Lanthanum oxide

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

61.5 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):

15

Dose descriptor starting point:

NOAEL

Value:

525 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

925.7 mg/m³

Explanation for the modification of the dose descriptor starting point:

Modification of starting point:

NOAEL, oral rat 90 day: 525 mg/kg bw/day

Allometric scaling to human inhalation exposure for 8 h at light activity:

Route to route extrapolation rat: Division by 0.38 m³/kg bw: 1381.6 mg/m³(8 h). (See ECHA R8., 2008)

Correction for absorption:

Based on the specific toxicokinetic information on lanthanum oxide and lanthanum carbonate it can reasonably be assumed that the absorption is comparable after oral and inhalation exposure and no correction is made in this case.

Correction for rest/versus light activity: x 6.7/10

Modified starting point 925.7 mg/m³

AF for dose response relationship:

1

Justification:

As no adverse effects were observed at the highest dose tested, no additional assessment factor is applied.

AF for differences in duration of exposure:

2

Justification:

Duration extrapolation
As the NOAEL is based on a 90-day study in rats a factor of 2 is used to account for human life time exposure. This is however considered conservative as available longer term studies in different species with lanthanum compounds have not shown relevant additional toxicity that would suggest a lowering of the NOAEL.

AF for interspecies differences (allometric scaling):

1

Justification:

The allometric scaling is already accounted for in the extrapolation for the modification of the starting point as per ECHA guidance R8. See above

AF for other interspecies differences:

2.5

Justification:

An additional factor of 2.5 apart from allometric scaling is recommended by ECHA R8, 2008 to account for remaining interspecies differences. The data of lanthanum compounds from different species would however suggest, that an additional factor is not warranted. If allometric scaling is used, although some interspecies variability may remain, it is estimated that this residual variability is largely accounted for in the default assessment factor proposed for intra-species variability, because of the inherent interdependency of those two variables. However, in this assessment the factor of 2.5 will be applied.

AF for intraspecies differences:

3

Justification:

An intraspecies extrapolation factor of 3 is considered sufficient for workers. This is based on considerations of ECETOC, 2003 and 2010 and metal specific considerations, see below.
Statistical analysis of the variability of toxicodynamic and toxicokinetic parameters within several published datasets has shown that the intra-species variability between humans can be covered by an AF of 5 for the general population and an AF of 3 for the more homogeneous worker population. ECETOC (2003) and its update (ECETOC, 2010) also stress the inherent interdependency between inter- and intra-species variability, concluding that it is not possible to clearly differentiate between inter- and intra-species variability factors. In cases where allometric scaling is performed, some residual interspecies variability may remain. This residual variability can be covered by an AF. However, ECETOC estimates that this variability is largely accounted for in the default assessment factor proposed for intra-species variability: ECETOC proposed, for the total (inter- and intra-species) variability, an overall factor of 5 for the general population and 3 for the workplace (ECETOC 2003, 2010). The German Auschuss für Gefahrstoffe - AGS (2006) seems to follow a comparable approach, not differentiating between inter- and intra-species variability. Apart from allometric scaling, they use an additional factor of 5 for overall (inter- and intra-species) variability for the workplace.
Furthermore it is anticipated that a low variability in response would be seen in human populations exposed to metal compounds that do not undergo extensive metabolism (and have lower genetic polymorphisms) than in populations exposed to substances that required more extensive metabolism.
No other assessment factors are considered necessary.

AF for the quality of the whole database:

1

Justification:

As the data set includes repeated dose studies of different species up to 90 days the data qulaity is suficient to not apply an additional assessment factor.

AF for remaining uncertainties:

1

Justification:

There are no major additional uncertainties specifc to this data set.

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:

8.75 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):

60

Dose descriptor starting point:

NOAEL

Value:

525 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

525 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Based on the specific toxicokinetic information on lanthanum oxide and lanthanum carbonate it can reasonably be assumed that the absorption is comparable after oral and dermal exposure and no correction is made. Normally dermal absorption will be lower than oral absorption.

AF for dose response relationship:

1

Justification:

As no adverse effects were observed at the highest dose tested, no additional assessment factor is applied.

AF for differences in duration of exposure:

2

Justification:

As the NOAEL is based on a 90-day study in rats a factor of 2 is used to account for human life time exposure. This is however considered conservative as available longer term studies in different species with lanthanum compounds have not shown relevant additional toxicity that would suggest a lowering of the NOAEL.

AF for interspecies differences (allometric scaling):

4

Justification:

An allometric scaling factor of 4 considering the different metabolic rates of rats and humans is applied to the rat NOAEL (ECHA R8., 2008).

AF for other interspecies differences:

2.5

Justification:

An additional factor of 2.5 apart from allometric scaling is recommended by ECHA R8., 2008 to account for remaining interspecies differences. The data of lanthanum compounds from different species would however suggest, that an additional factor is not warranted. If allometric scaling is used, although some interspecies variability may remain, it is estimated that this residual variability is largely accounted for in the default assessment factor proposed for intra-species variability, because of the inherent interdependency of those two variables. However, in this assessment the factor of 2.5 will be applied.

AF for intraspecies differences:

3

Justification:

An intraspecies extrapolation factor of 3 is considered sufficient for workers. This is based on considerations of ECETOC, 2003 and 2010 as well as metal specific considerations.
Statistical analysis of the variability of toxicodynamic and toxicokinetic parameters within several published datasets has shown that the intra-species variability between humans can be covered by an AF of 5 for the general population and an AF of 3 for the more homogeneous worker population. ECETOC (2003) and its update (ECETOC, 2010) also stress the inherent interdependency between inter- and intra-species variability, concluding that it is not possible to clearly differentiate between inter- and intra-species variability factors. In cases where allometric scaling is performed, some residual interspecies variability may remain. This residual variability can be covered by an AF. However, ECETOC estimates that this variability is largely accounted for in the default assessment factor proposed for intra-species variability: ECETOC proposed, for the total (inter- and intra-species) variability, an overall factor of 5 for the general population and 3 for the workplace (ECETOC 2003, 2010). The German Auschuss für Gefahrstoffe - AGS (2006) seems to follow a comparable approach, not differentiating between inter- and intra-species variability. Apart from allometric scaling, they use an additional factor of 5 for overall (inter- and intra-species) variability for the workplace.
Furthermore it is anticipated that a low variability in response would be seen in human populations exposed to metal compounds that do not undergo extensive metabolism (and have lower genetic polymorphisms) than in populations exposed to substances that required more extensive metabolism.

AF for the quality of the whole database:

1

Justification:

As the data set includes repeated dose studies of different species up to 90 days the data qulaity is suficient to not apply an additional assessment factor.

AF for remaining uncertainties:

1

Justification:

There are no major additional uncertainties specifc to this data set.

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:

no hazard identified

Additional information - workers

DNEL derivation:

Workers

The most relevant routes of exposure for workers are the dermal and inhalation routes.

Based on the available acute toxicity data lanthanum oxide is not acutely toxic and therefore the derivation of a DNEL_long-termwill be sufficient to control potential risks associated with short-term exposures. In addition, based on the available animal data lanthanum oxide is not irritating to skin and eyes and is no skin sensitizer. It is also unlikely to be a respiratory irritant or sensitizer. Lanthanum oxide based on the available data does not appear to elicit local toxicity effects. Therefore a derivation of a DNEL for local effects is not considered necessary.

The lowest reliable NOAEL was derived from a 90-day oral feeding study in rats with the analogous substance lanthanum tricarbonate. The NOAEL was calculated as lanthanum oxide and the lowest NOAEL for was derived for males as 525 mg/kg bw/day. It should be noted that no effects were observed at this dose level which was the highest dose tested in this study (Reißmüller, 2006).

A 52-week study in dogs receiving lanthanum carbonate by capsule once daily for 52 weeks did not reveal any treatment related effects at dose levels up to 2000 mg/kg bw/day, corresponding to ca. 1407 mg/kg bw of lanthanum oxide per day. (FDA, 2004).

A NOAEL for fertility was based on a one generation study with lanthanum tricarbonate that revealed no effects on male and female fertility of rats after daily oral (gavage) dosing of up to 2000 mg/kg bw/day of the test substance, corresponding to 1407 mg/kg bw/day of lanthanum oxide. (FDA, 2004). Other corroborating publications did also not report any effects on male and female fertility.

A NOAEL for developmental toxicity in rabbits after oral gavage administration of lathanum tricarbonate based on no clearly dose related effects on developmental toxicity at the highest dose tested of 1500 mg/kg bw/day, corresponding to 1073 mg/kg bw/day of lanthanum oxide was reported by FDA, 2004. In this study maternal toxicity (essentially reduced body weight gain and reduced food consumption) was observed at the highest dose level and a maternal NOAEL of 750 mg/kg bw/day of the test substance corresponding to 573 mg/kg/day of lanthanum oxide. One study reported possible effects on postnatal development in a pre-postnatal study with lanthanum carbonate in rats, but these could not be fully evaluated in the absence of single animal data, historical control values and litter based statistics and is thus not used in the DNEL derivation. However the NOAEL is in the same range as the one used for repeated dose toxicity and it can reasonably be assumed that the DNEL will protect from any potential postnatal effects as well.

Assessment for workers:

DNEL derivation for dermal exposure

Modification of starting point:

NOAEL, oral rat 90 day: 525 mg/kg bw/day

Correction for absorption:

Based on the specific toxicokinetic information on lanthanum oxide and lanthanum carbonate it can reasonably be assumed that the absorption is comparable after oral and dermal exposure and no correction is made. Normally dermal absorption will be lower than oral absorption.

Duration extrapolation

As the NOAEL is based on a 90-day study in rats a factor of 2 is used to account for human life time exposure. This is however considered conservative as available longer term studies in different species with lanthanum compounds have not shown relevant additional toxicity that would suggest a lowering of the NOAEL.

Interspecies extrapolation

An allometric scaling factor of 4 considering the different metabolic rates of rats and humans is applied to the rat NOAEL (ECHA R8., 2008).

An additional factor of 2.5 apart from allometric scaling is recommended by ECHA R8., 2008 to account for remaining interspecies differences.The data of lanthanum compounds from different species would however suggest, that an additional factor is not warranted.If allometric scaling is used, although some interspecies variability may remain, it is estimated that this residual variability is largely accounted for in the default assessment factor proposed for intra-species variability, because of the inherent interdependency of those two variables. However, in this assessment the factor of 2.5 will be applied.

Intraspecies extrapolation

An intraspecies extrapolation factor of 3 is considered sufficient for workers. This is based on considerations of ECETOC, 2003 and 2010.

Statistical analysis of the variability of toxicodynamic and toxicokinetic parameters within several published datasets has shown that the intra-species variability between humans can be covered by an AF of 5 for the general population and an AF of 3 for the more homogeneous worker population. ECETOC (2003) and its update (ECETOC, 2010) also stress the inherent interdependency between inter- and intra-species variability, concluding that it is not possible to clearly differentiate between inter- and intra-species variability factors. In cases where allometric scaling is performed, some residual interspecies variability may remain. This residual variability can be covered by an AF. However, ECETOC estimates that this variability is largely accounted for in the default assessment factor proposed for intra-species variability: ECETOC proposed, for the total (inter- and intra-species) variability, an overall factor of 5 for the general population and 3 for the workplace (ECETOC 2003, 2010).The German Auschuss für Gefahrstoffe - AGS (2006) seems to follow a comparable approach, not differentiating between inter- and intra-species variability. Apart from allometric scaling, they use an additional factor of 5 for overall (inter- and intra-species) variability for the workplace.

Furthermore it is anticipated that a low variability in response would be seen in human populations exposed to metal compounds that do not undergo extensive metabolism (and have lower genetic polymorphisms) than in populations exposed to substances that required more extensive metabolism.

No other assessment factors are considered necessary. An additional modification factor of 5/7 could be applied to account for the different exposure regimes (7 days/per week in the rat study, against 5 days per week worker’s exposure)

The overall assessment factor for workers for the dermal route starting from the rat oral NOAEL (90day) is : 2 x 4x 2.5 x 3 = 60

The resulting DNEL dermal, workers is 8.75 mg/kg bw/day

DNEL derivation for inhalation exposure

Modification of starting point:

NOAEL, oral rat 90 day: 525 mg/kg bw/day

Allometric scaling to human inhalation exposure for 8 h at light activity:

Route to route extrapolation rat: Division by 0.38 m³/kg bw: 1381.6 mg/m³(8 h). (See ECHA R8., 2008)

Correction for absorption:

Based on the specific toxicokinetic information on lanthanum oxide and lanthanum carbonate it can reasonably be assumed that the absorption is comparable after oral and inhalation exposure and no correction is made in this case.

Correction for rest/versus light activity: x 6.7/10

Modified starting point 925.7 mg/m³

Duration extrapolation

As the NOAEL is based on a 90-day study in rats a factor of 2 is used to account for human life time exposure. This is however considered conservative as available longer term studies in different species with lanthanum compounds have not shown relevant additional toxicity that would suggest a lowering of the NOAEL.

Interspecies extrapolation

An additional factor of 2.5 apart from allometric scaling is recommended by ECHA R8, 2008 to account for remaining interspecies differences.The data of lanthanum compounds from different species would however suggest, that an additional factor is not warranted.If allometric scaling is used, although some interspecies variability may remain, it is estimated that this residual variability is largely accounted for in the default assessment factor proposed for intra-species variability, because of the inherent interdependency of those two variables. However, in this assessment the factor of 2.5 will be applied.

Intraspecies extrapolation

An intraspecies extrapolation factor of 3 is considered sufficient for workers. This is based on considerations of ECETOC, 2003 and 2010.

Statistical analysis of the variability of toxicodynamic and toxicokinetic parameters within several published datasets has shown that the intra-species variability between humans can be covered by an AF of 5 for the general population and an AF of 3 for the more homogeneous worker population. ECETOC (2003) and its update (ECETOC, 2010) also stress the inherent interdependency between inter- and intra-species variability, concluding that it is not possible to clearly differentiate between inter- and intra-species variability factors. In cases where allometric scaling is performed, some residual interspecies variability may remain. This residual variability can be covered by an AF. However, ECETOC estimates that this variability is largely accounted for in the default assessment factor proposed for intra-species variability: ECETOC proposed, for the total (inter- and intra-species) variability, an overall factor of 5 for the general population and 3 for the workplace (ECETOC 2003, 2010).The German Auschuss für Gefahrstoffe - AGS (2006) seems to follow a comparable approach, not differentiating between inter- and intra-species variability. Apart from allometric scaling, they use an additional factor of 5 for overall (inter- and intra-species) variability for the workplace.

Furthermore it is anticipated that a low variability in response would be seen in human populations exposed to metal compounds that do not undergo extensive metabolism (and have lower genetic polymorphisms) than in populations exposed to substances that required more extensive metabolism.

No other assessment factors are considered necessary.

The overall assesssment factor for workers for the inhalation route starting from the modified

starting point that already includes allometric scaling is then: 2 x 2.5 x 3 = 15

The DNEL_{inahalation-longterm}is then 61.5 mg/m³

In the case of dust exposure it is however recommended to comply with existing workplace standards for inert dust of  3 mg/m3 as respirable dust and 10 mg/m3 as inhalable dust in most European countries or respective national limit values for dust.

References:

AGS. 2006. Technische Regeln für Gefahrstoffe. Begründungen und Erläuterungen zu Grenzwerten in der Luft am Arbeitsplatz. Ausschuss für Gefahrstoffe. TRGS 901, BArbBl. Heft 1/2006.www.baua.de

ECETOC. 2003. Derivation of Assessment Factors for Human Health Risk Assessment. Technical Report No.86.European Centre for Ecotoxicology and Toxicology of Chemicals,Brussels, Belgium

ECETOC.July 2010 Guidance on Assessment Factors to Derive DNELs, Draft Technical Report No. to be determined.European Centre for Ecotoxicology and Toxicology of Chemicals,Brussels, Belgium

ECETOC Workshop. March 2010: Draft Workshop report on Guidance on Assessment Factors to Derive DNELs, Report No: to be determined

ECHA R8. 2008. Guidance on Information Requirements and Chemical Safety Assessment. Chapter R.8: Characterisation of dose[concentration]-response for human health. Guidance for the implementation of REACH. European Chemicals Agency

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

18.26 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):

25

Dose descriptor starting point:

NOAEL

Value:

525 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

456.5 mg/m³

Explanation for the modification of the dose descriptor starting point:

Allometric scaling to human inhalation exposure for 24 h:

Route to route extrapolation rat: Division by 1.15 m³/kg bw: 456.5 mg/m³. (See ECHA R8., 2008).

Correction for absorption:

Based on the specific toxicokinetic information on lanthanum oxide and lanthanum carbonate it can reasonably be assumed that the absorption is comparable after oral and inhalation exposure and no correction is made in this case.

AF for dose response relationship:

1

Justification:

As no adverse effects were observed at the highest dose tested, no additional assessment factor is applied.

AF for differences in duration of exposure:

2

Justification:

As the NOAEL is based on a 90-day study in rats a factor of 2 is used to account for human life time exposure. This is however considered conservative as available longer term studies in different species with lanthanum compounds have not shown relevant additional toxicity that would suggest a lowering of the NOAEL

AF for interspecies differences (allometric scaling):

1

Justification:

Allometric scling was already accounted for in the modification of the strating point as per ECHA guidance R8.

AF for other interspecies differences:

2.5

Justification:

An additional factor of 2.5 apart from allometric scaling is recommended by ECHA R8, 2008 to account for remaining interspecies differences. The data of lanthanum compounds from different species would however suggest, that an additional factor is not warranted. If allometric scaling is used, although some interspecies variability may remain, it is estimated that this residual variability is largely accounted for in the default assessment factor proposed for intra-species variability, because of the inherent interdependency of those two variables. However, in this assessment the factor of 2.5 will be applied.

AF for intraspecies differences:

3

Justification:

An intraspecies extrapolation factor of 5 is considered sufficient for the general population. This is based on considerations of ECETOC, 2003 and 2010 and additional metal specific considerations.
Statistical analysis of the variability of toxicodynamic and toxicokinetic parameters within several published datasets has shown that the intra-species variability between humans can be covered by an AF of 5 for the general population and an AF of 3 for the more homogeneous worker population. ECETOC (2003) and its update (ECETOC, 2010) also stress the inherent interdependency between inter- and intra-species variability, concluding that it is not possible to clearly differentiate between inter- and intra-species variability factors. In cases where allometric scaling is performed, some residual interspecies variability may remain. This residual variability can be covered by an AF. However, ECETOC estimates that this variability is largely accounted for in the default assessment factor proposed for intra-species variability: ECETOC proposed, for the total (inter- and intra-species) variability, an overall factor of 5 for the general population and 3 for the workplace (ECETOC 2003, 2010). The German Auschuss für Gefahrstoffe - AGS (2006) seems to follow a comparable approach, not differentiating between inter- and intra-species variability. Apart from allometric scaling, they use an additional factor of 5 for overall (inter- and intra-species) variability for the workplace.
Furthermore it is anticipated that a low variability in response would be seen in human populations exposed to metal compounds that do not undergo extensive metabolism (and have lower genetic polymorphisms) than in populations exposed to substances that required more extensive metabolism.

AF for the quality of the whole database:

1

Justification:

As the data set includes repeated dose studies of different species up to 90 days the data qulaity is suficient to not apply an additional assessment factor.

AF for remaining uncertainties:

1

Justification:

There are no major additional uncertainties specific to this data set.

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

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

5.25 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):

100

Dose descriptor starting point:

NOAEL

Value:

525 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

525 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Based on the specific toxicokinetic information on lanthanum oxide and lanthanum carbonate it can reasonably be assumed that the absorption is comparable after oral and dermal exposure and no correction is made. Normally dermal absorption will be lower than oral absorption.

AF for dose response relationship:

1

Justification:

As no adverse effects were observed at the highest dose tested, no additional assessment factor is applied.

AF for differences in duration of exposure:

2

Justification:

As the NOAEL is based on a 90-day study in rats a factor of 2 is used to account for human life time exposure. This is however considered conservative as available longer term studies in different species with lanthanum compounds have not shown relevant additional toxicity that would suggest a lowering of the NOAEL.

AF for interspecies differences (allometric scaling):

4

Justification:

An allometric scaling factor of 4 considering the different metabolic rates of rats and humans is applied to the rat NOAEL (ECHA R8., 2008).

AF for other interspecies differences:

2.5

Justification:

An additional factor of 2.5 apart from allometric scaling is recommended by ECHA R8., 2008 to account for remaining interspecies differences. The data of lanthanum compounds from different species would however suggest, that an additional factor is not warranted. If allometric scaling is used, although some interspecies variability may remain, it is estimated that this residual variability is largely accounted for in the default assessment factor proposed for intra-species variability, because of the inherent interdependency of those two variables. However, in this assessment the factor of 2.5 will be applied.

AF for intraspecies differences:

5

Justification:

An intraspecies extrapolation factor of 5 is considered sufficient for the general population. This is based on considerations of ECETOC, 2003 and 2010 as well as metal specific considerations.
Statistical analysis of the variability of toxicodynamic and toxicokinetic parameters within several published datasets has shown that the intra-species variability between humans can be covered by an AF of 5 for the general population. ECETOC (2003) and its update (ECETOC, 2010) also stress the inherent interdependency between inter- and intra-species variability, concluding that it is not possible to clearly differentiate between inter- and intra-species variability factors. In cases where allometric scaling is performed, some residual interspecies variability may remain. This residual variability can be covered by an AF. However, ECETOC estimates that this variability is largely accounted for in the default assessment factor proposed for intra-species variability: ECETOC proposed, for the total (inter- and intra-species) variability, an overall factor of 5 for the general population and 3 for the workplace (ECETOC 2003, 2010). The German Auschuss für Gefahrstoffe - AGS (2006) seems to follow a comparable approach, not differentiating between inter- and intra-species variability. Apart from allometric scaling, they use an additional factor of 5 for overall (inter- and intra-species) variability for the workplace.
Furthermore it is anticipated that a low variability in response would be seen in human populations exposed to metal compounds that do not undergo extensive metabolism (and have lower genetic polymorphisms) than in populations exposed to substances that required more extensive metabolism.
No other assessment factors are considered necessary.
The overall assessment factor for workers for the dermal route starting from the rat oral NOAEL (90day) is: 2 x 4x 2.5 x 5 = 100
The resulting DNEL dermal, workers is 5.25 mg/kg bw/day

AF for the quality of the whole database:

1

Justification:

As the data set includes repeated dose studies of different species up to 90 days the data qulaity is suficient to not apply an additional assessment factor.

AF for remaining uncertainties:

1

Justification:

There are no mahor additional uncertainties speicif to this dataset.

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:

5.25 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):

100

Dose descriptor starting point:

NOAEL

Value:

525 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

525 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No modification is needed as the routes of exposure are identical.

AF for dose response relationship:

1

Justification:

As no adverse effects were observed at the highest dose tested, no additional assessment factor is applied.

AF for differences in duration of exposure:

2

Justification:

As the NOAEL is based on a 90-day study in rats a factor of 2 is used to account for human life time exposure. This is however considered conservative as available longer term studies in different species with lanthanum compounds have not shown relevant additional toxicity that would suggest a lowering of the NOAEL.

AF for interspecies differences (allometric scaling):

4

Justification:

An allometric scaling factor of 4 considering the different metabolic rates of rats and humans is applied to the rat NOAEL (ECHA R8., 2008).

AF for other interspecies differences:

2.5

Justification:

An additional factor of 2.5 apart from allometric scaling is recommended by ECHA R8., 2008 to account for remaining interspecies differences. The data of lanthanum compounds from different species would however suggest, that an additional factor is not warranted. If allometric scaling is used, although some interspecies variability may remain, it is estimated that this residual variability is largely accounted for in the default assessment factor proposed for intra-species variability, because of the inherent interdependency of those two variables. However, in this assessment the factor of 2.5 will be applied.

AF for intraspecies differences:

5

Justification:

An intraspecies extrapolation factor of 5 is considered sufficient for the general population. This is based on considerations of ECETOC, 2003 and 2010 adn metal specifc considerations.
Statistical analysis of the variability of toxicodynamic and toxicokinetic parameters within several published datasets has shown that the intra-species variability between humans can be covered by an AF of 5 for the general population and an AF of 3 for the more homogeneous worker population. ECETOC (2003) and its update (ECETOC, 2010) also stress the inherent interdependency between inter- and intra-species variability, concluding that it is not possible to clearly differentiate between inter- and intra-species variability factors. In cases where allometric scaling is performed, some residual interspecies variability may remain. This residual variability can be covered by an AF. However, ECETOC estimates that this variability is largely accounted for in the default assessment factor proposed for intra-species variability: ECETOC proposed, for the total (inter- and intra-species) variability, an overall factor of 5 for the general population and 3 for the workplace (ECETOC 2003, 2010). The German Auschuss für Gefahrstoffe - AGS (2006) seems to follow a comparable approach, not differentiating between inter- and intra-species variability. Apart from allometric scaling, they use an additional factor of 5 for overall (inter- and intra-species) variability for the workplace.
Furthermore it is anticipated that a low variability in response would be seen in human populations exposed to metal compounds that do not undergo extensive metabolism (and have lower genetic polymorphisms) than in populations exposed to substances that required more extensive metabolism.

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

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

Assessment for the general population:

DNEL derivation for oral exposure

Modification of starting point:

NOAEL, oral rat 90 day: 525 mg/kg bw/day

Duration extrapolation

As the NOAEL is based on a 90-day study in rats a factor of 2 is used to account for human life time exposure. This is however considered conservative as available longer term studies in different species with lanthanum compounds have not shown relevant additional toxicity that would suggest a lowering of the NOAEL.

Interspecies extrapolation

An allometric scaling factor of 4 considering the different metabolic rates of rats and humans is applied to the rat NOAEL (ECHA R8., 2008).

An additional factor of 2.5 apart from allometric scaling is recommended by ECHA R8., 2008 to account for remaining interspecies differences.The data of lanthanum compounds from different species would however suggest, that an additional factor is not warranted.If allometric scaling is used, although some interspecies variability may remain, it is estimated that this residual variability is largely accounted for in the default assessment factor proposed for intra-species variability, because of the inherent interdependency of those two variables. However, in this assessment the factor of 2.5 will be applied.

Intraspecies extrapolation

An intraspecies extrapolation factor of 5 is considered sufficient for the general population. This is based on considerations of ECETOC, 2003 and 2010.

Statistical analysis of the variability of toxicodynamic and toxicokinetic parameters within several published datasets has shown that the intra-species variability between humans can be covered by an AF of 5 for the general population and an AF of 3 for the more homogeneous worker population. ECETOC (2003) and its update (ECETOC, 2010) also stress the inherent interdependency between inter- and intra-species variability, concluding that it is not possible to clearly differentiate between inter- and intra-species variability factors. In cases where allometric scaling is performed, some residual interspecies variability may remain. This residual variability can be covered by an AF. However, ECETOC estimates that this variability is largely accounted for in the default assessment factor proposed for intra-species variability: ECETOC proposed, for the total (inter- and intra-species) variability, an overall factor of 5 for the general population and 3 for the workplace (ECETOC 2003, 2010).The German Auschuss für Gefahrstoffe - AGS (2006) seems to follow a comparable approach, not differentiating between inter- and intra-species variability. Apart from allometric scaling, they use an additional factor of 5 for overall (inter- and intra-species) variability for the workplace.

Furthermore it is anticipated that a low variability in response would be seen in human populations exposed to metal compounds that do not undergo extensive metabolism (and have lower genetic polymorphisms) than in populations exposed to substances that required more extensive metabolism.

No other assessment factors are considered necessary.

The overall assessment factor for the general population for the oral route starting from the rat oral NOAEL (90day) is : 2 x 4x 2.5 x 5 = 100

The resulting DNEL oral, general population is 5.25 mg/kg bw/day

DNEL derivation for dermal exposure

Modification of starting point:

NOAEL, oral rat 90 day: 525 mg/kg bw/day

Correction for absorption:

Based on the specific toxicokinetic information on lanthanum oxide and lanthanum carbonate it can reasonably be assumed that the absorption is comparable after oral and dermal exposure and no correction is made. Normally dermal absorption will be lower than oral absorption.

Duration extrapolation

As the NOAEL is based on a 90-day study in rats a factor of 2 is used to account for human life time exposure. This is however considered conservative as available longer term studies in different species with lanthanum compounds have not shown relevant additional toxicity that would suggest a lowering of the NOAEL.

Interspecies extrapolation

An allometric scaling factor of 4 considering the different metabolic rates of rats and humans is applied to the rat NOAEL (ECHA R8., 2008).

An additional factor of 2.5 apart from allometric scaling is recommended by ECHA R8., 2008 to account for remaining interspecies differences.The data of lanthanum compounds from different species would however suggest, that an additional factor is not warranted.If allometric scaling is used, although some interspecies variability may remain, it is estimated that this residual variability is largely accounted for in the default assessment factor proposed for intra-species variability, because of the inherent interdependency of those two variables. However, in this assessment the factor of 2.5 will be applied.

Intraspecies extrapolation

An intraspecies extrapolation factor of 5 is considered sufficient for the general population. This is based on considerations of ECETOC, 2003 and 2010.

Statistical analysis of the variability of toxicodynamic and toxicokinetic parameters within several published datasets has shown that the intra-species variability between humans can be covered by an AF of 5 for the general population and an AF of 3 for the more homogeneous worker population. ECETOC (2003) and its update (ECETOC, 2010) also stress the inherent interdependency between inter- and intra-species variability, concluding that it is not possible to clearly differentiate between inter- and intra-species variability factors. In cases where allometric scaling is performed, some residual interspecies variability may remain. This residual variability can be covered by an AF. However, ECETOC estimates that this variability is largely accounted for in the default assessment factor proposed for intra-species variability: ECETOC proposed, for the total (inter- and intra-species) variability, an overall factor of 5 for the general population and 3 for the workplace (ECETOC 2003, 2010).The German Auschuss für Gefahrstoffe - AGS (2006) seems to follow a comparable approach, not differentiating between inter- and intra-species variability. Apart from allometric scaling, they use an additional factor of 5 for overall (inter- and intra-species) variability for the workplace.

Furthermore it is anticipated that a low variability in response would be seen in human populations exposed to metal compounds that do not undergo extensive metabolism (and have lower genetic polymorphisms) than in populations exposed to substances that required more extensive metabolism.

No other assessment factors are considered necessary.

The overall assessment factor for workers for the dermal route starting from the rat oral NOAEL (90day) is : 2 x 4x 2.5 x 5 = 100

The resulting DNEL dermal, workers is 5.25 mg/kg bw/day

DNEL derivation for inhalation exposure

Modification of starting point:

NOAEL, oral rat 90 day: 525 mg/kg bw/day

Allometric scaling to human inhalation exposure for 24 h:

Route to route extrapolation rat: Division by 1.15 m³/kg bw: 456.5 mg/m³. (See ECHA R8., 2008)

Correction for absorption:

Based on the specific toxicokinetic information on lanthanum oxide and lanthanum carbonate it can reasonably be assumed that the absorption is comparable after oral and inhalation exposure and no correction is made in this case.

Duration extrapolation

As the NOAEL is based on a 90-day study in rats a factor of 2 is used to account for human life time exposure. This is however considered conservative as available longer term studies in different species with lanthanum compounds have not shown relevant additional toxicity that would suggest a lowering of the NOAEL.

Interspecies extrapolation

An additional factor of 2.5 apart from allometric scaling is recommended by ECHA R8, 2008 to account for remaining interspecies differences.The data of lanthanum compounds from different species would however suggest, that an additional factor is not warranted.If allometric scaling is used, although some interspecies variability may remain, it is estimated that this residual variability is largely accounted for in the default assessment factor proposed for intra-species variability, because of the inherent interdependency of those two variables. However, in this assessment the factor of 2.5 will be applied.

Intraspecies extrapolation

An intraspecies extrapolation factor of 5 is considered sufficient for the general population. This is based on considerations of ECETOC, 2003 and 2010.

Statistical analysis of the variability of toxicodynamic and toxicokinetic parameters within several published datasets has shown that the intra-species variability between humans can be covered by an AF of 5 for the general population and an AF of 3 for the more homogeneous worker population. ECETOC (2003) and its update (ECETOC, 2010) also stress the inherent interdependency between inter- and intra-species variability, concluding that it is not possible to clearly differentiate between inter- and intra-species variability factors. In cases where allometric scaling is performed, some residual interspecies variability may remain. This residual variability can be covered by an AF. However, ECETOC estimates that this variability is largely accounted for in the default assessment factor proposed for intra-species variability: ECETOC proposed, for the total (inter- and intra-species) variability, an overall factor of 5 for the general population and 3 for the workplace (ECETOC 2003, 2010).The German Auschuss für Gefahrstoffe - AGS (2006) seems to follow a comparable approach, not differentiating between inter- and intra-species variability. Apart from allometric scaling, they use an additional factor of 5 for overall (inter- and intra-species) variability for the workplace.

Furthermore it is anticipated that a low variability in response would be seen in human populations exposed to metal compounds that do not undergo extensive metabolism (and have lower genetic polymorphisms) than in populations exposed to substances that required more extensive metabolism.

No other assessment factors are considered necessary.

The overall assesssment factor for the genral population for the inhalation route starting from the modified starting point that already includes allometric scaling is then: 2 x 2.5 x 5 = 25

The DNEL_{inahalation-longterm}is then 18.26 mg/m³

Based on a general dust limit for worker exposure of 10 mg/m³ of inhalable and 3 mg/m³ of respirable dust, a DNEL for the general population can also be derived by applying a duration correction of 8/24 and an additional intraspecies factor of 2. This leads to an inhalation DNEL for the general population of 1.7 mg/m³inhalable dust and 0.5 mg/m³of inhalable dust.

References:

AGS. 2006. Technische Regeln für Gefahrstoffe. Begründungen und Erläuterungen zu Grenzwerten in der Luft am Arbeitsplatz. Ausschuss für Gefahrstoffe. TRGS 901, BArbBl. Heft 1/2006.www.baua.de

ECETOC. 2003. Derivation of Assessment Factors for Human Health Risk Assessment. Technical Report No.86.European Centre for Ecotoxicology and Toxicology of Chemicals,Brussels, Belgium

ECETOC.July 2010, Draft Guidance on Assessment Factors to Derive DNELs, Technical Report No. to be determined.European Centre for Ecotoxicology and Toxicology of Chemicals,Brussels, Belgium

ECETOC Workshop. March 2010: Draft Workshop reprot on Guidance on Assessment Factors to Derive DNELs, Report No: to be determined

ECHA R8. 2008. Guidance on Information Requirements and Chemical Safety Assessment. Chapter R.8: Characterisation of dose[concentration]-response for human health. Guidance for the implementation of REACH. European Chemicals Agency