[ethylenebis[nitrilobis(methylene)]]tetrakisphosphonic acid, calcium sodium salt

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.02 mg/m³

Most sensitive endpoint:

carcinogenicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

55

Modified dose descriptor starting point:

NOAEC

Value:

1.1 mg/m³

Explanation for the modification of the dose descriptor starting point:

Ratio of assumed uptake from lung (100%) to known oral uptake (4%) from G.I. tract, therefore NOAEC to account for differences in uptake = 15/25. Correction for respiratory rate and volume (rat to human worker): (6.7m3/d/10m3/d) *(1/0.38 m3/kg) (default). Therefore the corrected NOAEC for repeated dose systemic effects via the inhalation route is: (15/25)/(6.7/10*1/0.38) = 0.6/1.76 = 1.1 mg/m3

AF for dose response relationship:

10

Justification:

There is no specific guidance available on the value of an additional assessment factor for severity of effect. However, 10 is conservative and considered to be appropriate for the type of effects in this case (osteosarcoma).

AF for differences in duration of exposure:

1

Justification:

Default (chronic study)

AF for interspecies differences (allometric scaling):

1

Justification:

Default (oral rat to inhaled human)

AF for other interspecies differences:

2.5

Justification:

Default

AF for intraspecies differences:

2.2

Justification:

The intraspecies assessment factor takes account for the variability in sensitivity between individuals. The human population is far more diverse than experimental animals that are bred to be as similar as possible, and unhealthy animals are not allowed to start the study. This AF also covers differences between ethnic groups and age groups. The default intraspecies factors are typically broken down into equal factors accounting for toxicodynamic and toxicokinetic differences, respectively. Accordingly, an intraspecies factor of 10 is composed of two identical factors of √10 = 3.2. Likewise, the default for workers (AF = 5) can be split into AFs of √5 = 2.2. Since enzymatic metabolism is not relevant for the osteosarcoma effect of EDTMP, individual genetic dispositions are therefore without effect on these processes. As a result, the toxicokinetic components (3.2 and 2.2 for general population and workers, respectively) can be eliminated from the intraspecies AF.

AF for the quality of the whole database:

1

Justification:

Default (similar to guideline study)

AF for remaining uncertainties:

1

Justification:

Default (no remaining uncertainties)

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.02 mg/m³

Most sensitive endpoint:

carcinogenicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

55

DNEL extrapolated from long term DNEL

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:

0.011 mg/kg bw/day

Most sensitive endpoint:

carcinogenicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

55

Modified dose descriptor starting point:

NOAEL

Value:

0.6 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Ratio of assumed uptake from dermal (100%) to known oral uptake (4%) from G.I. tract, therefore NOAEL to account for differences in uptake = 15/25 = 0.6 mg/kg/day

AF for dose response relationship:

10

Justification:

There is no specific guidance available on the value of an additional assessment factor for severity of effect. However, 10 is conservative and considered to be appropriate for the type of effects in this case (osteosarcoma).

AF for differences in duration of exposure:

1

Justification:

Default (chronic study)

AF for interspecies differences (allometric scaling):

1

Justification:

Since the effect (osteosarcoma) is not as a result of metabolism, an assessment factor of 1 has been used for "correction for differences in metabolic rate per body weight" (instead of the default 4 value).

AF for other interspecies differences:

2.5

Justification:

Default

AF for intraspecies differences:

2.2

Justification:

The intraspecies assessment factor takes account for the variability in sensitivity between individuals. The human population is far more diverse than experimental animals that are bred to be as similar as possible, and unhealthy animals are not allowed to start the study. This AF also covers differences between ethnic groups and age groups. The default intraspecies factors are typically broken down into equal factors accounting for toxicodynamic and toxicokinetic differences, respectively. Accordingly, an intraspecies factor of 10 is composed of two identical factors of √10 = 3.2. Likewise, the default for workers (AF = 5) can be split into AFs of √5 = 2.2. Since enzymatic metabolism is not relevant for the osteosarcoma effect of EDTMP, individual genetic dispositions are therefore without effect on these processes. As a result, the toxicokinetic components (3.2 and 2.2 for general population and workers, respectively) can be eliminated from the intraspecies AF.

AF for the quality of the whole database:

1

Justification:

Default (similar to guideline study)

AF for remaining uncertainties:

1

Justification:

Default (no remaining uncertainties)

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.011 mg/kg bw/day

Most sensitive endpoint:

carcinogenicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

55

DNEL extrapolated from long term DNEL

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)

Most sensitive endpoint:

skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

An oral DNEL for workers (relevant to ingestion following inhalation of dusts and aerosols) has been calculated.

The DNEL is 0.12 mg active acid/kg bw/day based on the development of osteosarcomas observed in a chronic/carcinogenicity study. The starting NOAEL is 15 mg active acid/kg bw/day with an assessment factor of 1 applied for duration; 2.5 for interspecies differences, and an assessment factor of 5 applied for intraspecies differences. In addition an assessment factor of 10 has been used to compensate for the severity of the effect. Since the effect is not as a result of metabolism, an assessment factor of 1 has been used for "correction for differences in metabolic rate per body weight" (instead of the default 4 value).

The calculated DNELs are valid for both the acid and salt EDTMP substances since once absorbed the EDTMP salts will dissociate to become the acid and counter-ion, while the counter-ion is not expected to exhibit or influence toxicity.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.006 mg/m³

Most sensitive endpoint:

carcinogenicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

80

Modified dose descriptor starting point:

NOAEC

Value:

0.52 mg/m³

Explanation for the modification of the dose descriptor starting point:

Ratio of assumed uptake from lung (100%) to known oral uptake (4%) from G.I. tract, therefore NOAEC to account for differences in uptake = 15/25. Correction for respiratory rate and volume (rat to human general population): (1/1.15 m3/kg) (default). Therefore the corrected NOAEC for repeated dose systemic effects via the inhalation route is: (15/25)/(1/1.15) = 0.6/0.87 = 0.52 mg/m3

AF for dose response relationship:

10

Justification:

There is no specific guidance available on the value of an additional assessment factor for severity of effect. However, 10 is conservative and considered to be appropriate for the type of effects in this case (osteosarcoma).

AF for differences in duration of exposure:

1

Justification:

Default (chronic study)

AF for interspecies differences (allometric scaling):

1

Justification:

Default (oral rat to inhaled human)

AF for other interspecies differences:

2.5

Justification:

Default

AF for intraspecies differences:

3.2

Justification:

The intraspecies assessment factor takes account for the variability in sensitivity between individuals. The human population is far more diverse than experimental animals that are bred to be as similar as possible, and unhealthy animals are not allowed to start the study. This AF also covers differences between ethnic groups and age groups. The default intraspecies factors are typically broken down into equal factors accounting for toxicodynamic and toxicokinetic differences, respectively. Accordingly, an intraspecies factor of 10 is composed of two identical factors of √10 = 3.2. Likewise, the default for workers (AF = 5) can be split into AFs of √5 = 2.2. Since enzymatic metabolism is not relevant for the osteosarcoma effect of EDTMP, individual genetic dispositions are therefore without effect on these processes. As a result, the toxicokinetic components (3.2 and 2.2 for general population and workers, respectively) can be eliminated from the intraspecies AF.

AF for the quality of the whole database:

1

Justification:

Default (similar to guideline study)

AF for remaining uncertainties:

1

Justification:

Default (no remaining uncertainties)

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.006 mg/m³

Most sensitive endpoint:

carcinogenicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

80

DNEL extrapolated from long term DNEL

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:

0.008 mg/kg bw/day

Most sensitive endpoint:

carcinogenicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

80

Modified dose descriptor starting point:

NOAEL

Value:

0.6 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Ratio of assumed uptake from dermal (100%) to known oral uptake (4%) from G.I. tract, therefore NOAEL to account for differences in uptake = 15/25 = 0.6 mg/kg/day

AF for dose response relationship:

10

Justification:

There is no specific guidance available on the value of an additional assessment factor for severity of effect. However, 10 is conservative and considered to be appropriate for the type of effects in this case (osteosarcoma).

AF for differences in duration of exposure:

1

Justification:

Default (chronic study)

AF for interspecies differences (allometric scaling):

1

Justification:

Since the effect (osteosarcoma) is not as a result of metabolism, an assessment factor of 1 has been used for "correction for differences in metabolic rate per body weight" (instead of the default 4 value).

AF for other interspecies differences:

2.5

Justification:

Default

AF for intraspecies differences:

3.2

Justification:

The intraspecies assessment factor takes account for the variability in sensitivity between individuals. The human population is far more diverse than experimental animals that are bred to be as similar as possible, and unhealthy animals are not allowed to start the study. This AF also covers differences between ethnic groups and age groups. The default intraspecies factors are typically broken down into equal factors accounting for toxicodynamic and toxicokinetic differences, respectively. Accordingly, an intraspecies factor of 10 is composed of two identical factors of √10 = 3.2. Likewise, the default for workers (AF = 5) can be split into AFs of √5 = 2.2. Since enzymatic metabolism is not relevant for the osteosarcoma effect of EDTMP, individual genetic dispositions are therefore without effect on these processes. As a result, the toxicokinetic components (3.2 and 2.2 for general population and workers, respectively) can be eliminated from the intraspecies AF.

AF for the quality of the whole database:

1

Justification:

Default (similar to guideline study)

AF for remaining uncertainties:

1

Justification:

Default (no remaining uncertainties)

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.008 mg/kg bw/day

Most sensitive endpoint:

carcinogenicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

80

DNEL extrapolated from long term DNEL

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)

Most sensitive endpoint:

skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.19 mg/kg bw/day

Most sensitive endpoint:

carcinogenicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

80

Modified dose descriptor starting point:

NOAEL

Value:

15 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Oral uptake is limited (4%) but no correction is made since both NOAEL and modelled exposure are external doses

AF for dose response relationship:

10

Justification:

There is no specific guidance available on the value of an additional assessment factor for severity of effect. However, 10 is conservative and considered to be appropriate for the type of effects in this case (osteosarcoma).

AF for differences in duration of exposure:

1

Justification:

Default (chronic study)

AF for interspecies differences (allometric scaling):

1

Justification:

The substance is not metabolised prior to action, therefore the allometric scaling factor (AF = 4 for rat to human) is not used.

AF for other interspecies differences:

2.5

Justification:

Default

AF for intraspecies differences:

3.2

Justification:

The intraspecies assessment factor takes account for the variability in sensitivity between individuals. The human population is far more diverse than experimental animals that are bred to be as similar as possible, and unhealthy animals are not allowed to start the study. This AF also covers differences between ethnic groups and age groups. The default intraspecies factors are typically broken down into equal factors accounting for toxicodynamic and toxicokinetic differences, respectively. Accordingly, an intraspecies factor of 10 is composed of two identical factors of √10 = 3.2. Likewise, the default for workers (AF = 5) can be split into AFs of √5 = 2.2. Since enzymatic metabolism is not relevant for the osteosarcoma effect of EDTMP, individual genetic dispositions are therefore without effect on these processes. As a result, the toxicokinetic components (3.2 and 2.2 for general population and workers, respectively) can be eliminated from the intraspecies AF.

AF for the quality of the whole database:

1

Justification:

Default (similar to guideline study)

AF for remaining uncertainties:

1

Justification:

Default (no remaining uncertainties)

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.19 mg/kg bw/day

Most sensitive endpoint:

carcinogenicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

80

DNEL extrapolated from long term DNEL

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - General Population

The calculated DNELs are valid for both the EDTMP acid and salts since once absorbed the EDTMP salts will dissociate to become the acid and counter-ion, while the counter-ion is not expected to exhibit or influence toxicity.