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EC number: 225-306-3 | CAS number: 4767-03-7
Toxicological Summary
Administrative data
Workers - Hazard via inhalation route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 14 mg/m³
- Most sensitive endpoint:
- developmental toxicity / teratogenicity
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
- Overall assessment factor (AF):
- 12.5
- Modified dose descriptor starting point:
- NOAEC
- Value:
- 176 mg/m³
- Explanation for the modification of the dose descriptor starting point:
- The oral NOAEL of 200 mg/kg bw/d from the rat developmental toxicity study is corrected for breathing rate (/0.38), activity (*0.67/10) and assuming that inhalation absorption is twice the level of oral absorption. The corrected inhalation NOAEC is therefore 176 mg/m3.
- AF for dose response relationship:
- 1
- Justification:
- Default assessment factor. Effects seen at high dose levels in the developmental toxicity study are not considered to be of clear toxicological significance and do not constitute a severe developmental effect warranting the use of additional assessment factors.
- AF for differences in duration of exposure:
- 1
- Justification:
- Use of the NOAEL from the developmental toxicity study as a starting point provides an adequate margin of safety over the sub-chronic toxicity NOAEL
- AF for interspecies differences (allometric scaling):
- 1
- Justification:
- Already taken into account in route to route extrapolation
- AF for other interspecies differences:
- 2.5
- Justification:
- Default assessment factor (rat study)
- AF for intraspecies differences:
- 5
- Justification:
- Default assessment factor
- AF for the quality of the whole database:
- 1
- Justification:
- Default assessment factor
- AF for remaining uncertainties:
- 1
- Justification:
- Default assessment factor.
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
DNEL related information
Local effects
Long term exposure
- Hazard assessment conclusion:
- low hazard (no threshold derived)
- Most sensitive endpoint:
- irritation (respiratory tract)
Acute/short term exposure
- Hazard assessment conclusion:
- low hazard (no threshold derived)
- Most sensitive endpoint:
- irritation (respiratory tract)
DNEL related information
Workers - Hazard via dermal route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 4 mg/kg bw/day
- Most sensitive endpoint:
- developmental toxicity / teratogenicity
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
- Overall assessment factor (AF):
- 50
- Modified dose descriptor starting point:
- NOAEL
- Value:
- 200 mg/kg bw/day
- Explanation for the modification of the dose descriptor starting point:
- As a worst case default assumption, dermal absorption is assumed to be the same as oral absorption. A corrected dermal NOAEL of 200 mg/kg bw/d is therefore derived.
- AF for dose response relationship:
- 1
- Justification:
- Default assessment factor. Effects seen at high dose levels in the developmental toxicity study are not considered to be of clear toxicological significance and do not constitute a severe developmental effect warranting the use of additional assessment factors.
- AF for differences in duration of exposure:
- 1
- Justification:
- Use of the NOAEL from the developmental toxicity study as a starting point provides an adequate margin of safety over the sub-chronic toxicity NOAEL
- AF for interspecies differences (allometric scaling):
- 4
- Justification:
- Default assessment factor (rat study)
- AF for other interspecies differences:
- 2.5
- Justification:
- Default assessment factor
- AF for intraspecies differences:
- 5
- Justification:
- Default assessment factor (workers)
- AF for the quality of the whole database:
- 1
- Justification:
- Default assessment factor
- AF for remaining uncertainties:
- 1
- Justification:
- Default assessment factor
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
DNEL related information
Local effects
Long term exposure
- Hazard assessment conclusion:
- no hazard identified
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
Workers - Hazard for the eyes
Local effects
- Hazard assessment conclusion:
- low hazard (no threshold derived)
Additional information - workers
Endpoint selection
Bis-MPA is of low acute oral and dermal toxicity, is not a skin irritant or skin sensitiser, but is classified as an eye irritant. A report of accidental exposure to high levels of bis-MPA indicates that the substance may cause respiratory irritation, although this is not reported under normal conditions of use.
Two studies of repeated dose toxicity with bis-MPA are available. A NOAEL of 1000 mg/kg bw/d is reported for a 90-day rat toxicity study. In a rat developmental toxicity study, a maternal NOAEL of 1000 mg/kg bw/d is reported. A foetal NOAEL of 200 mg/kg bw/d is reported for this study based on slightly elevated incidences of early resorptions at dose levels of 500 and 1000 mg/kg bw/d. The magnitude of this effect is not large and values at 500 mg/kg bw/d (10%) and 1000 mg/kg bw/d (12%) are only slightly above the level seen in the concurrent controls (7%). The dose level of 200 mg/kg bw/d represents a clear NOAEL (7% early resorption incidence). The toxicological significance of the apparent increase in the proportion of early resorptions is unclear as findings at 500 and 1000 mg/kg bw/d are associated with (and may be secondary to) higher numbers of corpora lutea and implantations. Mean litter size was unaffected by treatment and was higher at 500 and 1000 mg/kg bw/d. Effects seen in this study at 500 and 1000 mg/kg bw/d are therefore not considered to be of clear toxicological significance and do not constitute a severe developmental effect warranting the use of additional assessment factors.
Based on the results of the 90-day and developmental toxicity studies, a starting point of 200 mg/kg bw/d (developmental toxicity NOAEL) is used for DNEL derivation.
Inhalation DNELs
Systemic Inhalation DNELs
The oral NOAEL of 200 mg/kg bw/d from the rat developmental toxicity study is corrected for breathing rate (/0.38), activity (*0.67) and assuming that inhalation absorption is twice the level of oral absorption. The corrected inhalation NOAEC is therefore 176 mg/m3.
Long-term systemic inhalation DNEL
Individual assessment factors of 1 (for dose-response relationship), 1 (for duration of exposure), 1 (for allometric scaling), 2.5 (for other interspecies differences), 5 (for intraspecies differences), 1 (for database quality) and 1 (for remaining uncertainties) are combined to give an overall assessment factor of 12.5. Application of the overall assessment factor to the corrected inhalation NOAEC results in a DNEL of 14 mg/m3. An assessment factor is not used to take into account the relatively short duration of exposure in the developmental toxicity study as the 90-day study identifies a NOAEL of 1000 mg/kg bw/d. This gives an adequate margin of safety for potential chronic exposures.
Short-term systemic inhalation DNEL
Long-term systemic DNEL values are derived from the NOAEL for embryofoetal toxicity from the rat developmental toxicity study. Although, theoretically, effects could occur from a single exposure in a susceptible window, REACH Guidance (Chapter R8) notes that the conservative nature of the methodology used to derive the long-term DNEL should be sufficient to ensure that adverse effects do not occur following high short-term exposures, which should not result in the daily DNEL value being exceeded. A separate DNEL for acute/short-term exposure is therefore not derived. There is no indication of short-term or acute toxicity from other studies and the substance is not classified for acute toxicity.
Local Inhalation DNELs
Local long-term and short-term inhalation DNEL values are not derived, in the absence of suitable dose-reponse data. Respiratory irritation is not seen under normal conditions of use but is reported following a single accidental high exposure.
Dermal DNELs
Systemic Dermal DNELs
As a worst case default assumption, dermal absorption is assumed to be the same as oral absorption. A corrected dermal NOAEL of 200 mg/kg bw/d is therefore derived. Derivation of a short-term systemic DNEL is required as the developmental toxicity effects may theoretically result from an acute exposure.
Long-term systemic dermal DNEL
Individual assessment factors of 1 (for dose-response relationship), 1 (for duration of exposure), 4 (for allometric scaling), 2.5 (for other interspecies differences), 5 (for intraspecies differences), 1 (for database quality) and 1 (for remaining uncertainties) are combined to give an overall assessment factor of 50. Application of the overall assessment factor to the corrected dermal NOAEL results in a DNEL of 4 mg/kg bw/d. An assessment factor is not used to take into account the relatively short duration of exposure in the developmental toxicity study as the 90-day study identifies a NOAEL of 1000 mg/kg bw/d. This gives an adequate margin of safety for potential chronic exposures.
Short-term systemic dermal DNEL
Long-term systemic DNEL values are derived from the NOAEL for embryofoetal toxicity from the rat developmental toxicity study. Although, theoretically, effects could occur from a single exposure in a susceptible window, REACH Guidance (Chapter R8) notes that the conservative nature of the methodology used to derive the long-term DNEL should be sufficient to ensure that adverse effects do not occur following high short-term exposures, which should not result in the daily DNEL value being exceeded. A separate DNEL for acute/short-term exposure is therefore not derived. There is no indication of short-term or acute toxicity from other studies and the substance is not classified for acute toxicity.
Local Dermal DNELs
Local long-term and short-term dermal DNEL values are not derived, in the absence of an identified hazard. The substance is not a skin irritant or skin sensitiser.
General Population - Hazard via inhalation route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 3.5 mg/m³
- Most sensitive endpoint:
- developmental toxicity / teratogenicity
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
- Overall assessment factor (AF):
- 25
- Modified dose descriptor starting point:
- NOAEC
- Value:
- 87 mg/m³
- Explanation for the modification of the dose descriptor starting point:
- The oral NOAEL of 200 mg/kg bw/d from the rat developmental toxicity study is corrected for breathing rate (/1.15) and assuming that inhalation absorption is twice the level of oral absorption. The corrected inhalation NOAEC is therefore 87 mg/m3.
- AF for dose response relationship:
- 1
- Justification:
- Default assessment factor. Effects seen at high dose levels in the developmental toxicity study are not considered to be of clear toxicological significance and do not constitute a severe developmental effect warranting the use of additional assessment factors.
- AF for differences in duration of exposure:
- 1
- Justification:
- Use of the NOAEL from the developmental toxicity study as a starting point provides an adequate margin of safety over the sub-chronic toxicity NOAEL
- AF for interspecies differences (allometric scaling):
- 1
- Justification:
- Already taken into account
- AF for other interspecies differences:
- 2.5
- Justification:
- Default assessment factor
- AF for intraspecies differences:
- 10
- Justification:
- Default assessment factor (general population)
- AF for the quality of the whole database:
- 1
- Justification:
- Default assessment factor
- AF for remaining uncertainties:
- 1
- Justification:
- Default assessment factor
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
DNEL related information
Local effects
Long term exposure
- Hazard assessment conclusion:
- low hazard (no threshold derived)
- Most sensitive endpoint:
- irritation (respiratory tract)
Acute/short term exposure
- Hazard assessment conclusion:
- low hazard (no threshold derived)
- Most sensitive endpoint:
- irritation (respiratory tract)
DNEL related information
General Population - Hazard via dermal route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 2 mg/kg bw/day
- Most sensitive endpoint:
- developmental toxicity / teratogenicity
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
- Overall assessment factor (AF):
- 100
- Modified dose descriptor starting point:
- NOAEL
- Value:
- 200 mg/kg bw/day
- Explanation for the modification of the dose descriptor starting point:
- As a worst case default assumption, dermal absorption is assumed to be the same as oral absorption. A corrected dermal NOAEL of 200 mg/kg bw/d is therefore derived.
- AF for dose response relationship:
- 1
- Justification:
- Default assessment factor. Effects seen at high dose levels in the developmental toxicity study are not considered to be of clear toxicological significance and do not constitute a severe developmental effect warranting the use of additional assessment factors.
- AF for differences in duration of exposure:
- 1
- Justification:
- Use of the NOAEL from the developmental toxicity study as a starting point provides an adequate margin of safety over the sub-chronic toxicity NOAEL
- AF for interspecies differences (allometric scaling):
- 4
- Justification:
- Default assessment factor (rat study)
- AF for other interspecies differences:
- 2.5
- Justification:
- Default assessment factor
- AF for intraspecies differences:
- 10
- Justification:
- Default assessment factor (general population)
- AF for the quality of the whole database:
- 1
- Justification:
- Default assessment factor
- AF for remaining uncertainties:
- 1
- Justification:
- Default assessment factor
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
DNEL related information
Local effects
Long term exposure
- Hazard assessment conclusion:
- no hazard identified
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
General Population - Hazard via oral route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 2 mg/kg bw/day
- Most sensitive endpoint:
- developmental toxicity / teratogenicity
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
- Overall assessment factor (AF):
- 100
- Modified dose descriptor starting point:
- NOAEL
- Value:
- 200 mg/kg bw/day
- Explanation for the modification of the dose descriptor starting point:
- Not required; the starting point is derived from an oral study
- AF for dose response relationship:
- 1
- Justification:
- Default assessment factor. Effects seen at high dose levels in the developmental toxicity study are not considered to be of clear toxicological significance and do not constitute a severe developmental effect warranting the use of additional assessment factors.
- AF for differences in duration of exposure:
- 1
- Justification:
- Use of the NOAEL from the developmental toxicity study as a starting point provides an adequate margin of safety over the sub-chronic toxicity NOAEL
- AF for interspecies differences (allometric scaling):
- 4
- Justification:
- Default assessment factor
- AF for other interspecies differences:
- 2.5
- Justification:
- Default assessment factor (rat study)
- AF for intraspecies differences:
- 10
- Justification:
- Default assessment factor (general population)
- AF for the quality of the whole database:
- 1
- Justification:
- Default assessment factor
- AF for remaining uncertainties:
- 1
- Justification:
- Default assessment factor
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
DNEL related information
General Population - Hazard for the eyes
Local effects
- Hazard assessment conclusion:
- medium hazard (no threshold derived)
Additional information - General Population
Endpoint selection
Bis-MPA is of low acute oral and dermal toxicity, is not a skin irritant or skin sensitiser, but is classified as an eye irritant. A report of accidental exposure to high levels of bis-MPA indicates that the substance may cause respiratory irritation, although this would not be predicted to occur in the general population.
Two studies of repeated dose toxicity with bis-MPA are available. A NOAEL of 1000 mg/kg bw/d is reported for a 90-day rat toxicity study. In a rat developmental toxicity study, a maternal NOAEL of 1000 mg/kg bw/d is reported. A foetal NOAEL of 200 mg/kg bw/d is reported for this study based on slightly elevated incidences of early resorptions at dose levels of 500 and 1000 mg/kg bw/d. The magnitude of this effect is not large and values at 500 mg/kg bw/d (10%) and 1000 mg/kg bw/d (12%) are only slightly above the level seen in the concurrent controls (7%). The dose level of 200 mg/kg bw/d represents a clear NOAEL (7% early resorption incidence). The toxicological significance of the apparent increase in the proportion of early resorptions is unclear as findings at 500 and 1000 mg/kg bw/d are associated with (and may be secondary to) higher numbers of corpora lutea and implantations. Mean litter size was unaffected by treatment and was higher at 500 and 1000 mg/kg bw/d. Effects seen in this study at 500 and 1000 mg/kg bw/d are therefore not considered to be of clear toxicological significance and do not constitute a severe developmental effect warranting the use of additional assessment factors.
Based on the results of the 90-day and developmental toxicity studies, a starting point of 200 mg/kg bw/d (developmental toxicity NOAEL) is used for DNEL derivation.
Inhalation DNELs
Systemic Inhalation DNELs
The oral NOAEL of 200 mg/kg bw/d from the rat developmental toxicity study is corrected for breathing rate (/1.15) and assuming that inhalation absorption is twice the level of oral absorption. The corrected inhalation NOAEC is therefore 87 mg/m3.
Long-term systemic inhalation DNEL
Individual assessment factors of 1 (for dose-response relationship), 1 (for duration of exposure), 1 (for allometric scaling), 2.5 (for other interspecies differences), 10 (for intraspecies differences), 1 (for database quality) and 1 (for remaining uncertainties) are combined to give an overall assessment factor of 25. Application of the overall assessment factor to the corrected inhalation NOAEC results in a DNEL of 3.5 mg/m3. An assessment factor is not used to take into account the relatively short duration of exposure in the developmental toxicity study as the 90-day study identifies a NOAEL of 1000 mg/kg bw/d. This gives an adequate margin of safety for potential chronic exposures.
Short-term systemic inhalation DNEL
Long-term systemic DNEL values are derived from the NOAEL for embryofoetal toxicity from the rat developmental toxicity study. Although, theoretically, effects could occur from a single exposure in a susceptible window, REACH Guidance (Chapter R8) notes that the conservative nature of the methodology used to derive the long-term DNEL should be sufficient to ensure that adverse effects do not occur following high short-term exposures, which should not result in the daily DNEL value being exceeded. A separate DNEL for acute/short-term exposure is therefore not derived. There is no indication of short-term or acute toxicity from other studies and the substance is not classified for acute toxicity.
Local Inhalation DNELs
Local long-term and short-term inhalation DNEL values are not derived, in the absence of suitable dose-reponse data. Respiratory irritation is not seen under normal conditions of use, but is reported following a single accidental high exposure in an industrial situation.
Dermal DNELs
Systemic Dermal DNELs
As a worst case default assumption, dermal absorption is assumed to be the same as oral absorption. A corrected dermal NOAEL of 200 mg/kg bw/d is therefore derived.
Long-term systemic dermal DNEL
Individual assessment factors of 1 (for dose-response relationship), 1 (for duration of exposure), 4 (for allometric scaling), 2.5 (for other interspecies differences), 10 (for intraspecies differences), 1 (for database quality) and 1 (for remaining uncertainties) are combined to give an overall assessment factor of 100. Application of the overall assessment factor to the corrected dermal NOAEL results in a DNEL of 2 mg/kg bw/d. An assessment factor is not used to take into account the relatively short duration of exposure in the developmental toxicity study as the 90-day study identifies a NOAEL of 1000 mg/kg bw/d. This gives an adequate margin of safety for potential chronic exposures.
Short-term systemic dermal DNEL
Long-term systemic DNEL values are derived from the NOAEL for embryofoetal toxicity from the rat developmental toxicity study. Although, theoretically, effects could occur from a single exposure in a susceptible window, REACH Guidance (Chapter R8) notes that the conservative nature of the methodology used to derive the long-term DNEL should be sufficient to ensure that adverse effects do not occur following high short-term exposures, which should not result in the daily DNEL value being exceeded. A separate DNEL for acute/short-term exposure is therefore not derived. There is no indication of short-term or acute toxicity from other studies and the substance is not classified for acute toxicity.
Local Dermal DNELs
Local long-term and short-term dermal DNEL values are not derived, in the absence of an identified hazard. The substance is not a skin irritant or skin sensitiser.
Oral DNELs
Systemic Oral DNELs
Correction of the starting point is not required.
Long-term systemic oral DNEL
Individual assessment factors of 1 (for dose-response relationship), 1 (for duration of exposure), 4 (for allometric scaling), 2.5 (for other interspecies differences), 10 (for intraspecies differences), 1 (for database quality) and 1 (for remaining uncertainties) are combined to give an overall assessment factor of 100. Application of the overall assessment factor to the oral NOAEL results in a DNEL of 2 mg/kg bw/d. An assessment factor is not used to take into account the relatively short duration of exposure in the developmental toxicity study as the 90-day study identifies a NOAEL of 1000 mg/kg bw/d. This gives an adequate margin of safety for potential chronic exposures.
Short-term systemic oral DNEL
Long-term systemic DNEL values are derived from the NOAEL for embryofoetal toxicity from the rat developmental toxicity study. Although, theoretically, effects could occur from a single exposure in a susceptible window, REACH Guidance (Chapter R8) notes that the conservative nature of the methodology used to derive the long-term DNEL should be sufficient to ensure that adverse effects do not occur following high short-term exposures, which should not result in the daily DNEL value being exceeded. A separate DNEL for acute/short-term exposure is therefore not derived. There is no indication of short-term or acute toxicity from other studies and the substance is not classified for acute toxicity.
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