Methacrylic acid

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

39.3 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

other: ECHA (2012) with substance-specific adaptations

Overall assessment factor (AF):

8.96

Dose descriptor starting point:

NOAEC

Value:

352 mg/m³

Modified dose descriptor starting point:

NOAEC

Value:

177 mg/m³

Explanation for the modification of the dose descriptor starting point:

- Correction of exposure duration in rats (6 hrs/day) to default worker exposure (8 hrs/day) is required.

- Correction for activity driven differences of respiratory volumes in workers compared to workers in rest (10 m3/6.7 m3) is required (both ECHA 2012).

AF for dose response relationship:

1

Justification:

The NOAEC is reliable. No adjustment is required.

AF for differences in duration of exposure:

1.5

Justification:

Specific AF for extrapolation subchronic-chronic exposure: With reference to an equal NOAEC in a rat study with chronic exposure to MMA (Lomax 1997), an aggravation of systemic effects over time was not detectable with the used dosing regimens. From this perspective, the application of the default extrapolation factor of 2 appears unjustifiable conservative and a safety margin of 50% to the experimental situation is considered as scientifically appropriate to address precautionary aspects.

AF for interspecies differences (allometric scaling):

1

Justification:

No allometric scaling rat to humans required for inhalation (ECHA 2012).

AF for other interspecies differences:

1

Justification:

not indicated

AF for intraspecies differences:

3

Justification:

Standard metabolism involving ubiquitous and general metabolic pathways (TCA/ valine pathway) makes a lower variability likely, hence the AF of 3 for workers is sufficiently conservative.

AF for the quality of the whole database:

1

Justification:

The key study is of high quality, being rated K1. No adjustment is required.

AF for remaining uncertainties:

1

Justification:

Due to the known metabolism of MAA via general metabolic pathways that are common and very similar to rodents and humans and the absence of any specific target organs indicating a specific MOA at high concentrations there is no reason to believe that an additional AF of 2.5 for remaining differences is justified. Moreover, the adversity of the unspecific effects on body weights and food consumption is not clear so that the NOAEC is rather conservative.

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

acute toxicity

Route of original study:

By inhalation

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

44 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

other: ECHA (2012) with substance-specific adaptations

Overall assessment factor (AF):

8

Dose descriptor:

NOAEC

Value:

352 mg/m³

AF for dose response relationship:

1

Justification:

The NOAEC is reliable. No adjustment is required.

AF for differences in duration of exposure:

2

Justification:

Default AF for extrapolation subchronic-chronic exposure (ECHA 2012).

AF for interspecies differences (allometric scaling):

1

Justification:

No additional adjustment required when setting an inhalation DNEL based on an inhalation study (ECHA 2012).

AF for other interspecies differences:

1.33

Justification:

- Correction of exposure duration in rats (6 hrs/day) to default worker exposure (8 hrs/day) is required.
-Correction for activity driven differences of respiratory volumes in workers compared to workers in rest (10 m3/6.7 m3; as for systemic effects) is not required (ECHA 2012) because it is a local, concentration-driven effect.

AF for intraspecies differences:

3

Justification:

Standard metabolism involving ubiquitous and general metabolic pathways (TCA/ valine pathway) makes a lower variability likely, hence the AF of 3 for workers is sufficiently conservative.

AF for the quality of the whole database:

1

Justification:

The key study is of high quality. No adjustment is required.

AF for remaining uncertainties:

1

Justification:

No adjustment is required. Considering the investigations on PBPK modelling on methacrylate esters and MAA of Jones (2002) it is understood that the human nasal olfactory epithelium as target tissue is significantly less sensitive than that of rats. Thus, the use of rat data is sufficiently conservative for human risk assessment.

Acute/short term exposure

Hazard assessment conclusion:

high 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:

4.25 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

other: ECHA (2012) with substance-specific adaptations

Overall assessment factor (AF):

24

Dose descriptor starting point:

NOAEC

Value:

352 mg/m³

Modified dose descriptor starting point:

NOAEL

Value:

102 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

- AF of 1 for route-to-route extrapolation (ECHA 2012)

- Correction factor of 0.29 m³/kg for rat standard breathing volume for 6h (ECHA R8 guidance p. 20, ECHA 2012)

AF for dose response relationship:

1

Justification:

The NOAEC is reliable. No adjustment is required.

AF for differences in duration of exposure:

2

Justification:

Default AF for extrapolation subchronic-chronic exposure (ECHA 2012).

AF for interspecies differences (allometric scaling):

4

Justification:

Default AF for allometric scaling rat to humans (ECHA 2012).

AF for other interspecies differences:

1

Justification:

not indicated

AF for intraspecies differences:

3

Justification:

Standard metabolism involving ubiquitous and general metabolic pathways (TCA/ valine pathway) makes a lower variability likely, hence the AF of 3 for workers is sufficiently conservative.

AF for the quality of the whole database:

1

Justification:

The key study is of high quality, being rated K1. No adjustment is required.

AF for remaining uncertainties:

1

Justification:

Due to the known metabolism of MAA via general metabolic pathways that are common and very similar to rodents and humans and the absence of any specific target organs indicating a specific MOA at high concentrations there is no reason to believe that an additional AF of 2.5 for remaining differences is justified. Moreover, the adversity of the unspecific effects on body weights and food consumption is not clear so that the NOAEC is rather conservative.

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

acute toxicity

Route of original study:

Dermal

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.38 mg/cm²

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

DNEL derivation method:

other: ECHA (2012) with substance-specific adaptations

Overall assessment factor (AF):

18

Dose descriptor:

NOAEC

Value:

6.9 mg/m³

AF for dose response relationship:

1

Justification:

The NOAEC is reliable. No adjustment is required.

AF for differences in duration of exposure:

3

Justification:

Specific AF for extrapolation “below subacute” (9 treatments within 21d period) to chronic exposure considering a relatively weak progression of irritative effects over time in “below subacute” treatment groups with acetone as solvent (alternative treatment in the same study).

AF for interspecies differences (allometric scaling):

1

Justification:

No additional adjustment required when setting an dermal DNEL based on an dermal study (ECHA 2012).

AF for other interspecies differences:

1

Justification:

not indicated

AF for intraspecies differences:

3

Justification:

Standard metabolism involving ubiquitous and general metabolic pathways (TCA/ valine pathway) makes a lower variability likely, hence the AF of 3 for workers is sufficiently conservative.

AF for the quality of the whole database:

2

Justification:

The key studies were of low-moderate quality, thus an additional safety margin of 100% is considered with an AF of 2.

AF for remaining uncertainties:

1

Justification:

(Shaved) mouse skin is considered as more sensitive as human skin so that the mouse model represents a conservative approach for human risk assessment.
Moreover, the exposed skin area in this study is likely larger than the value used in this calculation, thereby leading to a higher local concentration, which is considered as conservative approach.
Finally, it is considered that the mode of action of this acid (i.e. corrosion, including denaturation of dermal proteins) is ubiquitous to all relevant species. Thus, no further uncertainties remain from the MoA perspective.
In total, no adaption is required.

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

high hazard (no threshold derived)

Additional information - workers

WORKER

Short-term exposure (all routes) - local effects

MAA is corrosive and at lower concentrations irritating to tissue. For all routes, acute DNELs have to be derived according to ECHA Guidance on Information Requirements and Chemical Safety Assessment Part E, 2016. However, as valid acute DNELs cannot be quantified with the existing data, a qualitative assessment leads to the assessment of a high hazard for all routes, based on the classification for skin corrosion and eye damage and according to guidance chapter E.3.4.2 and Table E.3-1.

 

Short-term exposure (all routes) - systemic effects

Like for local effects, acute DNELs have to be derived for systemic effects according to ECHA Guidance on Information Requirements and Chemical Safety Assessment Part E, 2016. However, as valid acute DNELs cannot be quantified with the existing data, a qualitative assessment leads to the assessment of

- a low hazard for the inhalative and oral route, based on the Acute toxicity Cat. 4 classifications for these routes; and

-  a moderate hazard for the dermal route, based on the Acute toxicity Cat. 3 classification for this route,

according to guidance chapter E.3.4.2 and Table E.3-1.

 

Long-term exposure (inhalation) - systemic effects

There are two scientific valid approaches to assess the DNEL long-term inhalation/ systemic effects: As point of departure, either the subchronic study with MAA itself (BASF 2008) or the most suitable chronic study with methyl methycrylate (MMA), the metabolic precursor of MAA could be chosen. Here, the reliable study of Lomax (1997) with rats was selected due the lowest NOAEC, thus interpreted as most conservative value. MMA has been shown by Jones (2002, see chapter “Toxicokinetics”) to hydrolyse within <5 min by ubiquitous carboxylesterases to MAA and Methanol, so that MMA can be understood as metabolic precursor of MAA. Based on the available toxicokinetic data, studies with MMA can be used for read across to assess especially systemic toxicity of MAA with a high level of confidence (according to ECHA’s RAAF guidance, scenario #1; detailed read across assessment see target entries in the chapter “Repeated dose toxicity”, for example).

In order to identify the most appropriate DNEL, following information was taken into account:

- both studies have an identical NOAEC with 100 ppm, 352 mg/m3 or, on molar basis, 1.1 mMol/kg bw/d, on the basis of the same type of effect (unspecific bw effects)

- in terms of parameters that are relevant for DNEL calculation, both studies vary only in the exposure period (subchronic vs. chronic)

- The combination of different exposure periods and identical effect levels in the studies indicates that an aggravation of these systemic effects over time is not measurable and thus a default assessment factor of 2 for the extrapolation from subchronic to chronic exposure (ECHA, 2021) is not justified in this case. While an AF of 1 is possible based on data, an AF of 1.5 is considered as sufficiently conservative from a risk assessment perspective as an additional safety margin of 50% is then integrated in the resulting DNEL to address an anticipated weak aggravation over time. From a general perspective, this AF of 1.5 is supported by the investigations of Batke et al. (2011; Evaluation of time extrapolation factors based on the database RepDose. Toxicol Lett.; 205(2):122-129) that found a subchronic-chronic extrapolation factor of 1.4 using a broad chemical database.

Description	Value/ factor	Remark
Step 1) Relevant dose-descriptor	352 mg/m³ (100 ppm)	NOAEC in 6h/day, 5days/week, 90d inhalation study in rats (BASF 2008) based on unspecific effects on body weight and food consumption.
Step 2) Modification of starting point	8/6     10 m3/6.7 m3	- Correction of exposure duration in rats (6 hrs/day) to default worker exposure (8 hrs/day) is required. - Correction for activity driven differences of respiratory volumes in workers compared to workers in rest (10 m3/6.7 m3) is required (ECHA 2012).
NAEC worker	ca. 177 mg/m³ (50 ppm)
Step 3) Assessment factors
Interspecies	1	No allometric scaling rat to humans required for inhalation (ECHA 2012).
Intraspecies	3	Standard metabolism involving ubiquitous and general metabolic pathways (TCA/ valine pathway) makes a lower intraspecies variability likely, hence the AF of 3 for workers is sufficiently conservative.
Exposure duration	1.5	Specific AF for extrapolation subchronic-chronic exposure: With reference to an equal NOAEC in a rat study with chronic exposure to MMA (Lomax 1997), an aggravation of systemic effects over time was not detectable with the used dosing regimens. From this perspective, the application of the default extrapolation factor of 2 appears unjustifiable conservative and a safety margin of 50% to the experimental situation is considered as scientifically appropriate to address precautionary aspects.
Dose response	1	The NOAEC is reliable. No adjustment is required.
Quality of database	1	The key study is of high quality, being rated K1. No adjustment is required.
Remaining uncertainties	1	Due to the known metabolism of MAA via general metabolic pathways that are common and very similar to rodents and humans and the absence of any specific target organs indicating a specific MOA at high concentrations there is no reason to believe that an additional AF of 2.5 for remaining differences is justified. Moreover, the adversity of the unspecific effects on body weights and food consumption is not clear so that the selected NOAEC as starting point is rather conservative.
Overall AF	4.5
DNEL
Based on NOAEC of 352 mg/m3 (100 ppm) in a 6h/day, 5days/week 90 d inhalation study in rats (BASF 2008).	ca. 39.3 mg/m³ (11.1 ppm)	Using a total factor (POD modifier and AF) of 8.96 (8/6 x 10/6.7 x 4.5) a DNEL long-term systemic, inhal, worker of ca. 39.3 mg/m³ (11.1 ppm) is derived.

 

 

Long-term exposure (inhalation) - local effects

For local effects, the subchronic rat study with the corrosive MAA is the preferred point of departure. Potential alterative point of departures are chronic studies with the metabolic precursor MMA were considered as directly relevant.

Description	Value/ factor	Remark
Step 1) Relevant dose-descriptor	352 mg/m³ (100 ppm)	NOAEC in 6h/day, 5days/week, 90d inhalation study in rats (BASF 2008) based on hypertrophy/hyperplasia of the respiratory epithelium in the nasal cavity.
Step 2) Modification of starting point	8/6	- Correction of exposure duration in rats (6 hrs/day) to default worker exposure (8 hrs/day) is required. -Correction for activity driven differences of respiratory volumes in workers compared to workers in rest (10 m3/6.7 m3; as for systemic effects) is not required (ECHA 2012) because it is a local, concentration-driven effect.
NAEC worker	ca. 264 mg/m³ (75 ppm)
Step 3) Assessment factors
Interspecies	1	No additional adjustment required when setting an inhalation DNEL based on an inhalation study (ECHA 2012).
Intraspecies	3	Standard metabolism involving ubiquitous and general metabolic pathways (TCA/ valine pathway ) makes a lower variability likely, hence the AF of 3 for workers is sufficiently conservative.
Exposure duration	2	Default AF for extrapolation subchronic-chronic exposure (ECHA 2012).
Dose response	1	The NOAEC is reliable. No adjustment is required.
Quality of database	1	The key study is of high quality. No adjustment is required.
Remaining uncertainties	1	No adjustment is required. Considering the investigations on PBPK modelling on methacrylate esters and MAA of Jones (2002) it is understood that the human nasal olfactory epithelium as target tissue is significantly less sensitive than that of rats. Thus, the use of rat data is sufficiently conservative for human risk assessment.
Overall AF	6
DNEL
Based on NOAEC of 352 mg/m3 (100 ppm) in 6h/day, 5days/week 90 d inhalation study in rats (BASF 2008).	ca. 44 mg/m³ (12.5 ppm)	Using a total factor (POD modifier and AF) of 8 (8/6x3x2) a DNEL long-term local, inhal, worker of ca. 44 mg/m³ (12.5 ppm) is derived.

 

 Long-term exposure - systemic effects - dermal exposure

There is no study available that investigated systemic effects after dermal exposure. Thus, there are two scientific valid approaches to assess the DNEL long-term dermal/ systemic effects: As point of departure, either the subchronic inhalation study with MAA itself (BASF 2008) or the chronic drinking water study with methyl methycrylate (MMA), the metabolic precursor of MAA (Borzelleca, 1964). MMA has been shown by Jones (2002, see chapter “Toxicokinetics”) to hydrolyse within <5 min by ubiquitous carboxylesterases to MAA and Methanol, so that MMA can be understood as metabolic precursor of MAA. Based on the available toxicokinetic data, studies with MMA can be used for read across to assess especially systemic toxicity of MAA with a high level of confidence (according to ECHA’s RAAF guidance, scenario #1; detailed read across assessment see target entries in the chapter “Repeated dose toxicity”, for example).

Using appropriate assessment factors, separate DNEL calculations for each approach have been performed to define the most reliable DNEL. While both approaches ended with DNELs in the same order of magnitude and thereby increase the level of confidence in the calculations itself, the approach with the subchronic MAA study provided the somewhat lower DNEL. Understood as most conservative approach, this DNEL was thus considered for further risk assessment.

 

Approach #1: 90 d rat study with MAA

Description	Value/ factor	Remark
Step 1) Relevant dose-descriptor	352 mg/m³	NOAEC in 6h/day, 5days/week, 90d inhalation study in rats (BASF 2008) based on unspecific effects on body weight and food consumption.
Step 2) Modification of starting point	1   0.29 m^3/kg	Route-to-route extrapolation (ECHA 2012)   Correction for rat standard breathing volume for 6h (ECHA R8 guidance p. 20, ECHA 2012)
NAEL worker	ca. 102 mg/kg/d
Step 3) Assessment factors
Interspecies	4	Default allometric scaling rat to humans AF 4 (ECHA 2012).
Intraspecies	3	Standard metabolism involving ubiquitous and general metabolic pathways (TCA/ valine pathway ) makes a lower variability likely, hence the AF of 3 for workers is sufficiently conservative.
Exposure duration	2	Default AF for extrapolation subchronic-chronic exposure (ECHA 2012).
Dose response	1	The NOAEC is reliable. No adjustment is required.
Quality of database	1	The key study is of high quality, being rated K1. No adjustment is required.
Remaining uncertainties	1	Due to the known metabolism of MAA via general metabolic pathways that are common and very similar to rodents and humans and the absence of any specific target organs indicating a specific MOA at high concentrations there is no reason to believe that an additional AF of 2.5 for remaining differences is justified. Moreover, the adversity of the unspecific effects on body weights and food consumption is not clear so that the NOAEC is rather conservative.
Overall AF	24
DNEL
Based on NOAEC of 352 mg/m3 (100 ppm) in 6h/day, 5days/week 90 d inhalation study in rats (BASF 2008).	ca. 4.25 mg/kg/d	Using a total assessment factor 24 (4x3x2) a DNEL long-term systemic, dermal, worker of ca. 4.25 mg/kg/d is derived.

 

(Approach #2 – supporting information): 2 y rat study with the metabolic precursor MMA

Description	Value/ factor	Remark
Step 1) Relevant dose-descriptor	NOAEL 107 mg/kg/d	NOAEL in a 2yr drinking water study in rats with the metabolic precursor (Borcelleca 1964) representing the highest tested dose. NOAEL of 2000 ppm corresponds to 1.12 mMol/kg/d in male rats considering their fluid comsumption and body weight. This molar level is further transferred to 107 mg MAA/kg/d considering the molecular weight of 86 g MAA/ mol
Step 2) Modification of starting point	1	Oral to dermal route-to-route extrapolation (ECHA 2012).
NAEL worker (mg/kg bw/d)	107 mg/kg/d
Step 3) Assessment factors
Interspecies	4	Allometric scaling rat to humans AF 4 (ECHA 2012).
Intraspecies	3	Standard metabolism involving ubiquitous and general metabolic pathways (TCA/ valine pathway ) makes a lower variability likely, hence the AF of 3 for workers is sufficiently conservative.
Exposure duration	1	No adjustment is required. The key study is a chronic two year dw study in rats.
Dose response	1	The NOAEL is reliable. No adjustment is required.
Quality of database	1	The key studies were of high quality, being rated K2. No adjustment is required.
Remaining uncertainties	1	Due to the known metabolism of MMA via general metabolic pathways that are common and very similar to rodents and humans and the absence of any specific target organs indicating a specific MOA at high concentrations there is no reason to believe that an additional AF of 2.5 for remaining differences is justified.
Overall AF	12
DNEL
based on NOAELrat of 2000 ppm in drinking water = 1.12 mMol/kg bw/day	ca. 8.9 mg/kg bw/d	Using a total AF of 12 (4x3) a DNELlong-term systemic. dermal, worker of ca. 8.9 mg/kg bw/d is derived.

 

Long-term exposure (dermal) - local effects

For local effects, there is an older dermal mouse study with several limitations available as point of departure (Rohm & Haas 1986). Here, no local effects were observed in male ICR mice after nine-time treatment with 100 µL aqueous solutions of 4.8% MAA or 0.56 M MAA within a 21-day period, in absence of further experimental details. This concentration is considered as NOAEC, for mice skin that was likely shaved. In treatment groups with acetone at the same or higher concentrations, slight to moderate irritative effects were observed that however do remain stable over time in terms of severity from treatment 3 to 9, thus indicating that a progression of effects with increasing exposure period is relatively low, at least during subacute treatment periods. In absence of  dermal treatment details, a local dermal concentration is derived considering

• No publications were identified using ICR mice in dermal toxicity studies so that no direct information transfer can be made


• A standard exposure area for rodents (rats) in OECD guidelines for the dermal route (TG 402 & TG 410) suggests 10% of the body surface as appropriate exposure area


• A default body surface of mice being 0.007 m2 according to Nair & Jacob (2016; A simple practice guide for dose conversion between animals and human J Basic Clin Pharm. March 2016-May 2016; 7(2): 27–31)


•  


• Male ICR mice had a significantly higher bw in the study than mentioned in the Nair & Jacob paper (i.e. 30-36 g), thus a higher body surface area is very likely. As the impact of on the surface area cannot be assessed quantitatively, 0.007 m2 = 70 cm2 are considered for further calculations. This value represents an conservative approach as the calculated local concentration will be higher than the actual one in the Rohm & Haas study.


• 7cm2 is considered as treatment area (10% of 70 cm2)


• 2 mg/100 µL are considered as treatment dose (0.56 M MAA corresponds to 48.2 g/L considering 86 g MAA/mol)


• 9 mg/cm2 are considered as local doses and as NOAEC

Description	Value/ factor	Remark
Step 1) Relevant dose-descriptor	NOAEC 6.9 mg/cm2	NOAEC in an exploratory dermal irritation study with 9 treatments over 21 days in mice (Rohm & Haas 1986). NOAEC has been derived from a molar concentration of 0.56 M MAA, a dose of 100 µL, an estimated tenth part of estimated surface area of 70 cm2 and a molar weight of 86 g MAA/ mol
Step 2) Modification of starting point	1	Dermal study – no route-to-route adjustment required.
NAEC worker (mg/cm2)	6.9 mg/cm2
Step 3) Assessment factors
Interspecies	1	No additional adjustment required when setting a dermal DNEL based on an dermal study (ECHA 2012).
Intraspecies	3	Standard metabolism involving ubiquitous and general metabolic pathways (TCA/ valine pathway ) makes a lower variability likely, hence the AF of 3 for workers is sufficiently conservative.
Exposure duration	3	Specific AF for extrapolation “below subacute” (9 treatments within 21d period) to chronic exposure considering a relatively  weak progression of irritative effects over time in “below subacute” treatment groups with acetone as solvent (alternative treatment in the same study).
Dose response	1	The NOAEC is reliable. No adjustment is required.
Quality of database	2	The key studies were of low-moderate quality, thus an additional safety margin of 100% is considered with an AF of 2.
Remaining uncertainties	1	(Shaved) mouse skin is considered as more sensitive as human skin so that the mouse model represents a conservative approach for human risk assessment. Moreover, the exposed skin area in this study is likely larger than the value used in this calculation, thereby leading to a higher local concentration, which is considered as conservative approach. Finally, it is considered that the mode of action of this acid (i.e. corrosion, including denaturation of dermal proteins) is ubiquitous to all relevant species. Thus, no further uncertainties remain from the MoA perspective. In total, no adaption is required.
Overall AF	18
DNEL
based on NOAEC mouse of 6.9 mg/cm2	ca. 0.38 mg/cm2	Using a total AF of 18 (3x3x2) a DNELlong-term local, dermal, worker of ca. 0.38 mg/cm2 is derived.

 

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

11.7 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

other: ECHA (2012) with substance-specific adaptations

Overall assessment factor (AF):

30

Dose descriptor starting point:

NOAEC

Value:

352 mg/m³

Modified dose descriptor starting point:

NOAEC

Value:

88 mg/m³

Explanation for the modification of the dose descriptor starting point:

Correction of exposure duration in rats (6 hrs/day) to default general poulation exposure (24 hrs/day) is required.

AF for dose response relationship:

1

Justification:

The NOAEC is reliable. No adjustment is required.

AF for differences in duration of exposure:

1.5

Justification:

Specific AF for extrapolation subchronic-chronic exposure: With reference to an equal NOAEC in a rat study with chronic exposure to MMA (Lomax 1997), an aggravation of systemic effects over time was not detectable with the used dosing regimens. From this perspective, the application of the default extrapolation factor of 2 appears unjustifiable conservative and a safety margin of 50% to the experimental situation is considered as scientifically appropriate to address precautionary aspects.

AF for interspecies differences (allometric scaling):

1

Justification:

No allometric scaling rat to humans required for inhalation (ECHA 2012).

AF for other interspecies differences:

1

Justification:

not indicated

AF for intraspecies differences:

5

Justification:

Standard metabolism involving ubiquitous and general metabolic pathways (TCA/ valine pathway) makes a lower variability likely, hence the AF of 5 for the general population is sufficiently conservative.

AF for the quality of the whole database:

1

Justification:

The key study is of high quality, being rated K1. No adjustment is required.

AF for remaining uncertainties:

1

Justification:

Due to the known metabolism of MAA via general metabolic pathways that are common and very similar to rodents and humans and the absence of any specific target organs indicating a specific MOA at high concentrations there is no reason to believe that an additional AF of 2.5 for remaining differences is justified. Moreover, the adversity of the unspecific effects on body weights and food consumption is not clear so that the NOAEC is rather conservative.

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

acute toxicity

Route of original study:

By inhalation

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

8.8 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

other: ECHA (2012) with substance-specific modifications

Overall assessment factor (AF):

40

Dose descriptor:

NOAEC

Value:

352 mg/m³

AF for dose response relationship:

1

Justification:

The NOAEC is reliable. No adjustment is required.

AF for differences in duration of exposure:

2

Justification:

Default AF for extrapolation subchronic-chronic exposure (ECHA 2012).

AF for interspecies differences (allometric scaling):

1

Justification:

No additional adjustment required when setting an inhalation DNEL based on an inhalation study (ECHA 2012).

AF for other interspecies differences:

4

Justification:

Correction of exposure duration in rats (6 hrs/day) to default general population exposure (24 hrs/day) is required.

AF for intraspecies differences:

5

Justification:

Standard metabolism involving ubiquitous and general metabolic pathways (TCA/ valine pathway) makes a lower variability likely, hence the AF of 5 for the general population is sufficiently conservative.

AF for the quality of the whole database:

1

Justification:

The key study is of high quality. No adjustment is required.

AF for remaining uncertainties:

1

Justification:

No adjustment is required. Considering the investigations on PBPK modelling on methacrylate esters and MAA of Jones (2002) it is understood that the human nasal olfactory epithelium as target tissue is significantly less sensitive than that of rats. Thus, the use of rat data is sufficiently conservative for human risk assessment.

Acute/short term exposure

Hazard assessment conclusion:

high 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:

5.35 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECHA (2012) with substance-specific adaptations

Overall assessment factor (AF):

20

Dose descriptor starting point:

NOAEL

Value:

107 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

107 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Default oral to dermal route-to-route extrapolation (ECHA 2012).

AF for dose response relationship:

1

Justification:

The NOAEL is reliable. No adjustment is required.

AF for differences in duration of exposure:

1

Justification:

No adjustment is required. The key study is a chronic two year dw study in rats.

AF for interspecies differences (allometric scaling):

4

Justification:

Default AF for allometric scaling rat to humans (ECHA 2012).

AF for other interspecies differences:

1

Justification:

not indicated

AF for intraspecies differences:

5

Justification:

Standard metabolism involving ubiquitous and general metabolic pathways (ester hydrolysis followed by TCA/ valine pathway) makes a lower variability likely, hence the AF of 5 for the general population is sufficiently conservative.

AF for the quality of the whole database:

1

Justification:

The key studies were of high quality, being rated K2. No adjustment is required.

AF for remaining uncertainties:

1

Justification:

Due to the known metabolism of MMA and MAA via general metabolic pathways that are common and very similar to rodents and humans and the absence of any specific target organs indicating a specific MOA at high concentrations there is no reason to believe that an additional AF of 2.5 for remaining differences is justified.

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

acute toxicity

Route of original study:

Dermal

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.23 mg/cm²

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

DNEL derivation method:

other: ECHA (2012) with substance-specific adaptations

Overall assessment factor (AF):

30

Dose descriptor:

NOAEC

Value:

6.9 mg/L

AF for dose response relationship:

1

Justification:

The NOAEL is reliable. No adjustment is required.

AF for differences in duration of exposure:

3

Justification:

Specific AF for extrapolation subacute-chronic exposure considering a relatively weak progression of irritative effects over time in subacute treatment groups with acetone as solvent.

AF for interspecies differences (allometric scaling):

1

Justification:

No additional adjustment required when setting an dermal DNEL based on an dermal study (ECHA 2012).

AF for other interspecies differences:

1

Justification:

not indicated

AF for intraspecies differences:

5

Justification:

Standard metabolism involving ubiquitous and general metabolic pathways (TCA/ valine pathway) makes a lower variability likely, hence the AF of 5 for the general population is sufficiently conservative.

AF for the quality of the whole database:

1.5

Justification:

The key studies were of low-moderate quality, thus an additional safety margin of 100% is considered with an AF of 2

AF for remaining uncertainties:

1

Justification:

(Shaved) mouse skin is considered as more sensitive as human skin so that the mouse model represents a conservative approach for human risk assessment.
Moreover, the exposed skin area in this study is likely larger than the value used in this calculation, thereby leading to a higher local concentration, which is considered as conservative approach.
Finally, it is considered that the mode of action of this acid (i.e. corrosion, including denaturation of dermal proteins) is ubiquitous to all relevant species. Thus, no further uncertainties remain from the MoA perspective.
In total, no adaption is required.

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

5.35 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECHA (2012) with substance-specific adaptations

Overall assessment factor (AF):

20

Dose descriptor starting point:

NOAEL

Value:

107 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

107 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Oral study - no route-to-route extrapolation required.

AF for dose response relationship:

1

Justification:

The NOAEL is reliable. No adjustment is required.

AF for differences in duration of exposure:

1

Justification:

No adjustment is required. The key study is a chronic two year dw study in rats.

AF for interspecies differences (allometric scaling):

4

Justification:

Default AF for allometric scaling rat to humans (ECHA 2012).

AF for other interspecies differences:

1

Justification:

not indicated

AF for intraspecies differences:

5

Justification:

Standard metabolism involving ubiquitous and general metabolic pathways (ester hydrolysis followed by TCA/ valine pathway) makes a lower variability likely, hence the AF of 5 for the general population is sufficiently conservative.

AF for the quality of the whole database:

1

Justification:

The key study is of high quality. No adjustment is required.

AF for remaining uncertainties:

1

Justification:

Due to the known metabolism of MMA and MAA via general metabolic pathways that are common and very similar to rodents and humans and the absence of any specific target organs indicating a specific MOA at high concentrations there is no reason to believe that an additional AF of 2.5 for remaining differences is justified.

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

acute toxicity

Route of original study:

Oral

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

high hazard (no threshold derived)

Additional information - General Population

GENERAL POPULATION

The considerations on appropriate points of departure for the particular endpoints/ DNELs are the same as for workers. Therefore, please refer to the workers part for a specific discussion of the rationale for the particular DNELs/ endpoints.

 

Long-term exposure (inhalation) - systemic effects

Description	Value/ factor	Remark
Step 1) Relevant dose-descriptor	352 mg/m³ (100 ppm)	NOAEC in 6h/day, 5days/week, 90d inhalation study in rats (BASF 2008) based on unspecific effects on body weight and food consumption.
Step 2) Modification of starting point	24/6	Correction of exposure duration in rats (6 hrs/day) to default general poulation exposure (24 hrs/day) is required.
NAEC worker	ca. 88 mg/m³ (25 ppm)
Step 3) Assessment factors
Interspecies	1	No allometric scaling rat to humans required for inhalation (ECHA 2012).
Intraspecies	5	Standard metabolism involving ubiquitous and general metabolic pathways (TCA/ valine pathway ) makes a lower variability likely, hence the AF of 5 for the general population is sufficiently conservative.
Exposure duration	1.5	Specific AF for extrapolation subchronic-chronic exposure: With reference to an equal NOAEC in a rat study with chronic exposure to MMA (Lomax 1997), an aggravation of systemic effects over time was not detectable with the used dosing regimens. From this perspective, the application of the default extrapolation factor of 2 appears unjustifiable conservative and a safety margin of 50% to the experimental situation is considered as scientifically appropriate to address precautionary aspects.
Dose response	1	The NOAEC is reliable. No adjustment is required.
Quality of database	1	The key study is of high quality, being rated K1. No adjustment is required.
Remaining uncertainties	1	Due to the known metabolism of MAA via general metabolic pathways that are common and very similar to rodents and humans and the absence of any specific target organs indicating a specific MOA at high concentrations there is no reason to believe that an additional AF of 2.5 for remaining differences is justified. Moreover, the adversity of the unspecific effects on body weights and food consumption is not clear so that the selected NOAEC as starting point is rather conservative.
Overall AF	7.5
DNEL
Based on NOAEC of 352 mg/m3 (100 ppm) in 6h/day, 5days/week 90 d inhalation study in rats (BASF 2008).	ca. 11.7 mg/m³ (3.3 ppm)	Using a total factor (POD modifier and AF) of 30 (24/6x7.5) a DNEL long-term systemic, inhal, general pop. of ca. 11.7 mg/m³ (3.3 ppm) is derived.

 

Long-term exposure (inhalation) - local effects

Description	Value/ factor	Remark
Step 1) Relevant dose-descriptor	352 mg/m³ (100 ppm)	NOAEC in 6h/day, 5days/week, 90d inhalation study in rats (BASF 2008) based on hypertrophy/hyperplasia of the respiratory epithelium in the nasal cavity.
Step 2) Modification of starting point	24/6	Correction of exposure duration in rats (6 hrs/day) to default general population exposure (24 hrs/day) is required.
NAEC worker	ca. 88 mg/m³ (25 ppm)
Step 3) Assessment factors
Interspecies	1	No additional adjustment required when setting an inhalation DNEL based on an inhalation study (ECHA 2012).
Intraspecies	5	Standard metabolism involving ubiquitous and general metabolic pathways (TCA/ valine pathway ) makes a lower variability likely, hence the AF of 5 for the general population  is sufficiently conservative.
Exposure duration	2	Default AF for extrapolation subchronic-chronic exposure (ECHA 2012).
Dose response	1	The NOAEC is reliable. No adjustment is required.
Quality of database	1	The key study is of high quality. No adjustment is required.
Remaining uncertainties	1	No adjustment is required. Considering the investigations on PBPK modelling on methacrylate esters and MAA of Jones (2002) it is understood that the human nasal olfactory epithelium as target tissue is significantly less sensitive than that of rats. Thus, the use of rat data is sufficiently conservative for human risk assessment.
Overall AF	10
DNEL
Based on NOAEC of 352 mg/m3 (100 ppm) in 6h/day, 5days/week 90 d inhalation study in rats (BASF 2008).	ca. 8.8 mg/m³ (2.5 ppm)	Using a total factor (POD modifier and AF) of 40 (24/6x5x2) a DNEL long-term local, inhal, general pop. of ca. 8.8 mg/m³ (2.5 ppm) is derived.

 

 Long-term exposure - systemic effects - dermal exposure

Understood as most conservative approach for the general population, the DNEL using the chronic oral MMA study as point of departure was considered for further risk assessment, while the alternative DNEL with the subchronic inhalation study with MAA is used as supporting information.

 

Approach #1: 2 y rat study with the metabolic precursor MMA

Description	Value/ factor	Remark
Step 1) Relevant dose-descriptor	NOAEL 107 mg/kg/d	NOAEL in a 2yr drinking water study in rats with the metabolic precursor (Borcelleca 1964) representing the highest tested dose. NOAEL of 2000 ppm corresponds to 1.12 mMol/kg/d in male rats considering their fluid comsumption and body weight. This molar level is further transferred to 107 mg MAA/kg/d considering the molecular weight of 86 g MAA/ mol
Step 2) Modification of starting point	1	Default oral to dermal route-to-route extrapolation (ECHA 2012).
NAEL worker (mg/kg bw/d)	107 mg/kg/d
Step 3) Assessment factors
Interspecies	4	Allometric scaling rat to humans AF 4 (ECHA 2012).
Intraspecies	5	Standard metabolism involving ubiquitous and general metabolic pathways (ester hydrolysis followed by TCA/ valine pathway ) makes a lower variability likely, hence the AF of 5 for the general population is sufficiently conservative.
Exposure duration	1	No adjustment is required. The key study is a chronic two year dw study in rats.
Dose response	1	The NOAEL is reliable. No adjustment is required.
Quality of database	1	The key studies were of high quality, being rated K2. No adjustment is required.
Remaining uncertainties	1	Due to the known metabolism of MMA and MAAvia general metabolic pathways that are common and very similar to rodents and humans and the absence of any specific target organs indicating a specific MOA at high concentrations there is no reason to believe that an additional AF of 2.5 for remaining differences is justified.
Overall AF	20
DNEL
based on NOAELrat of 2000 ppm in drinking water = 1.12 mMol/kg bw/day	ca. 5.35 mg/kg bw/d	Using a total AF of 20 (4x5) a DNELlong-term systemic, dermal, general pop. of ca. 5.35 mg/kg bw/d is derived.

 

(Approach #2 – supporting information): 90 d rat study with MAA

Description	Value/ factor	Remark
Step 1) Relevant dose-descriptor	352 mg/m³	NOAEC in 6h/day, 5days/week, 90d inhalation study in rats (BASF 2008) based on unspecific effects on body weight and food consumption.
Step 2) Modification of starting point	1   1.15 m^3/kg	Route-to-route extrapolation (ECHA 2012)   Correction for rat standard breathing volume for 24h (ECHA R8 guidance p. 20, ECHA 2010)
NAEL worker	ca. 405 mg/kg/d
Step 3) Assessment factors
Interspecies	4	Default AF for allometric scaling rat to humans (ECHA 2012).
Intraspecies	5	Standard metabolism involving ubiquitous and general metabolic pathways (TCA/ Valine pathway) makes a lower variability likely, hence the AF of 5 for the general population is sufficiently conservative.
Exposure duration	2	Default AF for extrapolation subchronic-chronic exposure (ECHA 2012).
Dose response	1	The NOAEC is reliable. No adjustment is required.
Quality of database	1	The key study is of high quality. No adjustment is required.
Remaining uncertainties	1	Due to the known metabolism of MAA via general metabolic pathways that are common and very similar to rodents and humans and the absence of any specific target organs indicating a specific MOA at high concentrations there is no reason to believe that an additional AF of 2.5 for remaining differences is justified. Moreover, the adversity of the unspecific effects on body weights and food consumption is not clear so that the NOAEC is rather conservative.
Overall AF	40
DNEL
Based on NOAEC of 352 mg/m3 (100 ppm) in 6h/day, 5days/week 90 d inhalation study in rats (BASF 2008).	ca. 10.1 mg/kg/d	Using a total assessment factor 40 (4x5x2) a DNEL long-term systemic, dermal, general pop. of ca. 10.1 mg/kg/d is derived.

 

Long-term exposure (dermal) - local effects

Description	Value/ factor	Remark
Step 1) Relevant dose-descriptor	NOAEC 6.9 mg/cm2	NOAEC in an exploratory dermal irritation study with 9 treatments over 21 days in mice (Rohm & Haas 1986). NOAEC has been derived from a molar concentration of 0.56 M MAA, a dose of 100 µL, an estimated tenth part of estimated surface area of 70 cm2 and a molar weight of 86 g MAA/ mol
Step 2) Modification of starting point	1	Dermal study – no route-to-route adjustment required.
NAEC worker (mg/cm2)	6.9 mg/cm2
Step 3) Assessment factors
Interspecies	1	No additional adjustment required when setting an dermal DNEL based on an dermal study (ECHA 2012).
Intraspecies	5	Standard metabolism involving ubiquitous and general metabolic pathways (TCA/ valine pathway) makes a lower variability likely, hence the AF of 5 for the general population  is sufficiently conservative.
Exposure duration	3	Specific AF for extrapolation “below subacute” (9 treatments within 21d period) to chronic exposure considering a relatively  weak progression of irritative effects over time in “below subacute” treatment groups with acetone as solvent (alternative treatment in the same study).
Dose response	1	The NOAEC is reliable. No adjustment is required.
Quality of database	2	The key studies were of low-moderate quality, thus an additional safety margin of 100% is considered with an AF of 2
Remaining uncertainties	1	(Shaved) mouse skin is considered as more sensitive as human skin so that the mouse model represents a conservative approach for human risk assessment. Moreover, the exposed skin area in this study is likely larger than the value used in this calculation, thereby leading to a higher local concentration, which is considered as conservative approach. Finally, it is considered that the mode of action of this acid (i.e. corrosion, including denaturation of dermal proteins) is ubiquitous to all relevant species. Thus, no further uncertainties remain from the MoA perspective. In total, no adaption is required.
Overall AF	30
DNEL
based on NOAEC mouse of 6.9 mg/cm2	ca. 0.23 mg/cm2	Using a total AF of 30 (5x3x2) a DNELlong-term local, dermal, worker of ca. 0.23 mg/cm2 is derived.

 

 

 Long-term exposure - systemic effects – oral exposure

The most appropriate point of departure for this DNEL is the the chronic drinking water study with the metabolic precursor MMA.

 

Description	Value/ factor	Remark
Step 1) Relevant dose-descriptor	NOAEL 107 mg/kg/d	NOAEL in a 2yr drinking water study in rats with the metabolic precursor (Borcelleca 1964) representing the highest tested dose. NOAEL of 2000 ppm corresponds to 1.12 mMol/kg/d in male rats considering their fluid comsumption and body weight. This molar level is further transferred to 107 mg MAA/kg/d considering the molecular weight of 86 g MAA/ mol
Step 2) Modification of starting point	1	Oral study - no route-to-route extrapolation required.
NAEL worker (mg/kg bw/d)	107 mg/kg/d
Step 3) Assessment factors
Interspecies	4	Default AF for allometric scaling rat to humans (ECHA 2012).
Intraspecies	5	Standard metabolism involving ubiquitous and general metabolic pathways (ester hydrolysis followed by TCA/ valine pathway) makes a lower variability likely, hence the AF of 5 for the general population is sufficiently conservative.
Exposure duration	1	No adjustment is required. The key study is a chronic two year dw study in rats.
Dose response	1	The NOAEL is reliable. No adjustment is required.
Quality of database	1	The key studies were of high quality, being rated K2. No adjustment is required.
Remaining uncertainties	1	Due to the known metabolism of MMA and MAA via general metabolic pathways that are common and very similar to rodents and humans and the absence of any specific target organs indicating a specific MOA at high concentrations there is no reason to believe that an additional AF of 2.5 for remaining differences is justified.
Overall AF	20
DNEL
based on NOAELrat of 2000 ppm in drinking water = 1.12 mMol/kg bw/day	ca. 5.35 mg/kg bw/d	Using a total AF of 20 (4x5) a DNELlong-term systemic, oral, general pop. of ca. 5.35 mg/kg bw/d is derived.