Registration Dossier
Registration Dossier
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EC number: 800-484-0 | CAS number: 154518-38-4
Toxicological Summary
Administrative data
Workers - Hazard via inhalation route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 34.94 mg/m³
- Most sensitive endpoint:
- repeated dose toxicity
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- other: ECETOC
- Overall assessment factor (AF):
- 6
- Modified dose descriptor starting point:
- BMCL10
- Value:
- 209.64 mg/m³
- Explanation for the modification of the dose descriptor starting point:
- Long term inhalation studies are not available. The long term systemic DNEL for inhalation has been derived from the 90 d oral repeated dose toxicity study. For derivation of the dose descriptor staring point a factor of 2 has been included for route-to-route extrapolation from oral to inhalative. For details, see discussion.
- AF for dose response relationship:
- 1
- Justification:
- default ECHA AF for BMDL10 used as starting point
- AF for differences in duration of exposure:
- 2
- Justification:
- default ECHA AF for extrapolation from sub-chronic to chronic
- AF for interspecies differences (allometric scaling):
- 1
- Justification:
- default corrections for respiratory rate and respiratory volume have been included in route-to-route extrapolation
- AF for other interspecies differences:
- 1
- Justification:
- No additional AF for other interspecies differences is used as Phosphoric acid, mono- and di- C11-14 (linear and branched) alkyl esters can be degraded by different esterases (specific, unspecific esterases)/phosphatases (acidic and alkaline phosphatase – unspecific enzymes present in most animals). There is no evidence that there are differences in toxicodynamics for Phosphoric acid, mono- and di- C11-14 (linear and branched) alkyl esters in different species. Thus, all intraspecies differences can be considered covered by allometric scaling. For detailed justification, see discussion.
- AF for intraspecies differences:
- 3
- Justification:
- Based on toxicodynamics no great intraspecies differences are to be expected to justify a higher assessment factor. For detailed justification, see discussion.
- AF for the quality of the whole database:
- 1
- Justification:
- The available data are consistent and of high quality.
- AF for remaining uncertainties:
- 1
- Justification:
- no remaining uncertainties
Acute/short term exposure
- Hazard assessment conclusion:
- hazard unknown (no further information necessary)
DNEL related information
Local effects
Long term exposure
- Hazard assessment conclusion:
- hazard unknown (no further information necessary)
Acute/short term exposure
- Hazard assessment conclusion:
- hazard unknown (no further information necessary)
DNEL related information
Workers - Hazard via dermal route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 100.13 mg/kg bw/day
- Most sensitive endpoint:
- repeated dose toxicity
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- other: ECETOC
- Overall assessment factor (AF):
- 24
- Modified dose descriptor starting point:
- BMDL10
- Value:
- 2 403 mg/kg bw/day
- Explanation for the modification of the dose descriptor starting point:
- Long term dermal studies are not available. The long term systemic DNEL for dermal exposure has been derived from the 90 d oral repeated dose toxicity study. For derivation of the dose descriptor starting point information on toxicokinetics have been taken into account. The dermal absorption is considered to be 10% of the oral absorption. For details, see discussion.
- AF for dose response relationship:
- 1
- Justification:
- default ECHA AF for BMDL10 used as starting point
- AF for differences in duration of exposure:
- 2
- Justification:
- default ECHA AF for extrapolation from sub-chronic to chronic
- AF for interspecies differences (allometric scaling):
- 4
- Justification:
- default allometric scaling factor rat to human
- AF for other interspecies differences:
- 1
- Justification:
- No additional AF for other interspecies differences is used as Phosphoric acid, mono- and di- C11-14 (linear and branched) alkyl esters can be degraded by different esterases (specific, unspecific esterases)/phosphatases (acidic and alkaline phosphatase – unspecific enzymes present in most animals). There is no evidence that there are differences in toxicodynamics for Phosphoric acid, mono- and di- C11-14 (linear and branched) alkyl esters in different species. Thus, all intraspecies differences can be considered covered by allometric scaling. For detailed justification, see discussion.
- AF for intraspecies differences:
- 3
- Justification:
- Based on toxicodynamics no great intraspecies differences are to be expected to justify a higher assessment factor. For detailed justification, see discussion.
- AF for the quality of the whole database:
- 1
- Justification:
- The available data are consistent and of high quality.
- AF for remaining uncertainties:
- 1
- Justification:
- no remaining uncertainties
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
DNEL related information
Local effects
Long term exposure
- Hazard assessment conclusion:
- hazard unknown (no further information necessary)
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
Route-to-route extrapolation
Oral absorption
The low water solubility (0.041 - 0.07 g/L) may probably impair the complete uptake of Phosphoric acid, mono- and di- C11-14 (linear and branched) alkyl esters after oral administration. However, the log Kow is in the range of 2 to 2.5, favouring uptake.
As esterases/phosphatases are quite prevalent in the GI-tract, rapid breakage of the ester bond will probably take place leading to a short half-life of Phosphoric acid, mono- and di- C11-14 (linear and branched) alkyl esters in the GI tract. Following breakage of the ester bond all Phosphoric acid, mono- and di- C11-14 (linear and branched) alkyl esters possess an identical phosphoric acid part that contains ionisable groups. In general ionized substances do not readily diffuse across biological membranes. The fatty alcohol residues of Phosphoric acid, mono- and di- C11-14 (linear and branched) alkyl esters have probably higher absorption rates after cleavage of the ester bond (default 100%) but are not thought to be of toxicological relevance. They will be oxidised to the corresponding fatty acid and enter the normal fatty acid metabolism.
Phosphate is an essential nutrient which is absorbed in the small intestine via passive diffusion (paracellular transport) as well as via active transport by sodium-dependent phosphate co-transporters
The oral absorption of Phosphoric acid, mono- and di- C11-14 (linear and branched) alkyl esters and their metabolites should be considered to be 100%.
Oral to inhalatory
For inhalatory exposure as a worst case assumption a 100% inhalatory absorption and 50% oral absorption is assumed in absence of any experimental data (TGD R8).
For workers the corrected inhalatory BMCL10 is calculated according to the following equation:
corrected inhalatory BMCL10 = oral BMDL10 x 1/sRVratx ABSoral-rat/ ABSinh-humanx sRVhuman/ wRV
= 240.3 x 1/0.384 x 50/100 x 6.7/10
The corrected inhalatory BMCL10worker(8h) is therefore 209.64 mg/m3(8h-TWA)
Oral to dermal
Uptake of Phosphoric acid, mono- and di- C11-14 (linear and branched) alkyl esters after dermal application is expected to be very limited. A default value of 10% skin absorption is generally assumed when the molecular weight is above 500 and log P is outside the range [-1, 4]. This is not the case for the registered substance.
However, dermal absorption data for Trialkyl phosphates (ranging from Trimethyl phosphate to Tri-n-butyl phosphate) are available in public literature. The dermal penetration rates were between 0.0882 and 0.0108 mg/cm²/h. Trialkyl phosphates with longer chain lengths had lower penetration rates.It can be further assumed that ionised forms as Phosphoric acid mono- and dialkyl esters have a lower dermal penetration rate than Phosphoric acid trialkyl esters (see Guidance on information requirements and chemical safety assessment, Chapter R.7c). Based on that, the maximum steady state penetration rate of the registered substance will be lower than 0.01mg/cm²/h.
As this dermal penetration rate cannot be recalculated to %dermal absorption, a QSAR (IH SkinPerm) was used to estimate the dermal absorption of Phosphoric acid, mono- and di- C11-14 (linear and branched) alkyl esters. As predicted the penetration rates were lower than 0.01mg/cm²/h (the highest was calculated for Monoisododecyl phosphate: 0.00182 mg/cm²/h). This model also estimates the %dermal absorption; the highest was obtained for Monoisododecyl phosphate with 4.4%.Based on a QSAR model the dermal absorption of Phosphoric acid, mono- and di- C11-14 (linear and branched) alkyl esters can be assumed to be <10%.
The corrected dermal BMDL10 for Phosphoric acid, mono- and di- C11-14 (linear and branched) alkyl esters is therefore: 240.3 mg/kg bw/d x 10 = 2403 mg/kg/day
Dose response relationship
The effects seen in the 90-day study are only minor toxicological effects.The possibly substance related effects in the adrenal gland seen in the 90-day study have not been confirmed by the 28-day study. In the 28 day study there were no effects up to the limit dose. It is therefore not necessary to apply a factor to take account of this.
Differences in duration of exposure
For the extrapolation from sub-chronic to chronic the default AF of 2 has been used.
Interspecies differences
The starting point is an oral dose descriptor from a rat study. It is therefore necessary to include an allometric scaling factor of 4 to take account of differences in basal metabolic rates between rats and humans.
Other interspecies differences
Phosphoric acid, mono- and di- C11-14 (linear and branched) alkyl esters can be degraded by different esterases (specific and unspecific esterases)/phosphatases (acidic and alkaline phosphatase). Many of them are unspecific enzymes present in most animals.
Ester bonds are susceptible to rapid degradation by hydrolysis. Hydrolysis due to biotic and/or abiotic mechanisms is likely to be the most important reaction (although it may be actually not just one, but the sum of three reactions: acid, neutral and basic hydrolysis) of organic compounds with water in aqueous environments and is a significant environmental fate process for these compounds.
The resulting fatty alcohols are oxidised to the corresponding fatty acid which may enter the normal fatty acid metabolism in humans as well as in laboratory animals.
For those “unspecific” ways of degradation, no great inter- and intraspecific differences are to be expected (even if substance specific data is not really available).
According to EFSA (European Food Safety Authority, 2005) hyperphosphataemia due to elevated phosphorus intake may occur in rats, but has not been observed in humans:
“Adverse effects of excessive phosphorus intake, such as hyperphosphatemia, leading to secondary hyperparathyroidism, skeletal deformations, bone loss, and/or ectopic calcification have been reported in animal studies. However, such effects were not observed in studies in humans, except in patients with end stage renal disease.“
Based on this, no relevant differences in the toxicodynamics are expected, and thus the use of the additional factor of 2.5 is not justified.
Intraspecies differences
There are no data to quantify variability in susceptibility to the effects of long-term exposure to Phosphoric acid, mono- and di- C11-14 (linear and branched) alkyl esters in the human population. The default factor of 3 for workers will therefore be used to take account of intraspecies variability.
According to ECETOC (Technical Report 110) “the desired conservatism or the acceptable uncertainty must be balanced against the severity of effect”. And “for many compounds alternative or multiple pathways of elimination are operative. Poor metabolisers for one pathway may switch to another one resulting in little or no increase in plasma concentrations of the parent compound compared to normal metabolisers. Thus, polymorphism will not automatically require an increased AF.“
Based on literature reviews, ECETOC arrived at the AF of 3 for workers. We follow this approach.
Moreover, intraspecies variation in metabolism of Phosphoric acid, mono- and di- C11-14 (linear and branched) alkyl esters is considered to be low. Phosphoric acid, mono- and di- C11-14 (linear and branched) alkyl esters can be degraded by different esterases (specific and unspecific esterases)/phosphatases (acidic and alkaline phosphatase). The metabolites, fatty alcohols, are oxidised to the corresponding fatty acid which may enter the normal fatty acid metabolism in humans.
The second metabolite, Phosphate, is an essential nutrient. Dietary intakes are on average ca. 1000-1500 mg/d, ranging up to ca. 2600 mg/d (EFSA, 2005). The contribution to phosphate intake by exposure to Phosphoric acid, mono- and di- C11-14 (linear and branched) alkyl esters is negligible.
No great intraspecies differences are to be expected to justify higher conservativism.
Quality of the whole database
The available studies were conducted to modern regulatory standards and were adequately reported, it is therefore not necessary to apply an additional factor.
References
ECETOC (2010) Technical report 110, Guidance on Assessment Factors to Derive a DNEL; available via internet: www.ecetoc.org/publications
EFSA (2005) Opinion of the Scientific Panel on Dietetic Products, Nutrition and Allergies on a request from the Commission related to the Tolerable Upper Intake Level of Phosphorus, The EFSA Journal (2005) 233, 1-19; available via internet:http://www.efsa.europa.eu/en/efsajournal/doc/233.pdf
General Population - Hazard via inhalation route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 10.43 mg/m³
- Most sensitive endpoint:
- repeated dose toxicity
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- other: ECETOC
- Overall assessment factor (AF):
- 10
- Modified dose descriptor starting point:
- BMCL10
- Value:
- 104.3 mg/m³
- Explanation for the modification of the dose descriptor starting point:
- Long term inhalation studies are not available. The long term systemic DNEL for inhalation has been derived from the 90 d oral repeated dose toxicity study. For derivation of the dose descriptor staring point a factor of 2 has been included for route-to-route extrapolation from oral to inhalative. For details, see discussion.
- AF for dose response relationship:
- 1
- Justification:
- default ECHA AF for BMDL10 used as starting point
- AF for differences in duration of exposure:
- 2
- Justification:
- default ECHA AF for extrapolation from sub-chronic to chronic
- AF for interspecies differences (allometric scaling):
- 1
- Justification:
- default corrections for respiratory rate and respiratory volume have been included in route-to-route extrapolation
- AF for other interspecies differences:
- 1
- Justification:
- No additional AF for other interspecies differences is used as Phosphoric acid, mono- and di- C11-14 (linear and branched) alkyl esters can be degraded by different esterases (specific, unspecific esterases)/phosphatases (acidic and alkaline phosphatase – unspecific enzymes present in most animals). There is no evidence that there are differences in toxicodynamics for Phosphoric acid, mono- and di- C11-14 (linear and branched) alkyl esters in different species. Thus, all intraspecies differences can be considered covered by allometric scaling. For detailed justification, see discussion.
- AF for intraspecies differences:
- 5
- Justification:
- Based on toxicodynamics no great intraspecies differences are to be expected to justify a higher assessment factor. For detailed justification, see discussion.
- AF for the quality of the whole database:
- 1
- Justification:
- The available data are consistent and of high quality.
- AF for remaining uncertainties:
- 1
- Justification:
- no remaining uncertainties
Acute/short term exposure
- Hazard assessment conclusion:
- hazard unknown (no further information necessary)
DNEL related information
Local effects
Long term exposure
- Hazard assessment conclusion:
- hazard unknown (no further information necessary)
Acute/short term exposure
- Hazard assessment conclusion:
- hazard unknown (no further information necessary)
DNEL related information
General Population - Hazard via dermal route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 60.08 mg/kg bw/day
- Most sensitive endpoint:
- repeated dose toxicity
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- other: ECETOC
- Overall assessment factor (AF):
- 40
- Modified dose descriptor starting point:
- BMDL10
- Value:
- 2 403 mg/kg bw/day
- Explanation for the modification of the dose descriptor starting point:
- Long term dermal studies are not available. The long term systemic DNEL for dermal exposure has been derived from the 90 d oral repeated dose toxicity study. For derivation of the dose descriptor starting point information on toxicokinetics have been taken into account. The dermal absorption is considered to be 10% of the oral absorption. For details, see discussion.
- AF for dose response relationship:
- 1
- Justification:
- default ECHA AF for BMDL10 used as starting point
- AF for differences in duration of exposure:
- 2
- Justification:
- default ECHA AF for extrapolation from sub-chronic to chronic
- AF for interspecies differences (allometric scaling):
- 4
- Justification:
- default allometric scaling factor rat to human
- AF for other interspecies differences:
- 1
- Justification:
- No additional AF for other interspecies differences is used as Phosphoric acid, mono- and di- C11-14 (linear and branched) alkyl esters can be degraded by different esterases (specific, unspecific esterases)/phosphatases (acidic and alkaline phosphatase – unspecific enzymes present in most animals). There is no evidence that there are differences in toxicodynamics for Phosphoric acid, mono- and di- C11-14 (linear and branched) alkyl esters in different species. Thus, all intraspecies differences can be considered covered by allometric scaling. For detailed justification, see discussion.
- AF for intraspecies differences:
- 5
- Justification:
- Based on toxicodynamics no great intraspecies differences are to be expected to justify a higher assessment factor. For detailed justification, see discussion.
- AF for the quality of the whole database:
- 1
- Justification:
- The available data are consistent and of high quality.
- AF for remaining uncertainties:
- 1
- Justification:
- no remaining uncertainties
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
DNEL related information
Local effects
Long term exposure
- Hazard assessment conclusion:
- hazard unknown (no further information necessary)
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:
- 6.01 mg/kg bw/day
- Most sensitive endpoint:
- repeated dose toxicity
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- other: ECETOC
- Overall assessment factor (AF):
- 40
- Modified dose descriptor starting point:
- BMDL10
- Value:
- 240.3 mg/kg bw/day
- Explanation for the modification of the dose descriptor starting point:
- no route-to-route extrapolation
- AF for dose response relationship:
- 1
- Justification:
- default ECHA AF for BMDL10 used as starting point
- AF for differences in duration of exposure:
- 2
- Justification:
- default ECHA AF for extrapolation from sub-chronic to chronic
- AF for interspecies differences (allometric scaling):
- 4
- Justification:
- default allometric scaling factor rat to human
- AF for other interspecies differences:
- 1
- Justification:
- No additional AF for other interspecies differences is used as Phosphoric acid, mono- and di- C11-14 (linear and branched) alkyl esters can be degraded by different esterases (specific, unspecific esterases)/phosphatases (acidic and alkaline phosphatase – unspecific enzymes present in most animals). There is no evidence that there are differences in toxicodynamics for Phosphoric acid, mono- and di- C11-14 (linear and branched) alkyl esters in different species. Thus, all intraspecies differences can be considered covered by allometric scaling. For detailed justification, see discussion.
- AF for intraspecies differences:
- 5
- Justification:
- Based on toxicodynamics no great intraspecies differences are to be expected to justify a higher assessment factor. For detailed justification, see discussion.
- AF for the quality of the whole database:
- 1
- Justification:
- The available data are consistent and of high quality.
- AF for remaining uncertainties:
- 1
- Justification:
- no remaining uncertainties
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
DNEL related information
General Population - Hazard for the eyes
Local effects
- Hazard assessment conclusion:
- medium hazard (no threshold derived)
Additional information - General Population
Route-to-route extrapolation
Oral absorption
The low water solubility (0.041 - 0.07 g/L) may probably impair the complete uptake of Phosphoric acid, mono- and di- C11-14 (linear and branched) alkyl esters after oral administration. However, the log Kow is in the range of 2 to 2.5, favouring uptake.
As esterases/phosphatases are quite prevalent in the GI-tract, rapid breakage of the ester bond will probably take place leading to a short half-life of Phosphoric acid, mono- and di- C11-14 (linear and branched) alkyl esters in the GI tract. Following breakage of the ester bond all Phosphoric acid, mono- and di- C11-14 (linear and branched) alkyl esters possess an identical phosphoric acid part that contains ionisable groups. In general ionized substances do not readily diffuse across biological membranes.The fatty alcohol residues of Phosphoric acid, mono- and di- C11-14 (linear and branched) alkyl esters have probably higher absorption rates after cleavage of the ester bond (default 100%) but are not thought to be of toxicological relevance. They will be oxidised to the corresponding fatty acid and enter the normal fatty acid metabolism.
Phosphate is an essential nutrient which is absorbed in the small intestine via passive diffusion (paracellular transport) as well as via active transport by sodium-dependent phosphate co-transporters
The oral absorption of Phosphoric acid, mono- and di- C11-14 (linear and branched) alkyl esters and their metabolites should be considered to be 100%.
Oral to inhalatory
For inhalatory exposure as a worst case assumption a 100% inhalatory absorption and 50% oral absorption is assumed in absence of any experimental data (TGD R8).
For general population in case of 24 h exposure/d the corrected inhalatory BMCL10 is calculated according to the following equation:
corrected inhalatory BMCL10 = oral BMDL10 x 1/sRVratx ABSoral-rat/ ABSinh-human
=240.3 x 1/1.152 x 50/100
The corrected inhalatory BMCL10general population(24h) is therefore 104.30 mg/m³
Oral to dermal
Uptake of Phosphoric acid, mono- and di- C11-14 (linear and branched) alkyl esters after dermal application is expected to be very limited. A default value of 10% skin absorption is generally assumed when the molecular weight is above 500 and log P is outside the range [-1, 4]. This is not the case for the registered substance.
However, dermal absorption data for Trialkyl phosphates (ranging from Trimethyl phosphate to Tri-n-butyl phosphate) are available in public literature. The dermal penetration rates were between 0.0882 and 0.0108 mg/cm²/h. Trialkyl phosphates with longer chain lengths had lower penetration rates.It can be further assumed that ionised forms as Phosphoric acid mono- and dialkyl esters have a lower dermal penetration rate than Phosphoric acid trialkyl esters (see Guidance on information requirements and chemical safety assessment, Chapter R.7c). Based on that, the maximum steady state penetration rate of the registered substance will be lower than 0.01mg/cm²/h.
As this dermal penetration rate cannot be recalculated to %dermal absorption, a QSAR (IH SkinPerm) was used to estimate the dermal absorption of Phosphoric acid, mono- and di- C11-14 (linear and branched) alkyl esters. As predicted the penetration rates were lower than 0.01mg/cm²/h (the highest was calculated for Monoisododecyl phosphate: 0.00182 mg/cm²/h). This model also estimates the %dermal absorption; the highest was obtained for Monoisododecyl phosphate with 4.4%.Based on a QSAR model the dermal absorption of Phosphoric acid, mono- and di- C11-14 (linear and branched) alkyl esters can be assumed to be <10%.
The corrected dermal BMDL10 for Phosphoric acid, mono- and di- C11-14 (linear and branched) alkyl esters is therefore:240.3 mg/kg bw/d x 10 = 2403 mg/kg/day
Dose response relationship
The effects seen in the 90-day study are only minor toxicological effects.The possibly substance related effects in the adrenal gland seen in the 90-day study have not been confirmed by the 28-day study.In the 28 day study there were no effects up to the limit dose.It is therefore not necessary to apply a factor to take account of this.
Differences in duration of exposure
For the extrapolation from sub-chronic to chronic the default AF of 2 has been used.
Interspecies differences
The starting point is an oral dose descriptor from a rat study. It is therefore necessary to include an allometric scaling factor of 4 to take account of differences in basal metabolic rates between rats and humans.
Other interspecies differences
Phosphoric acid, mono- and di- C11-14 (linear and branched) alkyl esters can be degraded by different esterases (specific and unspecific esterases)/phosphatases (acidic and alkaline phosphatase). Many of them are unspecific enzymes present in most animals.
Ester bonds are susceptible to rapid degradation by hydrolysis. Hydrolysis due to biotic and/or abiotic mechanisms is likely to be the most important reaction (although it may be actually not just one, but the sum of three reactions: acid, neutral and basic hydrolysis) of organic compounds with water in aqueous environments and is a significant environmental fate process for these compounds.
The resulting fatty alcohols are oxidised to the corresponding fatty acid which may enter the normal fatty acid metabolism in humans as well as in laboratory animals.
For those “unspecific” ways of degradation, no great inter- and intraspecific differences are to be expected (even if substance specific data is not really available).
According to EFSA (European Food Safety Authority, 2005) hyperphosphataemia due to elevated phosphorus intake may occur in rats, but has not been observed in humans:
“Adverse effects of excessive phosphorus intake, such as hyperphosphatemia, leading to secondary hyperparathyroidism, skeletal deformations, bone loss, and/or ectopic calcification have been reported in animal studies. However, such effects were not observed in studies in humans, except in patients with end stage renal disease.“
Based on this, no relevant differences in the toxicodynamics are expected, and thus the use of the additional factor of 2.5 is not justified.
Intraspecies differences
There are no data to quantify variability in susceptibility to the effects of long-term exposure to Phosphoric acid, mono- and di- C11-14 (linear and branched) alkyl esters in the human population. The default factor of 5 for general population will therefore be used to take account of intraspecies variability.
According to ECETOC (Technical Report 110) “the desired conservatism or the acceptable uncertainty must be balanced against the severity of effect”. And “for many compounds alternative or multiple pathways of elimination are operative. Poor metabolisers for one pathway may switch to another one resulting in little or no increase in plasma concentrations of the parent compound compared to normal metabolisers. Thus, polymorphism will not automatically require an increased AF.“
Based on literature reviews, ECETOC arrived at the AF of 5 for the general population. We follow this approach.
Moreover, intraspecies variation in metabolism of Phosphoric acid, mono- and di- C11-14 (linear and branched) alkyl esters is considered to be low. Phosphoric acid, mono- and di- C11-14 (linear and branched) alkyl esters can be degraded by different esterases (specific and unspecific esterases)/phosphatases (acidic and alkaline phosphatase). The metabolites, fatty alcohols, are oxidised to the corresponding fatty acid which may enter the normal fatty acid metabolism in humans.
The second metabolite, Phosphate, is an essential nutrient. Dietary intakes are on average ca. 1000-1500 mg/d, ranging up to ca. 2600 mg/d (EFSA, 2005). The contribution to phosphate intake by exposure to Phosphoric acid, mono- and di- C11-14 (linear and branched) alkyl esters is negligible.
No great intraspecies differences are to be expected to justify higher conservativism.
Quality of the whole database
The available studies were conducted to modern regulatory standards and were adequately reported, it is therefore not necessary to apply an additional factor.
References
ECETOC (2010) Technical report 110,Guidance on Assessment Factors to Derive a DNEL; available via internet: www.ecetoc.org/publications
EFSA (2005) Opinion of the Scientific Panel on Dietetic Products, Nutrition and Allergies on a request from the Commission related to the Tolerable Upper Intake Level of Phosphorus, The EFSA Journal (2005) 233, 1-19; available via internet:http://www.efsa.europa.eu/en/efsajournal/doc/233.pdf
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
