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Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
23.29 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
3
AF for dose response relationship:
1
Justification:
No adjustment is required, since an unbounded NOAEC is used. The NOAEC was the highest dose tested and no LOAEC was established.
AF for differences in duration of exposure:
1
Justification:
Usually it is expected that the experimental NOAEC will decrease with increasing duration of application. Furthermore, other and more serious adverse effects may appear with prolonged exposure time. For duration adjustment, a default AF of 2 is usually proposed for extrapolation from sub-chronic exposure (13 weeks) to chronic exposure. However, in case of this MoO3 inhalation study, a duration adjustment is not considered necessary by taking into account the results of the 2-year inhalation carcinogenicity study with MoO3 in rats and mice (NTP), in which no treatment-related effects on survival rates and mean body weights of rats of all exposed groups were observed despite the exposure-dependent increases of Mo concentration in blood. Thus, the prolongation of exposure did not result in any severe non-neoplastic systemic effects in both species as compared to the controls.
AF for interspecies differences (allometric scaling):
1
Justification:
Inter-species variability with respect to toxicokinetics following oral or inhalation administration of molybdenum substances is not to be expected: both in laboratory animals (rodents) as well as in humans, absorption of “molybdenum” from the gastrointestinal tract, to which part of inhaled material is translocated, has been shown to be practically complete in several species; homeostatic control is not on the level of uptake, but rather via rapid renal elimination. With regards to material staying in the respiratory tract after inhalation, complete dissolution to molybdate and complete uptake is assumed (conservative approach). Following uptake, all molybdenum substances (regardless of their speciation, valence and solubility) have been demonstrated to have transformed to molybdate anions; this is based on chemical reactivity and thermodynamics and is therefore independent of animal species or human biology. Molybdate anions are absorbed into the body by passive diffusion and not via selective transport mechanism. Upon uptake, they are distributed widely in the body, but accumulation in organ tissues does not occur. Any metabolism of molybdenum substances as such can be excluded, as update, distribution and elimination occurs with the molybdate ion. Therefore, it is considered justified to replace default assessment factors (4 and 2.5, respectively) accounting for a correction for differences in metabolic rate by “1” and for remaining differences also by “1”.
AF for other interspecies differences:
1
Justification:
Inter-species variability with respect to toxicokinetics following oral or inhalation administration of molybdenum substances is not to be expected: both in laboratory animals (rodents) as well as in humans, absorption of “molybdenum” from the gastrointestinal tract, to which part of inhaled material is translocated, has been shown to be practically complete in several species; homeostatic control is not on the level of uptake, but rather via rapid renal elimination. With regards to material staying in the respiratory tract after inhalation, complete dissolution to molybdate and complete uptake is assumed (conservative approach). Following uptake, all molybdenum substances (regardless of their speciation, valence and solubility) have been demonstrated to have transformed to molybdate anions; this is based on chemical reactivity and thermodynamics and is therefore independent of animal species or human biology. Molybdate anions are absorbed into the body by passive diffusion and not via selective transport mechanism. Upon uptake, they are distributed widely in the body, but accumulation in organ tissues does not occur. Any metabolism of molybdenum substances as such can be excluded, as update, distribution and elimination occurs with the molybdate ion. Therefore, it is considered justified to replace default assessment factors (4 and 2.5, respectively) accounting for a correction for differences in metabolic rate by “1” and for remaining differences also by “1”.
AF for intraspecies differences:
3
Justification:
This assessment factor is introduced since it is expected that a greater variability in response from the most to least sensitive human would be seen, relative to an experimental animal population. ECETOC (2003) has reviewed scientific literature on the distribution of human data for various toxicokinetic and toxicodynamic parameters to assess intraspecies variability within the human population, specifically by Renwick and Lazarus (1998) and Hattis et al. (1999). Considering that the data analysed by these authors includes both sexes, a variety of disease states and ages, the use of the 95th percentile of the distribution of the variability for these datasets is considered sufficiently conservative to account for intraspecies variability for the general population. Based on this, a default assessment factor of 5 is recommended by ECETOC (2003), with a lower factor of 3 (i.e. closer to the 90th percentile of the distribution of the variability for these datasets) for the more homogeneous worker population. In the worker population, the more susceptible groups are typically excluded and/or may be protected from specific exposures. Thus, and in consideration of normal hygiene practices at the workplace, a lower value for the assessment factor is considered appropriate for workers. References: ECETOC (2003): Derivation of Assessment Factors for Human Health Risk Assessment. Technical Report No. 86. European Centre for Ecotoxicology and Toxicology of Chemicals. ISSN-0773-6347-86, Brussels, February 2003; Hattis et al. (1999): Human interindividual variability in parameters related to health risks. Risk Anal 19: 711-726; Renwick and Lazarus (1998): Human variability and noncancer risk assessment. An analysis of the default uncertainty factor. Reg Toxicol Pharmacol 27: 3-20.
AF for the quality of the whole database:
1
Justification:
No need for a further assessment factor (data of high relevance and reliability is used)
AF for remaining uncertainties:
1
Justification:
No need for a further assessment factor (data of high relevance and reliability is used)
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:
no hazard identified
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

This dossier is one of several dossiers prepared under the auspices of the REACH Molybdenum Consortium (“MoCon”). To avoid unnecessary (animal) testing, a comprehensive grouping and read-across concept has been developed amongst several molybdenum containing substances. This grouping/category approach is described in detail in a separate report, in accordance with the ECHA's "Read-Across Assessment Framework" (RAAF). This document is attached to section 13 in the technical dossier and to the CSR.

Detailed information about the derivation of DNELs is given in a separate "DNEL report" that is also attached to the technical dossier (IUCLID section 13) and to the CSR.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
6.94 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
5
AF for dose response relationship:
1
Justification:
No adjustment is required, since an unbounded NOAEC is used. The NOAEC was the highest dose tested and no LOAEC was established.
AF for differences in duration of exposure:
1
Justification:
Usually it is expected that the experimental NOAEC will decrease with increasing duration of application. Furthermore, other and more serious adverse effects may appear with prolonged exposure time. For duration adjustment, a default AF of 2 is usually proposed for extrapolation from sub-chronic exposure (13 weeks) to chronic exposure. However, in case of this MoO3 inhalation study, a duration adjustment is not considered necessary by taking into account the results of the 2-year inhalation carcinogenicity study with MoO3 in rats and mice (NTP), in which no treatment-related effects on survival rates and mean body weights of rats of all exposed groups were observed despite the exposure-dependent increases of Mo concentration in blood. Thus, the prolongation of exposure did not result in any severe non-neoplastic systemic effects in both species as compared to the controls.
AF for interspecies differences (allometric scaling):
1
Justification:
Inter-species variability with respect to toxicokinetics following oral or inhalation administration of molybdenum substances is not to be expected: both in laboratory animals (rodents) as well as in humans, absorption of “molybdenum” from the gastrointestinal tract, to which part of inhaled material is translocated, has been shown to be practically complete in several species; homeostatic control is not on the level of uptake, but rather via rapid renal elimination. With regards to material staying in the respiratory tract after inhalation, complete dissolution to molybdate and complete uptake is assumed (conservative approach). Following uptake, all molybdenum substances (regardless of their speciation, valence and solubility) have been demonstrated to have transformed to molybdate anions; this is based on chemical reactivity and thermodynamics and is therefore independent of animal species or human biology. Molybdate anions are absorbed into the body by passive diffusion and not via selective transport mechanism. Upon uptake, they are distributed widely in the body, but accumulation in organ tissues does not occur. Any metabolism of molybdenum substances as such can be excluded, as update, distribution and elimination occurs with the molybdate ion. Therefore, it is considered justified to replace default assessment factors (4 and 2.5, respectively) accounting for a correction for differences in metabolic rate by “1” and for remaining differences also by “1”.
AF for other interspecies differences:
1
Justification:
Inter-species variability with respect to toxicokinetics following oral or inhalation administration of molybdenum substances is not to be expected: both in laboratory animals (rodents) as well as in humans, absorption of “molybdenum” from the gastrointestinal tract, to which part of inhaled material is translocated, has been shown to be practically complete in several species; homeostatic control is not on the level of uptake, but rather via rapid renal elimination. With regards to material staying in the respiratory tract after inhalation, complete dissolution to molybdate and complete uptake is assumed (conservative approach). Following uptake, all molybdenum substances (regardless of their speciation, valence and solubility) have been demonstrated to have transformed to molybdate anions; this is based on chemical reactivity and thermodynamics and is therefore independent of animal species or human biology. Molybdate anions are absorbed into the body by passive diffusion and not via selective transport mechanism. Upon uptake, they are distributed widely in the body, but accumulation in organ tissues does not occur. Any metabolism of molybdenum substances as such can be excluded, as update, distribution and elimination occurs with the molybdate ion. Therefore, it is considered justified to replace default assessment factors (4 and 2.5, respectively) accounting for a correction for differences in metabolic rate by “1” and for remaining differences also by “1”.
AF for intraspecies differences:
5
Justification:
This assessment factor is introduced since it is expected that a greater variability in response from the most to least sensitive human would be seen, relative to an experimental animal population. ECETOC (2003) has reviewed scientific literature on the distribution of human data for various toxicokinetic and toxicodynamic parameters to assess intraspecies variability within the human population, specifically by Renwick and Lazarus (1998) and Hattis et al. (1999). Considering that the data analysed by these authors includes both sexes, a variety of disease states and ages, the use of the 95th percentile of the distribution of the variability for these datasets is considered sufficiently conservative to account for intraspecies variability for the general population. Based on this, a default assessment factor of 5 is recommended by ECETOC (2003), with a lower factor of 3 (i.e. closer to the 90th percentile of the distribution of the variability for these datasets) for the more homogeneous worker population. In the worker population, the more susceptible groups are typically excluded and/or may be protected from specific exposures. Thus, and in consideration of normal hygiene practices at the workplace, a lower value for the assessment factor is considered appropriate for workers. References: ECETOC (2003): Derivation of Assessment Factors for Human Health Risk Assessment. Technical Report No. 86. European Centre for Ecotoxicology and Toxicology of Chemicals. ISSN-0773-6347-86, Brussels, February 2003; Hattis et al. (1999): Human interindividual variability in parameters related to health risks. Risk Anal 19: 711-726; Renwick and Lazarus (1998): Human variability and noncancer risk assessment. An analysis of the default uncertainty factor. Reg Toxicol Pharmacol 27: 3-20.
AF for the quality of the whole database:
1
Justification:
No need for a further assessment factor (data of high relevance and reliability is used).
AF for remaining uncertainties:
1
Justification:
No need for a further assessment factor (data of high relevance and reliability is used).
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
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:
7.09 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):
5
AF for dose response relationship:
1
Justification:
No adjustment is required, since a NOAEL from reliable subchronic toxicity study with 3 dose levels and an appropriate spacing is used.
AF for differences in duration of exposure:
1
Justification:
According to the guidance on information requirements and chemical safety assessment Chapter R.8: Characterization of dose [concentration]- response for human health, an exposure duration assessment factor is based on the assumption that N(L)OAELs in toxicity studies decrease with increasing exposure duration. This DNEL is based on a NOAEL from a 13-week study (sub-chronic) so that conventionally an assessment factor would be required for extrapolation from sub-chronic to chronic exposures. However, such a factor is not deemed required in this case, for the following reasons: In NTP inhalation studies no difference in systemic toxicity between the rats and mice exposed to MoO3 via inhalation for 13 weeks or for 2 years was seen: Comparison of systemic dose in inhalation studies (NTP) and oral studies: The mean whole blood Molybdenum concentration of 2.6 – 2.9 ppm in rats orally administered the NOAEL (17 mg Mo/kg bw/day) in the 13 week oral study was comparable to the mean whole blood Molybdenum concentrations of 2.4 – 6 ppm in rats exposed to the NOAEC of 100 mg MoO3/m3 (~24.23 mg Mo/kg bw/day; estimated via route-to-route extrapolation) via inhalation for 2 years. The blood samples were taken at the end of each study and represent steady state conditions. Key systemic end point measurements for both studies were similar and included body weight changes, reproductive parameters, and full histological evaluation, with no adverse effects on these parameters in either study. Despite the longer exposure duration, no toxicity was observed in the 2-year study and both studies resulted in similar NOAELs when expressed in terms of mass Mo/kg bw/day. Therefore, no exposure duration assessment factor is considered to be required for extrapolation from sub-chronic to chronic exposure in this case.
AF for interspecies differences (allometric scaling):
1
Justification:
Inter-species variability with respect to toxicokinetics following oral administration of molybdenum substances is not to be expected: both in laboratory animals (rodents) as well as in humans, absorption of “molybdenum” from the gastrointestinal tract has been shown to be practically complete in several species; homeostatic control is not on the level of uptake, but rather via rapid renal elimination. Following uptake, all molybdenum substances (regardless of their speciation, valence and solubility) have been demonstrated to have transformed to molybdate anions; this is based on chemical reactivity and thermodynamics and is therefore independent of animal species or human biology. Molybdate anions are absorbed into the body by passive diffusion and not via selective transport mechanism. Upon uptake, they are distributed widely in the body, but accumulation in organ tissues does not occur. Any metabolism of molybdenum substances as such can be excluded, as update, distribution and elimination occurs with the molybdate ion. Therefore, it is considered justified to replace default assessment factors (4 and 2.5, respectively) accounting for a correction for differences in metabolic rate by “1” and for remaining differences also by “1”.
AF for other interspecies differences:
1
Justification:
Inter-species variability with respect to toxicokinetics following oral administration of molybdenum substances is not to be expected: both in laboratory animals (rodents) as well as in humans, absorption of “molybdenum” from the gastrointestinal tract has been shown to be practically complete in several species; homeostatic control is not on the level of uptake, but rather via rapid renal elimination. Following uptake, all molybdenum substances (regardless of their speciation, valence and solubility) have been demonstrated to have transformed to molybdate anions; this is based on chemical reactivity and thermodynamics and is therefore independent of animal species or human biology. Molybdate anions are absorbed into the body by passive diffusion and not via selective transport mechanism. Upon uptake, they are distributed widely in the body, but accumulation in organ tissues does not occur. Any metabolism of molybdenum substances as such can be excluded, as update, distribution and elimination occurs with the molybdate ion. Therefore, it is considered justified to replace default assessment factors (4 and 2.5, respectively) accounting for a correction for differences in metabolic rate by “1” and for remaining differences also by “1”.
AF for intraspecies differences:
5
Justification:
This assessment factor is introduced since it is expected that a greater variability in response from the most to least sensitive human would be seen, relative to an experimental animal population. ECETOC (2003) has reviewed scientific literature on the distribution of human data for various toxicokinetic and toxicodynamic parameters to assess intraspecies variability with the human population, specifically by Renwick and Lazarus (1998) and Hattis et al. (1999). Considering that the data analysed by these authors includes both sexes, a variety of disease states and ages, the use of the 95th percentile of the distribution of the variability for these datasets is considered sufficiently conservative to account for intraspecies variability for the general population. Based on this, a default assessment factor of 5 is recommended by ECETOC (2003) for the general population). References: ECETOC (2003): Derivation of Assessment Factors for Human Health Risk Assessment. Technical Report No. 86. European Centre for Ecotoxicology and Toxicology of Chemicals. ISSN-0773-6347-86, Brussels, February 2003; Hattis et al. (1999): Human interindividual variability in parameters related to health risks. Risk Anal 19: 711-726; Renwick and Lazarus (1998): Human variability and noncancer risk assessment. An analysis of the default uncertainty factor. Reg Toxicol Pharmacol 27: 3-20.
AF for the quality of the whole database:
1
Justification:
No need for a further assessment factor (data of high relevance and reliability is used).
AF for remaining uncertainties:
1
Justification:
No need for a further assessment factor (data of high relevance and reliability is used).
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

This dossier is one of several dossiers prepared under the auspices of the REACH Molybdenum Consortium (“MoCon”). To avoid unnecessary (animal) testing, a comprehensive grouping and read-across concept has been developed amongst several molybdenum containing substances. This grouping/category approach is described in detail in a separate report, in accordance with the ECHA's "Read-Across Assessment Framework" (RAAF). This document is attached to section 13 in the technical dossier and to the CSR. Detailed information about the derivation of DNELs is given in a separate "DNEL report" that is also attached to the technical dossier (IUCLID section 13) and to the CSR.