3 333 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
300
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

Workers - Hazard for the eyes

Additional information - workers

This dossier is a registration update of a previously notified substance and contains the info on the required endpoints under the previous legislation.

A NOAEL of 200 mg/kg bw was observed in an oral subacute study; at the next higher level of 1000 mg/kg bw intestinal effects were noted.

DNEL Inhalation long-term systemic

- As no inhalation study is available, it is only possible to derive a DNEL for systemic effects, not for local effects

- For intestinal absorption a figure of 5% has been used based on the European RAR (2004) on EDTA-H4, a substance which has a very similar structure (only one C-atom more in the backbone).

Inhalation of aerosol (nebulized):

For intestinal absorption a figure of 5% has been used.

For inhalation: 20% (based on studies using nebulized DTPA solutions in humans – Jolly et al., 1972)

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

This will be:

200 x [1/0.38 m3(8h)] x [5/20] x [6.7 m3(8h) / 10 m3(8h)] = 87 mg/m3

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: 6 (sub-acute to chronic).

This results in a total assessment factor of 2.5 x 5 x 6 = 75, or the DNEL will be: 87/75 = 1.2 mg/m3

If ECETOC TR110 recommendations are followed for deriving the DNELs, a factor 3 for intraspecies worker would be used instead of 5 resulting in a DNEL of 1.9 mg/m3.

 

Inhalation of aerosol (dust)

For intestinal absorption a figure of 5% has been used.

For inhalation absorption the following is suggested: Based on the particle size distribution, it is expected that 90% of the inhaled substance will be deposited in the upper respiratory tract, which will finally be taken up orally. Of this, only 5% will be absorbed in the gastrointestinal tract and become available systematically, i.e. 0.9 x 0.05 = 0.045. The other 10% may reach the alveoli and it is assumed that this will be absorbed completely (worst case). Therefore, the total inhalation absorption factor will be 0.045 + 0.10 = 0.145.

 

Corrected inh NOAEL =

oral NOAEL x [1/sRV(rat)] x [absorption (oral-rat) / absorption (inh-human)] x [sRV(human) / wRV]

This will be: 200 x [1/0.38 m3 (8h)] x [5/14.5] x [6.7 m3 (8h) / 10 m3 (8h)] = 120 mg/m3

 

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: 6 (sub-acute to chronic).

This results in a total assessment factor of 2.5 x 5 x 2 = 75, or the DNEL will be: 120/75 = 1.6 mg/m3

 

If ECETOC TR110 recommendations are followed for deriving the DNELs, a factor 3 for intraspecies worker would be used instead of 5 resulting in a DNEL of 2.7 mg/m3.

It should, however, be understood that the Inhalation DNEL is significantly overconservative for the following 2 reasons: 1) The likelihood of a worker being exposed to PDTA-FeNH4 via a nebulized aerosol of PDTA-FeNH4 inserted into the nose is VERY unlikely, thus the degree of absorption is likely an overestimate of what would actually happen. 2) The period for which the DNEL is calculated (8h) assumes a worker would be exposed to an aerosol of PDTA-FENH4 for 8 hours, 5 days/week, during working-life. PDTA-FeNH4 is not volatile and any spray of PDTA-FeNH4 would settle out of the air in a short period after spraying, i.e. the PDTA-FeNH4 would not remain in the breathable air for long periods of time. Thus exposure via inhalation will be limited to the time periods directly following the production of an aerosol containing PDTA-FeNH4.

DNEL dermal long-term systemic

As no dermal exposure study is available but PDTA-FeNH4 is not irritating to the skin, no DNEL for repeated local dermal effects can be established.

Based on EDTA-H4, dermal absorption is 0.001%; oral absorption 5% (European RAR; 2004).

 

Corrected dermal NOAEL = oral NOAEL x [absorption (oral-rat) / absorption (dermal-human)]

This will be: 200 x 5/0.001 = 1,000,000 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 worker: 5

Exposure duration: 6 (sub-acute to chronic)

 

This results in a total assessment factor of 4 x 2.5 x 5 x 6 = 300, indicating that the DNEL dermal will be 1,000,000 / 300 = 3333 mg/kg

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.29 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
150
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1 667 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
600
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.83 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
240
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

This dossier is a registration update of a previously notified substance and contains the info on the required endpoints under the previous legislation.

A NOAEL of 200 mg/kg bw was observed in an oral subacute study; at the next higher level intestinal effects have been observed.

DNEL oral long-term systemic

Assuming that absorption is similar for rats and humans:

Next the following assessment factors should minimally be used

Interspecies:

- difference in BW (allometric scaling): 4

- remaining differences: there is no indication that the toxicity of chelating agents such as DTPA differs significantly between animals and humans; they are absorbed poorly by both animals and man and excreted rapidly with no evidence of tissue sequestration.

- Intraspecies general population: 10

Exposure duration: 6 (sub-acute to chronic)

This results in a total assessment factor of 4 x 2.5 x 10 x 6 = 240, indicating that the DNEL oral will be 200 / 240 = 0.83 mg/kg

 

DNEL dermal long-term systemic

As no dermal exposure study is available but PDTA-FeNH4 is not irritating to the skin, no DNEL for repeated local dermal effects can be established.

Dermal absorption is 0.001%; oral absorption 5% (Euroepan RAR on EDTA-H4; 2004).

Corrected dermal NOAEL = oral NOAEL x [absorption (oral-rat) / absorption (dermal-human)]

This will be: 200 x 5/0.001 = 1,000,000 mg/kg

 

Next the following assessment factors should minimally be used

Interspecies:

- difference in BW (allometric scaling): 4

- remaining differences: 2.5 (in case of systemic effects)

Intraspecies general population: 10

Exposure duration: 6 (sub-acute to chronic)

This results in a total assessment factor of 4 x 2.5 x 10 x 6 = 600, indicating that the DNEL dermal will be 1,000,000 / 600 = 1667 mg/kg

 

DNEL inhalation long-term systemic

Inhalation of aerosol (nebulized):

For intestinal absorption a figure of 5% has been used.

For inhalation: 20% (based on studies using nebulized DTPA solutions in humans – Jolly et al., 1972)

 

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

This will be: 200 x [1/1.15 m3(24h)] x [5/20] = 43 mg/m3

 

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: 2 (sub-acute to chronic)

This results in a total assessment factor of 2.5 x 10 x 6 = 150, thus the DNEL will be: 43/150 = 0.29 mg/m3

It should, however, be understood that the Inhalation DNEL is significantly overconservative for the following 2 reasons: 1) The likelihood of a consumer or member of the general population being exposed to PDTA-FeNH4 via a nebulized aerosol of PDTA-FeNH4 inserted into the nose is VERY unlikely, thus the degree of absorption is likely an overestimate of what would actually happen. 2) The period for which the DNEL is calculated (24h) assumes a consumer or general population would be exposed to an aerosol of PDTA-FeNH4 for 24 hours. PDTA-FeNH4 is not volatile and any spray of PDTA-FeNH4 would settle out of the air in a short period after spraying, i.e. the PDTA-FeNH4 would not remain in the breathable air for long periods of time. Thus exposure via inhalation will be limited to the time periods directly following the production of an aerosol containing PDTA-FeNH4.