1-Octadecanol, phosphate, potassium salt

Toxicological Summary

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: Substance specific

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 (100% inhalatory absorption and 50% 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):

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 the substance 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 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: Substance specific

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 the substance 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 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:

no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)

Additional information - workers

Route-to-route extrapolation

Oral absorption

The low water solubility may probably impair the complete uptake of 1-Octadecanol, phosphate, potassium salt after oral administration. The weighed log Kow is calculated as 8.5, which is supporting the assumption.

However, 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 1-Octadecanol, phosphate, potassium salt in the GI tract.

The fatty alcohol residues of 1-Octadecanol, phosphate, potassium salt 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. As well potassium is an essential nutrient which is absorbed in the small intestine. It is mainly absorbed or secreted by passive mechanisms.  

The oral absorption of 1-Octadecanol, phosphate, potassium salt 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/sRV_ratx ABS_oral-rat/ ABS_inh-humanx sRV_human/ wRV

                                                  = 240.3 x 1/0.384 x 50/100 x 6.7/10

 

                                     

The corrected inhalatory BMCL10_worker(8h) is therefore 209.64 mg/m³(8h-TWA)

 

 

Oral to dermal

Uptake of 1-Octadecanol, phosphate, potassium salt 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]. 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. 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 1-Octadecanol, phosphate, potassium salt can be assumed to be <10%.

The corrected dermal BMDL10 for 1-Octadecanol, phosphate, potassium salt 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

1-Octadecanol, phosphate, potassium salt 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 and humans.

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 to1-Octadecanol, phosphate, potassium saltin 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 1-Octadecanol, phosphate, potassium salt is considered to be low. 1-Octadecanol, phosphate, potassium salt 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 third metabolite, potassium, as well is an essential nutrient. According to EFSA (2006) the recommended daily intakes in Europe are in the order of 3.1-3.5 g/day (SCF, 1993). The contribution to phosphate and potassium intake by exposure to 1-Octadecanol, phosphate, potassium salt 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

EFSA (2006) Tolerable upper intake levels for vitamins and minerals, Scientific Committee on Food Scientific Panel on Dietetic Products, Nutrition and Allergies available via internet:http://www.efsa.europa.eu/en/ndatopics/docs/ndatolerableuil.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: Substance specific

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 (100% inhalatory absorption and 50% 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):

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 the substance 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 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: Substance specific

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 the substance 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 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:

no hazard identified

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: Substance specific

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 the substance 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 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:

low hazard (no threshold derived)

Additional information - General Population

Route-to-route extrapolation

Oral absorption

The low water solubility may probably impair the complete uptake of 1-Octadecanol, phosphate, potassium salt after oral administration. The weighed log Kow is calculated as 8.5, which is supporting the assumption.

However, 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 1-Octadecanol, phosphate, potassium salt in the GI tract.

The fatty alcohol residues of 1-Octadecanol, phosphate, potassium salt 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. As well potassium is an essential nutrient which is absorbed in the small intestine. It is mainly absorbed or secreted by passive mechanisms.  

The oral absorption of 1-Octadecanol, phosphate, potassium salt 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 1-Octadecanol, phosphate, potassium salt 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]. 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. 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 1-Octadecanol, phosphate, potassium salt can be assumed to be <10%.

The corrected dermal BMDL10 for 1-Octadecanol, phosphate, potassium salt 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

1-Octadecanol, phosphate, potassium salt 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 and humans.

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 1-Octadecanol, phosphate, potassium salt 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 1-Octadecanol, phosphate, potassium salt is considered to be low.

1-Octadecanol, phosphate, potassium salt 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 third metabolite, potassium, as well is an essential nutrient. According to EFSA (2006) the recommended daily intakes in Europe are in the order of 3.1-3.5 g/day (SCF, 1993).

The contribution to phosphate and potassium intake by exposure to 1-Octadecanol, phosphate, potassium salt is negligible.

No great intraspecies differences are to be expected to justify higher conservativism.

 

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

EFSA (2006) Tolerable upper intake levels for vitamins and minerals, Scientific Committee on Food Scientific Panel on Dietetic Products, Nutrition and Allergies available via internet:http://www.efsa.europa.eu/en/ndatopics/docs/ndatolerableuil.pdf