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Administrative data

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
Dose descriptor starting point:
NOAEL
Value:
15 mg/kg bw/day
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 to chronic)
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
AF for remaining uncertainties:
1
Justification:
Default
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:
1.1 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
Dose descriptor starting point:
NOAEL
Value:
15 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
60 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.

Data on phosphonates indicate that absorption through the lipid layer is <1%. The following correction was made for the NOAEL (oral): Correction for absorption 0.1. Therefore, the corrected NOAEL for repeated-dose systemic effects via the dermal route is: 0.6/0.01 = 60 mg/kg bw/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
AF for interspecies differences (allometric scaling):
1
Justification:
Default
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
AF for remaining uncertainties:
1
Justification:
Default
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.1 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:
no hazard identified
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:
no hazard identified

Additional information - workers

There are no repeat dose data with HMDTMP from which to derive a DNEL value. Therefore, until such data are available, DNELs derived for a related susbtance in the aminomethylenephosphonates analogue group will be used. The use of these DNEL values do not imply that HMDTMP will result in the same toxicological effects as the related susbstance. An oral DNEL for workers (relevant to ingestion following inhalation of dusts and aerosols) has been read across.

The DNEL is 0.27 mg active acid/kg bw/day based on a chronic/carcinogenicity study. The starting NOAEL is 15 mg active acid/kg bw/day with an overall assessment factor of 55.

The calculated DNELs are used for HMDTMP acid and salts since once absorbed HMDTMP salts will dissociate to become the phosphonate ion and counter-ions, 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
Dose descriptor starting point:
NOAEL
Value:
15 mg/kg bw/day
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 to chronic)
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
AF for remaining uncertainties:
1
Justification:
Default
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:
0.8 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
Dose descriptor starting point:
NOAEL
Value:
15 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
60 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.

Data on phosphonates indicate that absorption through the lipid layer is <1%. The following correction was made for the NOAEL (oral): Correction for absorption 0.1. Therefore, the corrected NOAEL for repeated-dose systemic effects via the dermal route is: 0.6/0.01 = 60 mg/kg bw/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 to chronic)
AF for interspecies differences (allometric scaling):
1
Justification:
Default
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
AF for remaining uncertainties:
1
Justification:
Default
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.8 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:
no hazard identified
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
Dose descriptor starting point:
NOAEL
Value:
15 mg/kg bw/day
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 to chronic)
AF for interspecies differences (allometric scaling):
1
Justification:
Default
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
AF for remaining uncertainties:
1
Justification:
Default
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:
no hazard identified

Additional information - General Population

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