Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
7.27 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:
82.5 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
72.7 mg/m³
Explanation for the modification of the dose descriptor starting point:

The following correction was made to the NOAEL (oral): Correction respiratory volume rat (8 hour) 1/0.38 m³/kg bw/day, Correction for respiratory volume (worker): 6.7 m³/10 m³. Correction for oral to inhaled 1/2. Therefore the corrected NOAEC for repeated-dose systemic effects via the inhalation route is: oral 82.5*(1/0.38) *(6.7 m³/10 m³)*(1/2) = 72.7 mg/m³.

AF for dose response relationship:
1
Justification:
Default
AF for differences in duration of exposure:
2
Justification:
Default (subchronic to chronic)
AF for interspecies differences (allometric scaling):
1
Justification:
Default (oral rat to inhaled human)
AF for other interspecies differences:
1
Justification:
The effects observed in the oral study were indicative of the iron binding capacity of the test substance and its influence on calcium homeostasis, however, without causing any changes in calcium plasma levels, therefore no intraspecies differenced apply.
AF for intraspecies differences:
5
Justification:
Default (worker)
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:
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:
8.25 mg/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):
20
Dose descriptor starting point:
NOAEL
Value:
82.5 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
165 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Measured data are available for DTPMP acid, which indicate that oral absorption is around 2% and dermal abrorption is < 1%. The following correction was made for the NOAEL (oral): Correction for absorption 2/1. Therefore, the corrected NOAEL for repeated -dose systemic effects via the dermal route is: 82.5*(2/1) = 165 mg/kg bw/day.

AF for dose response relationship:
1
Justification:
Default
AF for differences in duration of exposure:
2
Justification:
Default (subchronic to chronic)
AF for interspecies differences (allometric scaling):
2
Justification:
The effects observed in the oral study were indicative of the iron binding capacity of the test substance and its influence on calcium homeostasis, however, without causing any changes in calcium plasma levels. Therefore, the proposed assessment factor for interspecies differences is 2.
AF for other interspecies differences:
1
Justification:
The effects observed in the oral study were indicative of the iron binding capacity of the test substance and its influence on calcium homeostasis, however, without causing any changes in calcium plasma levels, therefore no intraspecies differenced apply.
AF for intraspecies differences:
5
Justification:
Default (worker)
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:
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:
low hazard (no threshold derived)

Additional information - workers

DNELs for workers long-term systemic effects via the inhalation and dermal routes were derived from a 90-day feeding study (reliability score 1) conducted according to OECD 408 guideline and the principles of GLP, groups of 12 male and 12 female Wistar-derived rats were fed diets containing 0 (control), 100, 1000 or 10000 ppm (equivalent to 8.2, 82.5 and 841.9 mg/kg bw/day in males and 9.2, 92.3 and 902.6 mg/kg for females) Dequest 2066A for 90 consecutive days. Clinical observations, bodyweights and food consumption were measured. Ophthalmoscopic and haematology examinations, clinical chemistry and urinalysis were conducted. At the end of the exposure period all animals were killed and a full microscopic examination conducted. Bone mineral density was evaluated for bone collected at termination. There were no deaths and the majority of parameters were unaffected by the treatment. Minor changes in certain haematological parameters (red blood cell count was significantly increased, mean cell volume and mean cell haemoglobin concentration were significantly decreased) were noted at the highest dose. There was also a decreased incidence in Perls' staining of the spleen. It is unlikely that DTPMP exerts a true systemic effect and the observed anaemia is much more likely to be due to inhibition of iron uptake in the gastrointestinal tract.

Bone density was significantly increased in both sexes in the highest dose group, and the incidence of microlithiasis in the kidney was reduced at all dose levels. These changes are indicative of the influence of Dequest 2066A on calcium homeostasis, however, without causing any changes in calcium plasma levels. Therefore, the changes were not considered to be of toxicological significance, and the NOAEL was 1000 ppm (equivalent to to 82.5 and 92.3 mg/kg bw/day of active acid in males and females, respectively).

General Population - 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):
20
Dose descriptor starting point:
NOAEL
Value:
82.5 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
35.9 mg/m³
Explanation for the modification of the dose descriptor starting point:

The followingcorrection was made to the NOAEL (oral): Correction respiratory volume rat (24 hour) 1/1.15 m³/kg bw. Correction for oral to inhaled 1/2. Therefore the corrected NOAEC for repeated-dose systemic effects via the inhalation route is: 82.5*(1/1.15)*(1/2) = 35.9 mg/m³.


AF for dose response relationship:
1
Justification:
Default
AF for differences in duration of exposure:
2
Justification:
Default (subchronic to chronic)
AF for interspecies differences (allometric scaling):
1
Justification:
Default (oral rat to inhaled human)
AF for other interspecies differences:
1
Justification:
The effects observed in the oral study were indicative of the iron binding capacity of the test substance and its influence on calcium homeostasis, however, without causing any changes in calcium plasma levels, therefore no intraspecies differenced apply.
AF for intraspecies differences:
10
Justification:
Default (general population)
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:
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:
4.1 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Dose descriptor starting point:
NOAEL
Value:
82.5 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
165 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Measured data are available for DTPMP acid, which indicate that oral absorption is around 2% and dermal absorption is < 1%. The following correction was made for the NOAEL (oral): Correction for absorption 2/1. Therefore, the corrected NOAEL for repeated -dose systemic effects via the dermal route is: 82.5*(2/1) = 165 mg/kg bw/day.

AF for dose response relationship:
1
Justification:
Default
AF for differences in duration of exposure:
2
Justification:
Default (subchronic to chronic)
AF for interspecies differences (allometric scaling):
2
Justification:
The effects observed in the oral study were indicative of the iron binding capacity of the test substance and its influence on calcium homeostasis, however, without causing any changes in calcium plasma levels. Therefore, the proposed assessment factor for interspecies differences is 2.
AF for other interspecies differences:
1
Justification:
The effects observed in the oral study were indicative of the iron binding capacity of the test substance and its influence on calcium homeostasis, however, without causing any changes in calcium plasma levels, therefore, no intraspecies differenced apply.
AF for intraspecies differences:
10
Justification:
Default (general population)
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:
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:
2.1 mg/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):
40
Dose descriptor starting point:
NOAEL
Value:
82.5 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No correction was applied to the dose descriptor starting point.

AF for dose response relationship:
1
Justification:
Default
AF for differences in duration of exposure:
2
Justification:
Default (subchronic to chronic)
AF for interspecies differences (allometric scaling):
2
Justification:
The effects observed in the oral study were indicative of the iron binding capacity of the test substance and its influence on calcium homeostasis, however, without causing any changes in calcium plasma levels. Therefore, the proposed assessment factor for interspecies differences is 2.
AF for other interspecies differences:
1
Justification:
Since the effect was most likely to have been caused by inhibition of iron uptake in the gastrointestinal tract (i.e. a local physicochemical effect in the gut), no allometric scaling or assessment factor for interspecies differences were included in the DNEL calculation. This is justified by the fact that test species used (rats) are more susceptible to iron deficiencies than humans and other standard laboratory species.
AF for intraspecies differences:
10
Justification:
Defalut (general population)
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:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

DNELs for general population long-term systemic effects via the inhalation, dermal and oral routes were derived from a 90-day feeding study (reliability score 1) conducted according to OECD 408 guideline and the principles of GLP, groups of 12 male and 12 female Wistar-derived rats were fed diets containing 0 (control), 100, 1000 or 10000 ppm (equivalent to 8.2, 82.5 and 841.9 mg/kg bw/day in males and 9.2, 92.3 and 902.6 mg/kg for females) Dequest 2066A for 90 consecutive days. Clinical observations, bodyweights and food consumption were measured. Ophthalmoscopic and haematology examinations, clinical chemistry and urinalysis were conducted. At the end of the exposure period all animals were killed and a full microscopic examination conducted. Bone mineral density was evaluated for bone collected at termination. There were no deaths and the majority of parameters were unaffected by the treatment. Minor changes in certain haematological parameters (red blood cell count was significantly increased, mean cell volume and mean cell haemoglobin concentration were significantly decreased) were noted at the highest dose. There was also a decreased incidence in Perls' staining of the spleen. It is unlikely that DTPMP exerts a true systemic effect and the observed anaemia is much more likely to be due to inhibition of iron uptake in the gastrointestinal tract.

Bone density was significantly increased in both sexes in the highest dose group, and the incidence of microlithiasis in the kidney was reduced at all dose levels. These changes are indicative of the influence of Dequest 2066A on calcium homeostasis, however, without causing any changes in calcium plasma levels.

Therefore, the changes were not considered to be of toxicological significance, and the NOAEL was 1000 ppm (equivalent to to 82.5 and 92.3 mg/kg bw/day of active acid in males and females, respectively).

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