Registration Dossier

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

8.8 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

10

Modified dose descriptor starting point:

NOAEC

Value:

88 mg/m³

Explanation for the modification of the dose descriptor starting point:

Systemic effects

AF for dose response relationship:

1

Justification:

the NOAEL was at least 50 mg/kg bw

AF for differences in duration of exposure:

2

Justification:

subchronic exposure

AF for interspecies differences (allometric scaling):

1

Justification:

has aleardy been done at the correction in sRV

AF for other interspecies differences:

1

Justification:

hardly absorbed and not metabolized

AF for intraspecies differences:

5

Justification:

standard for workers

AF for the quality of the whole database:

1

Justification:

several repeated dose studies available

AF for remaining uncertainties:

1

Justification:

no remaining uncertainties

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.83 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Dermal

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

120

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 is used for setting dermal DNEL. In this study both local and systemic effects were observed

AF for dose response relationship:

1

Justification:

the NOAEL was at least 100 mg/kg bw

AF for differences in duration of exposure:

6

Justification:

subacute study

AF for interspecies differences (allometric scaling):

4

Justification:

allometric scaling

AF for other interspecies differences:

1

Justification:

hardly any absorption, not metabolized

AF for intraspecies differences:

5

Justification:

workers

AF for the quality of the whole database:

1

Justification:

several repeated dose studies available

AF for remaining uncertainties:

1

Justification:

no remaining uncertainties

Hazard assessment conclusion:

low hazard (no threshold derived)

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, EDDHMA-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 4 -h LC50 value of >1240 mg/m³ (technically highest attainable concentration). Therefore, EDDHMA-Fe is not subject to classification for acute toxicity according to Directive 67/548/EEC and Regulation 1272/2008/EC, 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, EDDHMA-Fe is not subject to classification for skin, eye and/or respiratory 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]-repsonse 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 structurally related substance EDDHA-FeNa (CIBA-GEIGY Limited, 1996b) is regarded as the relevant dose descriptor for systemic effects associated with long-term dermal exposure to EDDHMA-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 NOAEL of 50 mg/kg bw/day from the key subchronic oral toxicity study (Schoenmakers, 1996) is considered to represent the appropriate dose descriptor for systemic effects related to long-term inhalation exposure to EDDHMA-Fe.

In this study, treatment with the test item resulted in slight haematological changes and a slightly increased relative liver weight in male rats treated at 100 mg/kg bw/day. The slight increase in relative kidney weight was, however, not corroborated by histopathological renal effects, and was not seen in female rats at this level (NOEL 100 mg/kg bw). Histopathological kidney effects were observed in both male and female rats at the next higher level of 500 mg/kg bw.

Estimation of NOAEL: A more realistic NOAEL was estimated from the LOAEL of 100 mg/kg bw/day in males applying an assessment factor of 2. This is scientifically justified for this test, as only slight slight adverse effects were observed at 100 mg/kg bw/day in males only (see above). To take the relatively large concentration gap between 20 (clear NOEL) and 100 mg/kg bw/day into account, 20 mg/kg bw/day was not taken as NOAEL, but extrapolated from the LOAEL in males. An assessment factor of 2 seems to be approprate and conservative enough for the current study as only slight effects were observed at the LOAEL of 100 mg/kg bw/day in males. Also in the oral one-generation test (Rejinders, 1997), applying a treatment period of at least 13 weeks, a parental NOAEL of 50 mg/kg was established. The NOAEL in an oral 4 -week study (Banks, 1988) was 200 mg/kg bw; in a second oral 4 -week study (Korn, 1990) 200 mg/kg bw was a LOAEL, the only change observed at that level consisted of

slight fatty degenerations of renal tubular epithelial cells; no increase in relative kidney weight was observed at that level.

Consequently a NOAEL of 50 mg/kg bw/day is calculated for the 90 -day 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 NOAEL is converted into an inhalation NOAEC according to the following formula:

inhalation NOAEC = oral NOAEL × 1/sRV(rat) × ABSoral(rat)/ABSinhalation(human) × sRV(human)/wRV(human) with:

oral NOAEL: 50 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]. See also section 7.1: based on physical-chemical characteristics, particularly water solubility, octanol-water partition coefficient and vapour pressure, no or only limited absorption by the dermal and inhalation routes is expected, which is further supported by the dermal and inhalation acute toxicity studies results. For the oral route uptake is more likely compared to the other routes. As such no higher absorption for inhalation should have to be taken into account.

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

Accordingly, the oral NOAEL of 50 mg/kg bw/day is transformed in an inhalation NOAEC of 88 mg/m³.

The following assessment factors are used for the derivation of worker DNEL LT systemic for inhalation exposure to EDDHMA-Fe:

Interspecies factor (rat to human): 1 (inhalation exposure)

Remaining differences (systemic effects): 1 (EDDHMA-Fe is hardly absorbed and not metabolized, as such no differences in toxicokinetics expected)

Intraspecies factor (worker): 5

Exposure duration factor: 2 (subchronic to chronic)

Dose-response factor: 1

Quality of whole database factor: 1

Total assessment factor: 10

The resulting worker DNEL LT inhalation systemic is:

worker DNEL (inhalation exposure) = 88 mg/m³ / 10 = 8.8 mg/m³

The following assessment factors are used for the derivation of worker DNEL LT systemic/local for dermal exposure to EDDHMA-Fe:

Interspecies factor (rat to human): 4

Intraspecies factor (worker): 5

Exposure duration factor: 6 (subacute to chronic)

Dose-response factor: 1

Quality of whole database factor: 1

Total assessment factor: 120

The resulting worker DNEL LT dermal local/systemic is:

worker DNEL (dermal exposure) = 100 mg/kg bw/day / 120 = 0.83 mg/kg bw/day, rounded to 0.8 mg/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".

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.2 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

20

Modified dose descriptor starting point:

NOAEC

Value:

43.5 mg/m³

Explanation for the modification of the dose descriptor starting point:

Systemic effects

AF for dose response relationship:

1

Justification:

the NOAEL was at least 50 mg/kg bw

AF for differences in duration of exposure:

2

Justification:

subchronic exposure

AF for interspecies differences (allometric scaling):

1

Justification:

has already been done at the correction in sRV

AF for other interspecies differences:

1

Justification:

hardly absorbed and not metabolized

AF for intraspecies differences:

10

Justification:

general population

AF for the quality of the whole database:

1

Justification:

several repeated dose toxicity studies available

AF for remaining uncertainties:

1

Justification:

no remaining uncertainties

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.42 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Dermal

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

240

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 used

AF for dose response relationship:

1

Justification:

the NOAEL is at least 100 mg/kg bw

AF for differences in duration of exposure:

6

Justification:

subacute study

AF for interspecies differences (allometric scaling):

4

Justification:

allometric scaling

AF for other interspecies differences:

1

Justification:

hardly absorbed and not metabolized

AF for intraspecies differences:

10

Justification:

general population

AF for the quality of the whole database:

1

Justification:

several repeated studies available

AF for remaining uncertainties:

1

Justification:

no remaining uncertainties

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.62 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

80

Modified dose descriptor starting point:

NOAEL

Value:

50 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

not applicable, oral study used

AF for dose response relationship:

1

Justification:

the NOAEL is at least 50 mg/kg bw

AF for differences in duration of exposure:

2

Justification:

subchronic study

AF for interspecies differences (allometric scaling):

4

Justification:

allometric scaling

AF for other interspecies differences:

1

Justification:

hardly absorbed and not metabolized

AF for intraspecies differences:

10

Justification:

general population

AF for the quality of the whole database:

1

Justification:

several repeated studies available

AF for remaining uncertainties:

1

Justification:

no remaining uncertainties

Hazard assessment conclusion:

low hazard (no threshold derived)

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, EDDHMA-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 4 -h LC50 value of > 1.24 mg/L (technically highest attainable concentration) determined in rats for the inhalation route. Therefore, EDDHMA-Fe is not subject to classification for acute toxicity according to Directive 67/548/EEC and Regulation 1272/2008/EC, 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, EDDHMA-Fe is not subject to classification for skin, eye and/or respiratory 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]-repsonse 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 structurally related substance EDDHA-FeNa (CIBA-GEIGY Limited, 1996b) is regarded as the relevant dose descriptor for systemic effects associated with long-term dermal exposure to EDDHMA-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 NOAEL of 50 mg/kg bw/day from the key subchronic oral toxicity study (Schoenmakers, 1996) is considered to represent the appropriate dose descriptor for systemic effects related to long-term inhalation exposure to EDDHMA-Fe.

In this study, treatment with the test item resulted in slight haematological changes and a slightly increased relative liver weight in male rats treated at 100 mg/kg bw/day. The slight increase in relative kidney weight was, however, not corroborated by histopathological renal effects, and was not seen in female rats at this level (NOEL 100 mg/kg bw). Histopathological kidney effects were observed in both male and female rats at the next higher level of 500 mg/kg bw.

Estimation of NOAEL: A more realistic NOAEL was estimated from the LOAEL of 100 mg/kg bw/day in males applying an assessment factor of 2. This is scientifically justified for this test, as only slight slight adverse effects were observed at 100 mg/kg bw/day in males only (see above). To take the relatively large concentration gap between 20 (clear NOEL) and 100 mg/kg bw/day into account, 20 mg/kg bw/day was not taken as NOAEL, but extrapolated from the LOAEL in males. An assessment factor of 2 seems to be approprate and conservative enough for the current study as only slight effects were observed at the LOAEL of 100 mg/kg bw/day in males. Also in the oral one-generation test (Rejinders, 1997), applying a treatment period of at least 13 weeks, a parental NOAEL of 50 mg/kg was established. The NOAEL in an oral 4 -week study (Banks, 1988) was 200 mg/kg bw; in a second oral 4 -week study (Korn, 1990) 200 mg/kg bw was a LOAEL, the only change observed at that level consisted of

slight fatty degenerations of renal tubular epithelial cells; no increase in relative kidney weight was observed at that level.

Consequently a NOAEL of 50 mg/kg bw/day is calculated for the 90 -day study and used for DNEL and PNEC(oral) derivation.

For the oral route, the NO(A)EL of 50 mg/kg bw/day from the key subchronic oral toxicity study and the one-generation study is used as the dose descriptor for systemic effects after long-term exposure to EDDHMA-Fe.

In order to derive a general population DNEL and under the assumption of a daily exposure period of 8 hours, the oral NOAEL is converted into an inhalation NOAEC according to the following formula:

inhalation NOAEC = oral NOAEL × 1/sRV(rat) × ABSoral(rat)/ABSinhalation(human) × sRV(human)/wRV(human)with:

oral NOAEL: 50 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] See also section 7.1: based on physical-chemical characteristics, particularly water solubility, octanol-water partition coefficient and vapour pressure, no or only limited absorption by the dermal and inhalation routes is expected, which is further supported by the dermal and inhalation acute toxicity studies results. For the oral route uptake is more likely compared to the other routes. As such no higher absorption for inhalation should have to be taken into account

Accordingly, the oral NOAEL of 50 mg/kg bw/day is transformed in an inhalation NOAEC of 43.5 mg/m³.

The following assessment factors are used for the derivation of general population DNELs for oral, dermal or inhalation exposure to EDDHMA-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) = 100/240 = 0.42 mg/kg bw/day

general population DNEL (inhalation exposure) = 43.5 mg/m³ / (10 × 2 × 1 × 1) = 43.5/20 = 2.2 mg/m³

general population DNEL (oral exposure) = 50 mg/kg bw/day / (4 × 10 × 2 × 1 × 1) = 50/80 = 0.62 mg/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".