Registration Dossier

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
DNEL 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
DNEL 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
DNEL 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
DNEL 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
DNEL 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.