Registration Dossier

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

348.4 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL derivation method:

other: ECHA 2012 & ECETOC 2010

Overall assessment factor (AF):

5.97

Dose descriptor starting point:

NOAEC

Value:

2 080 mg/m³

Modified dose descriptor starting point:

NOAEC

Value:

1 045 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 (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

Justification:

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

AF for interspecies differences (allometric scaling):

1

Justification:

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

AF for other interspecies differences:

1

Justification:

No adjustment is required.

AF for intraspecies differences:

3

Justification:

Standard metabolism involving ubiquitous and general metabolic pathways (ester hydrolysis followed by TCA) makes a lower variability likely, hence the AF of 3 by ECETOC (2010) is sufficiently conservative.

AF for the quality of the whole database:

1

Justification:

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

AF for remaining uncertainties:

1

Justification:

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 not justified.

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

208 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL derivation method:

other: SCOEL

Overall assessment factor (AF):

1

Dose descriptor:

other: SCOEL IOLV

Value:

208 mg/m³

AF for dose response relationship:

1

Justification:

The NOAEC is reliable. No adjustment is required.

AF for differences in duration of exposure:

1

Justification:

No adjustment is required. The key studies were worker health studies on workforces with long employment histories (in excess of 25 yrs in some cases) and full shift (8-hr) work activities.

AF for interspecies differences (allometric scaling):

1

Justification:

No additional adjustment required when setting an inhalation DNEL based on an inhalation study (ECHA 2012). 8h-NOAEC of approximately 50 ppm and 8h-LOAEC “somewhere in excess” of 100 ppm for occupationally exposed workers.

AF for other interspecies differences:

1

Justification:

No adjustment is required.

AF for intraspecies differences:

1

Justification:

No adjustment required. The key studies for SCOEL were large groups of workers.

AF for the quality of the whole database:

1

Justification:

The key studies were of high quality. No adjustment is required.

AF for remaining uncertainties:

1

Justification:

No adjustment is required (SCOEL).

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

416 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL derivation method:

other: SCOEL STEL

Overall assessment factor (AF):

1

Dose descriptor starting point:

NOAEC

Value:

416 mg/m³

AF for dose response relationship:

1

Justification:

The NOAEC is reliable. No adjustment is required.

AF for interspecies differences (allometric scaling):

1

Justification:

No additional adjustment required when setting an inhalation DNEL based on an inhalation study (ECHA 2012). 8h-NOAEC of approximately 50 ppm and 8h-LOAEC “somewhere in excess” of 100 ppm for occupationally exposed workers.

AF for other interspecies differences:

1

Justification:

No additional adjustment required

AF for intraspecies differences:

1

Justification:

No adjustment required. The key studies for SCOEL were large groups of workers.

AF for the quality of the whole database:

1

Justification:

The key studies were of high quality. No adjustment is required.

AF for remaining uncertainties:

1

Justification:

No adjustment is required (SCOEL).

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

13.67 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

other: ECHA and ECETOC

Overall assessment factor (AF):

12

Dose descriptor starting point:

NOAEL

Value:

164 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

164 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Oral to dermal route-to-route extrapolation (ECHA 2012). Conversion to food equivalent using water consumption data.

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:

Allometric scaling rat to humans AF 4 (ECHA 2012).

AF for other interspecies differences:

1

Justification:

No adjustment is required.

AF for intraspecies differences:

3

Justification:

Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases) makes a lower variability likely, hence the AF of 3 by ECETOC (2010) 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 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 not justified.

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.5 mg/cm²

Most sensitive endpoint:

sensitisation (skin)

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

10

Dose descriptor:

other: EC3

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.5 mg/cm²

Most sensitive endpoint:

sensitisation (skin)

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

10

Dose descriptor starting point:

other: EC3

Hazard assessment conclusion:

no hazard identified

WORKER

Since MMA is of low acute toxicity with the median lethal dose values (LD50) being significantly greater than 2000 mg/kg by oral and dermal routes and above 5000 ppm (20800 mg/m³) by inhalation, with the exeption of the acute dermal DNEL the oral and inhalation DNELs derived for long-term exposure are considered sufficiently protective of acute exposure.

Long-term exposure (inhalation) - systemic effects

SCOEL in its review on MMA placed greater emphasis on the local effect in the nasal passages although they did recognize no long term adverse systemic health effects in workers occupationally exposed for many years. In order to verify that this approach was sufficiently protective for systemic effects a long term systemic DNEL has been derived from the available animal data.

During the ESR for methyl methacrylate the observation of reduced body weight gain in repeat dose inhalation studies was discussed and in the absence of definitive food consumption data in these studies it could not be concluded that this effect was a consequence of the local irritation and reduced feeding and was therefore considered a substance-related systemic finding. Subsequent to the completion of the ESR two studies were conducted; a 90 d repeat dose inhalation study with MAA and a 2-generation study with MMA. In which reduced body weight gain effects were observed in both studies and concurrent food and drinking consumption data clearly demonstrated that this effect was not general systemic toxicity.

In the repeated dose section the point of departure for the derivation of the repeat-dose, systemic, DNEL for inhalation was identified as the observation of general toxicity and increasing lethality at 2000 ppm and above in a 14 week inhalation study in rats (Battelle, 1980). The highest no-effect-concentration observed in the 2-year inhalation studies was 500ppm (NTP, 1986).

Description	Value/ factor	Remark
Step 1) Relevant dose-descriptor	2080 mg/m³ (500 ppm)	NOAEC in 6h/day, 5days/week 2 yr inhalation study in rats (NTP, 1986)
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. 1045 mg/m³ (251 ppm)
Step 3) Assessment factors
Interspecies	1	No allometric scaling rat to humans as inhalation (ECHA 2012).
Intraspecies	3	Standard metabolism involving ubiquitous and general metabolic pathways (ester hydrolysis followed by TCA) makes a lower variability likely, hence the AF of 3 by ECETOC (2010) is sufficiently conservative.
Exposure duration	1	No adjustment is required. The key study is a chronic two year inhalation study in rats.
Dose response	1	The NOAEC is reliable. No adjustment is required.
Quality of database	1	The key studies were of high quality, being rated K1. 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 not justified.
Overall AF	3
DNEL
Based on NOAEC of 2080 mg/m3(500 ppm) in 6h/day, 5days/week 2 yr inhalation study in rats (NTP, 1986).	348.4 mg/m³ (83.75 ppm)	Using a total factor (POD modifier and AF) of 5.97 (8/6 x 10/6.7 x 3) a DNEL long-term systemic, inhal, worker of 348.4 mg/m³ (83.75 ppm)is derived.

Long-term exposure (inhalation) - local effects

Animal data

Extensive repeated dose studies have been reported on the inhalation toxicity of MMA. For local effects, the most appropriate value is the NOEL of 25 ppm (102.5 mg/m³) in rats exposed to MMA for 2 years (Rohm & Haas, 1979). Effects at the next higher concentration (100 ppm; 410 mg/m³) were degenerative changes in the olfactory epithelium. The pattern of the critical effects of inhalation of MMA in animal studies (i. e. the olfactory epithelium being affected at lowest concentration) is consistent with toxicity resulting from metabolism of the inhaled material in the olfactory tissue by carboxylic esterases to methacrylic acid. Based on limited data from human tissue samples (that may not have been morphologically normal taken at polyp biopsy), the activity of alpha-naphthylbutyrate carboxylesterase in human nasal respiratory tissue is less than that in the rat (Mattes & Mattes, 1992). In addition, rodents are obligate nose breathers, whereas humans can also breathe through their mouths, which is expected to reduce exposure of the nasal epithelium. There are also differing nasal flow patterns, with the greater airflow across the human olfactory epithelium during the expiratory phase when the vapour concentration would be considerably reduced as a result of absorption in the lower respiratory tract. Furthermore, there are significant morphological differences between species in the structure of the nasal cavity, which result in differences in concentrations of inhaled materials at the nasal tissue. These are reflected in differences in surface area normalized to minute ventilation, being fivefold greater in rodents than in humans (DeSesso, 1993). A much greater percentage of the nasal cavity is lined by olfactory epithelium in rats than in humans.

Therefore, the extrapolation of data on nasal irritation of the olfactory epithelium observed in rodents in local DNEL derivation for humans is considered to be inapplicable and exposure related observations in humans were used for the derivation of the DNEL for workers by long-term inhalation.

Human data

Records of 211 workers from an acrylic sheet production plant almost exclusively exposed to MMA for an average of 8.8 years at 8-hour average concentrations of up to 40 ppm (160 mg/m³) did not show any symptoms of a MMA exposure related rhinopathy or any signs of MMA related abnormalities in the nasal cavity (Röhm 1994; Muttray et al. 1997). Local irritations occurred only at short term peak exposures at concentrations > 100 ppm (420 mg/m³). Based on these data, the national occupational exposure limit (OEL) for MMA inhas been set to 50 ppm (210 mg/m³).

SCOEL reviewed MMA after the EU-ESR and established a health-based occupational exposure limit (SCOEL, 2005). The critical effect identified by SCOEL was focal lesion of the olfactory region of the nasal epithelium in both rats and mice following repeated exposure as a consequence of local metabolism of MMA to methacrylic acid by carboxylesterases in the nasal epithelial cells. For defining the “critical inhalation exposure level at the workplace” a reliable NOAEC of 25 ppm and LOAEC of 100ppm was available from a 2-year inhalation study in rats. SCOEL judged that “extensive” PBPK modelling work predicted that on kinetic grounds, for a given level of exposure to MMA, human nasal olfactory epithelium will be at least 3 times less sensitive than that of rats to the toxicity of MMA. SCOEL also judged that the available studies of workforces provided reassuring evidence that workers exposed to MMA levels of up to approximately 50 ppm (8-hr TWA) have not suffered any respiratory ill-health consequences related to their long-term exposure with the occasional respiratory symptoms reported seem to be clearly connected with short-term peak exposures and the sensory irritant potential of MMA which starts to be expressed at concentrations somewhere in excess of 100 ppm.

Description	Value/ factor	Remark
Step 1) Relevant dose-descriptor	208 mg/m³ (50 ppm)	NOAEC in workers (SCOEL IOLV)
Step 2) Modification of starting point	1	As the human effects data were long term, full-shift duration, worker-health studies no adjustment factors were considered necessary
NAEL worker	208 mg/m³ (50 ppm)
Step 3) Assessment factors
Interspecies	1	No additional adjustment required when setting an inhalation DNEL based on an inhalation study (ECHA 2012). 8h-NOAEC of approximately 50 ppm and 8h-LOAEC “somewhere in excess” of 100 ppm for occupationally exposed workers.
Intraspecies	1	No adjustment required. The key studies for SCOEL were large groups of workers.
Exposure duration	1	No adjustment is required. The key studies were worker health studies on workforces with long employment histories (in excess of 25 yrs in some cases) and full shift (8-hr) work activities.
Dose response	1	The NOAEC is reliable. No adjustment is required.
Quality of database	1	The key studies were of high quality. No adjustment is required.
Remaining uncertainties	1	No adjustment is required (SCOEL).
Overall AF	1
DNEL
Based on a SCOEL IOLV of 50 ppm (8-h TWA)	208 mg/m³ (50 ppm)	Using a total factor (POD modifier and AF) of 1 a DNEL long-term local, inhal, worker of 208 mg/m³ (50 ppm) is derived.

Acute, short-term exposure - local effects - inhalation

Calculation from the weight-of-evidence review of the inhalation toxicity of MMA performed by SCOEL:

The critical effect identified by SCOEL was focal lesion of the olfactory region of the nasal epithelium in both rats and mice following repeated exposure as a consequence of local metabolism of MMA to methacrylic acid by carboxylesterases in the nasal epithelial cells. For defining the “critical inhalation exposure level at the workplace” a reliable NOAEC of 25 ppm and LOAEC of 100ppm was available from a 2-year inhalation study in rats. SCOEL judged that “extensive” PBPK modelling work predicted that on kinetic grounds, for a given level of exposure to MMA, human nasal olfactory epithelium will be at least 3 times less sensitive than that of rats to the toxicity of MMA. SCOEL also judged that the available studies of workforces provided reassuring evidence that workers exposed to MMA levels of up to approximately 50 ppm (8-hr TWA) have not suffered any respiratory ill-health consequences related to their long-term exposure with the occasional respiratory symptoms reported seem to be clearly connected with short-term peak exposures and the sensory irritant potential of MMA which starts to be expressed at concentrations somewhere in excess of 100 ppm. SCOEL concluded further that ‘While there are no data to clearly indicate the threshold concentration above which such irritancy begins to be expressed in humans … irritant concentrations clearly lie above 100 ppm. Hence a STEL of 100 ppm is recommended’.

Description	Value/ factor	Remark
Step 1) Relevant dose-descriptor	416 mg/m³ (100 ppm)	NOAEC in workers (SCOEL STEL)
Step 2) Modification of starting point	1	As the human effects data were long term, full-shift duration, worker-health studies no adjustment factors were considered necessary
NAEL worker	416 mg/m³ (100 ppm)
Step 3) Assessment factors
Interspecies	1	No additional adjustment required when setting an inhalation DNEL based on an inhalation study (ECHA 2012). 8h-NOAEC of approximately 50 ppm and 8h-LOAEC “somewhere in excess” of 100 ppm for occupationally exposed workers.
Intraspecies	1	No adjustment required. The key studies for SCOEL were large groups of workers.
Exposure duration	1	No adjustment is required. The key studies were worker health studies on workforces with long employment histories (in excess of 25 yrs in some cases) and full shift (8-hr) work activities.
Dose response	1	The NOAEC is reliable. No adjustment is required.
Quality of database	1	The key studies were of high quality. No adjustment is required.
Remaining uncertainties	1	No adjustment is required (SCOEL).
Overall AF	1
DNEL
Based on a SCOEL STEL of 100 ppm	416 mg/m³ (100 ppm)	Using a total factor (POD modifier and AF) of 1 a DNEL short-term local , inhal, worker of 416 mg/m³ (100 ppm) is derived.

Long-term exposure - systemic effects - dermal exposure

The most relevant point of departure for the dermal DNEL was identified in a 2-year repeat-dose oral (drinking water) exposure study with MMA in which the NOAEL was 164 mg/kg bw/day (2,000 ppm in drinking water) (Borzelleca et al, 1964).

Description	Value/ factor	Remark
Step 1) Relevant dose-descriptor	NOAEL 2000 ppm	NOAEL for rats (7 days/week) for 2 years
Step 2) Modification of starting point	1	Oral to dermal route-to-route extrapolation (ECHA 2012).
NAEL worker (mg/kg bw/d)	164 mg/kg bw/day	Conversion to food equivalent using water consumption data
Step 3) Assessment factors
Interspecies	4	Allometric scaling rat to humans AF 4 (ECHA 2012).
Intraspecies	3	Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases) makes a lower variability likely, hence the AF of 3 by ECETOC (2010) 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 not justified.
Overall AF	12
DNEL
based on NOAELrat of 2000 ppm in drinking water = 164 mg/kg bw/day	13.67 mg/kg bw/d	Using a total AF of 12 ( 4 x 3 x 1 x 1) a DNELlong-term systemic. dermal, worker of 13.67 mg/kg bw/d is derived.

Acute, short-term and long-term exposure - local effects - dermal

An induction-specific DNEL was derived for skin sensitization based on the EC3 value from a LLNA study (Betts et al., 2006). The sensitisation threshold (EC3 value) was reported to be 60% w/v, indicative of a sensitiser of moderate potency. According to the Guidance on information requirements and chemical safety assessment, Chapter R.8, the EC3 value (in mg/cm²) can be used as a surrogate for the NOAEL for induction. EC3 data generally correlate well with human skin sensitisation thresholds. However, there are cases where this correlation is poor and the two values may differ by 10-fold or more. Therefore, using the default AF of 10 for interspecies variation, the acute dermal DNEL was calculated to be 1.5 mg/cm²/day.

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

74.3 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL derivation method:

other: ECHA and ECETOC

Overall assessment factor (AF):

28

Dose descriptor starting point:

NOAEC

Value:

2 080 mg/m³

Modified dose descriptor starting point:

NOAEC

Value:

371 mg/m³

Explanation for the modification of the dose descriptor starting point:

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

Justification:

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

AF for interspecies differences (allometric scaling):

1

Justification:

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

AF for other interspecies differences:

1

Justification:

No adjustment is required.

AF for intraspecies differences:

1

Justification:

Standard metabolism involving ubiquitous and general metabolic pathways (ester hydrolysis followed by TCA) makes a lower variability likely, hence the AF of 5 by ECETOC (2010) is sufficiently conservative.

AF for the quality of the whole database:

1

Justification:

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

AF for remaining uncertainties:

1

Justification:

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 not justified.

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

104 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL derivation method:

other: SCOEL and ECHA

Overall assessment factor (AF):

2

Dose descriptor:

NOAEC

Value:

208 mg/m³

AF for dose response relationship:

1

Justification:

The NOAEC is reliable. No adjustment is required.

AF for differences in duration of exposure:

1

Justification:

No adjustment is required. The key studies were worker health studies on workforces with long employment histories (in excess of 25 yrs in some cases) and full shift (8-hr) work activities.

AF for interspecies differences (allometric scaling):

1

Justification:

No additional adjustment required when setting an inhalation DNEL based on an inhalation study (ECHA 2012). 8h-NOAEC of approximately 50 ppm and 8h-LOAEC “somewhere in excess” of 100 ppm for occupationally exposed workers.

AF for other interspecies differences:

1

Justification:

No adjustment is required.

AF for intraspecies differences:

2

Justification:

Default AF for extrapolation from workers to general population (ECHA 2012).

AF for the quality of the whole database:

1

Justification:

The key studies were of high quality. No adjustment is required.

AF for remaining uncertainties:

1

Justification:

No adjustment is required (SCOEL).

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

208 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL derivation method:

other: SCOEL & ECHA

Overall assessment factor (AF):

2

Dose descriptor starting point:

NOAEC

Value:

416 mg/m³

AF for dose response relationship:

1

Justification:

No adjustment is required. The NOAEC is reliable.

AF for interspecies differences (allometric scaling):

1

Justification:

No additional adjustment required when setting an inhalation DNEL based on an inhalation study (ECHA 2012). 8h-NOAEC of approximately 50 ppm and 8h-LOAEC “somewhere in excess” of 100 ppm for occupationally exposed workers.

AF for other interspecies differences:

1

Justification:

No adjustment is required.

AF for intraspecies differences:

2

Justification:

Default AF for extrapolation from workers to general population (ECHA 2012).

AF for the quality of the whole database:

1

Justification:

The key studies were of high quality. No adjustment is required.

AF for remaining uncertainties:

1

Justification:

No adjustment is required (SCOEL).

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

8.2 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

other: ECHA & ECETOC

Overall assessment factor (AF):

20

Dose descriptor starting point:

NOAEL

Value:

164 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

164 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Oral to dermal route-to-route extrapolation (ECHA 2012). Conversion to food equivalent using water consumption data

AF for dose response relationship:

1

Justification:

No adjustment is required. The NOAEC is reliable.

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:

Allometric scaling rat to humans AF 4 (ECHA 2012).

AF for other interspecies differences:

1

Justification:

No adjustment is required.

AF for intraspecies differences:

5

Justification:

Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases) makes a lower variability likely, hence the AF of 5 by ECETOC (2010) 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 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 not justified.

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.5 mg/cm²

Most sensitive endpoint:

sensitisation (skin)

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

10

Dose descriptor:

other: EC3

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.5 mg/cm²

Most sensitive endpoint:

sensitisation (skin)

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

10

Dose descriptor starting point:

other: EC3

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

8.2 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

other: ECHA and ECETOC

Overall assessment factor (AF):

20

Dose descriptor starting point:

NOAEL

Value:

164 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

164 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Conversion to food equivalent using water consumption data

AF for dose response relationship:

1

Justification:

No adjustment is required. The NOAEC is reliable.

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):

1

Justification:

Allometric scaling rat to humans AF 4 (ECHA 2012).

AF for other interspecies differences:

1

Justification:

No adjustment is required.

AF for intraspecies differences:

1

Justification:

Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases) makes a lower variability likely, hence the AF of 5 by ECETOC (2010) 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 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 not justified.

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

GENERAL POPULATION

The general points of departure are the same as for workers. Therefore, for a more detailed discussion please refer to the workers part for a specific discussion of the rationale for the particular endpoints.

The details of the calculations with the consumer-specific assessment factors are detailed in the tables below. The points of departure for the consumer assessment deviate from the worker assessment in one point: For the chronic inhalation exposure, the DNEL derived for systemic effects from the chronic inhalation studies (NTP, 1986) is lower than the DNEL for local effects derived from the IOLV by SCOEL. Therefore, the lower DNEL has been carried forward for the risk assessment.

Long-term exposure - systemic effects - inhalation

In the repeated dose section the point of departure for the derivation of the repeat-dose, systemic, DNEL for inhalation was identified as the observation of general toxicity and increasing lethality at 2000 ppm and above in a 14 week inhalation study in rats (Battelle, 1980). The highest no-effect-concentration observed in the 2-year inhalation studies was 500ppm (NTP, 1986).

Description	Value/ factor	Remark
Step 1) Relevant dose-descriptor	2080 mg/m³ (500 ppm)	NOAEC in 6h/day, 5days/week 2 yr inhalation study in rats (NTP, 1986)
Step 2) Modification of starting point	24/6 7/5	Correction of exposure duration in rats (6 hrs/day) to default general population exposure (24 hrs/day) is required.
NAEL worker	ca. 371 mg/m³ (89 ppm)
Step 3) Assessment factors
Interspecies	1	No allometric scaling rat to humans as inhalation (ECHA 2012).
Intraspecies	5	Standard metabolism involving ubiquitous and general metabolic pathways (ester hydrolysis followed by TCA) makes a lower variability likely, hence the AF of 5 by ECETOC (2010) is sufficiently conservative.
Exposure duration	1	No adjustment is required. The key study is a chronic two year inhalation study in rats.
Dose response	1	The NOAEC is reliable. No adjustment is required.
Quality of database	1	The key studies were of high quality, being rated K1. 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 not justified.
Overall AF	5
DNEL
Based on NOAEC of 2080 mg/m3(500 ppm) in 6h/day, 5days/week 2 yr inhalation study in rats (NTP, 1986).	74.3 mg/m³ (17.9 ppm)	Using a total factor (POD modifier and AF) of 28 (24 / 6 x 7 / 5 x 5) a DNEL long-term systemic, inhal, gen pop of 74.3 mg/m³ (17.9 ppm) is derived.

Long-term exposure (inhalation) - local effects

Animal data

Extensive repeated dose studies have been reported on the inhalation toxicity of MMA. For local effects, the most appropriate value is the NOEL of 25 ppm (102.5 mg/m³) in rats exposed to MMA for 2 years (Rohm & Haas, 1979). Effects at the next higher concentration (100 ppm; 410 mg/m³) were degenerative changes in the olfactory epithelium. The pattern of the critical effects of inhalation of MMA in animal studies (i. e. the olfactory epithelium being affected at lowest concentration) is consistent with toxicity resulting from metabolism of the inhaled material in the olfactory tissue by carboxylic esterases to methacrylic acid. Based on limited data from human tissue samples (that may not have been morphologically normal taken at polyp biopsy), the activity of alpha-naphthylbutyrate carboxylesterase in human nasal respiratory tissue is less than that in the rat (Mattes & Mattes, 1992). In addition, rodents are obligate nose breathers, whereas humans can also breathe through their mouths, which is expected to reduce exposure of the nasal epithelium. There are also differing nasal flow patterns, with the greater airflow across the human olfactory epithelium during the expiratory phase when the vapour concentration would be considerably reduced as a result of absorption in the lower respiratory tract. Furthermore, there are significant morphological differences between species in the structure of the nasal cavity, which result in differences in concentrations of inhaled materials at the nasal tissue. These are reflected in differences in surface area normalized to minute ventilation, being fivefold greater in rodents than in humans (DeSesso, 1993). A much greater percentage of the nasal cavity is lined by olfactory epithelium in rats than in humans.

Therefore, the extrapolation of data on nasal irritation of the olfactory epithelium observed in rodents in local DNEL derivation for humans is considered to be inapplicable and exposure related observations in humans were used for the derivation of the DNEL for workers by long-term inhalation.

Human data

Records of 211 workers from an acrylic sheet production plant almost exclusively exposed to MMA for an average of 8.8 years at 8-hour average concentrations of up to 40 ppm (160 mg/m³) did not show any symptoms of a MMA exposure related rhinopathy or any signs of MMA related abnormalities in the nasal cavity (Röhm 1994; Muttray et al. 1997). Local irritations occurred only at short term peak exposures at concentrations > 100 ppm (420 mg/m³). Based on these data, the national occupational exposure limit (OEL) for MMA inhas been set to 50 ppm (210 mg/m³).

SCOEL reviewed MMA after the EU-ESR and established a health-based occupational exposure limit (SCOEL, 2005). The critical effect identified by SCOEL was focal lesion of the olfactory region of the nasal epithelium in both rats and mice following repeated exposure as a consequence of local metabolism of MMA to methacrylic acid by carboxylesterases in the nasal epithelial cells. For defining the “critical inhalation exposure level at the workplace” a reliable NOAEC of 25 ppm and LOAEC of 100ppm was available from a 2-year inhalation study in rats. SCOEL judged that “extensive” PBPK modelling work predicted that on kinetic grounds, for a given level of exposure to MMA, human nasal olfactory epithelium will be at least 3 times less sensitive than that of rats to the toxicity of MMA. SCOEL also judged that the available studies of workforces provided reassuring evidence that workers exposed to MMA levels of up to approximately 50 ppm (8-hr TWA) have not suffered any respiratory ill-health consequences related to their long-term exposure with the occasional respiratory symptoms reported seem to be clearly connected with short-term peak exposures and the sensory irritant potential of MMA which starts to be expressed at concentrations somewhere in excess of 100 ppm.

Description	Value/ factor	Remark
Step 1) Relevant dose-descriptor	208 mg/m³ (50 ppm)	NOAEC in workers (SCOEL IOLV)
Step 2) Modification of starting point	1	As the human effects data were long term, full-shift duration, worker-health studies no adjustment factors were considered necessary
NAEL worker	208 mg/m³ (50 ppm)
Step 3) Assessment factors
Interspecies	1	No additional adjustment required when setting an inhalation DNEL based on an inhalation study (ECHA 2012). 8h-NOAEC of approximately 50 ppm and 8h-LOAEC “somewhere in excess” of 100 ppm for occupationally exposed workers.
Intraspecies	2	Default AF for extrapolation from workers to general population (ECHA 2012).
Exposure duration	1	No adjustment is required. The key studies were worker health studies on workforces with long employment histories (in excess of 25 yrs in some cases) and full shift (8-hr) work activities.
Dose response	1	The NOAEC is reliable. No adjustment is required.
Quality of database	1	The key studies were of high quality. No adjustment is required.
Remaining uncertainties	1	No adjustment is required (SCOEL).
Overall AF	1
DNEL
Based on a SCOEL IOLV of 50 ppm (8-h TWA)	104 mg/m³ (25 ppm)	Using a total factor (POD modifier and AF) of 2 a DNEL long-term local, inhal, gen pop of 104 mg/m³ (25 ppm) is derived.

Acute, short-term exposure - local effects - inhalation

Calculation from the weight-of-evidence review of the inhalation toxicity of MMA performed by SCOEL:

The critical effect identified by SCOEL was focal lesion of the olfactory region of the nasal epithelium in both rats and mice following repeated exposure as a consequence of local metabolism of MMA to methacrylic acid by carboxylesterases in the nasal epithelial cells. For defining the “critical inhalation exposure level at the workplace” a reliable NOAEC of 25 ppm and LOAEC of 100ppm was available from a 2-year inhalation study in rats. SCOEL judged that “extensive” PBPK modelling work predicted that on kinetic grounds, for a given level of exposure to MMA, human nasal olfactory epithelium will be at least 3 times less sensitive than that of rats to the toxicity of MMA. SCOEL also judged that the available studies of workforces provided reassuring evidence that workers exposed to MMA levels of up to approximately 50 ppm (8-hr TWA) have not suffered any respiratory ill-health consequences related to their long-term exposure with the occasional respiratory symptoms reported seem to be clearly connected with short-term peak exposures and the sensory irritant potential of MMA which starts to be expressed at concentrations somewhere in excess of 100 ppm. SCOEL concluded further that ‘While there are no data to clearly indicate the threshold concentration above which such irritancy begins to be expressed in humans … irritant concentrations clearly lie above 100 ppm. Hence a STEL of 100 ppm is recommended’.

Description	Value/ factor	Remark
Step 1) Relevant dose-descriptor	416 mg/m³ (100 ppm)	NOAEC in workers (SCOEL STEL)
Step 2) Modification of starting point	1	As the human effects data were long term, full-shift duration, worker-health studies no adjustment factors were considered necessary
NAEL worker	416 mg/m³ (100 ppm)
Step 3) Assessment factors
Interspecies	1	No additional adjustment required when setting an inhalation DNEL based on an inhalation study (ECHA 2012). 8h-NOAEC of approximately 50 ppm and 8h-LOAEC “somewhere in excess” of 100 ppm for occupationally exposed workers.
Intraspecies	2	Default AF for extrapolation from workers to general population (ECHA 2012).
Exposure duration	1	No adjustment is required. The key studies were worker health studies on workforces with long employment histories (in excess of 25 yrs in some cases) and full shift (8-hr) work activities.
Dose response	1	The NOAEC is reliable. No adjustment is required.
Quality of database	1	The key studies were of high quality. No adjustment is required.
Remaining uncertainties	1	No adjustment is required (SCOEL).
Overall AF	2
DNEL
Based on a SCOEL STEL of 100 ppm	208 mg/m³ (50 ppm)	Using a total factor (POD modifier and AF) of 2, a DNEL short-term local , inhal, gen pop of 208 mg/m³ (50 ppm) is derived.

Long-term exposure - systemic effects - dermal

In a 2-year repeat oral (drinking water) exposure study with MMA the NOAEL was 164 mg/kg bw/day (2,000 ppm in drinking water) (Borzelleca et al, 1964). In the absence of a comparable dermal study this study is used as the departure point for long-term dermal exposure.

Description	Value/ factor	Remark
Step 1) Relevant dose-descriptor	NOAEL 2000 ppm	NOAEL for rats (7 days/week) for 2 years
Step 2) Modification of starting point	1	Oral to dermal route-to-route extrapolation (ECHA 2012).
NAEL worker (mg/kg bw/d)	164 mg/kg bw/day	Conversion to food equivalent using water consumption data
Step 3) Assessment factors
Interspecies	4	Allometric scaling rat to humans AF 4 (ECHA 2012).
Intraspecies	5	Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases) makes a lower variability likely, hence the AF of 5 by ECETOC (2010) 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 NOAEC 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 not justified.
Overall AF	20
DNEL
based on NOAELrat of 2000 ppm in drinking water = 164 mg/kg bw/day	8.2 mg/kg bw/d	Using a total AF of 20 ( 4 x 5 x 1 x 1) a DNELlong-term systemic. dermal, gen pop of 8.2 mg/kg bw/d is derived.

Acute, short-term and long-term exposure - local effects - dermal

An induction-specific DNEL was derived for skin sensitization based on the EC3 value from a LLNA study (Betts et al., 2006). The sensitisation threshold (EC3 value) was reported to be 60% w/v, indicative of a sensitiser of moderate potency. According to the Guidance on information requirements and chemical safety assessment, Chapter R.8, the EC3 value (in mg/cm²) can be used as a surrogate for the NOAEL for induction. EC3 data generally correlate well with human skin sensitisation thresholds. However, there are cases where this correlation is poor and the two values may differ by 10 -fold or more. Therefore, using the default AF of 10 for interspecies variation, the acute dermal DNEL was calculated to be 1.5 mg/cm²/day.

Long-term exposure - systemic effects - oral

In a 2-year repeat oral (drinking water) exposure study with MMA the NOAEL was 164 mg/kg bw/day (2,000 ppm in drinking water) (Borzelleca et al, 1964).

Description	Value/ factor	Remark
Step 1) Relevant dose-descriptor	NOAEL 2000 ppm	NOAEL for rats (7 days/week) for 2 years
Step 2) Modification of starting point
NAEL worker (mg/kg bw/d)	164 mg/kg bw/day	Conversion to food equivalent using water consumption data
Step 3) Assessment factors
Interspecies	4	Allometric scaling rat to humans AF 4 (ECHA 2012).
Intraspecies	5	Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases) makes a lower variability likely, hence the AF of 5 by ECETOC (2010) 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 NOAEC 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 not justified.
Overall AF	20
DNEL
based on NOAELrat of 2000 ppm in drinking water = 164 mg/kg bw/day	8.2 mg/kg bw/d	Using a total AF of 20 ( 4 x 5 x 1 x 1), a DNEL long-term systemic, oral, gen pop of 8.2 mg/kg bw/d is derived.

Registration Dossier

Registration Dossier

Diss Factsheets

Methyl methacrylate

Toxicological Summary

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

DNEL related information

Acute/short term exposure

DNEL related information

Local effects

Long term exposure

DNEL related information

Acute/short term exposure

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

DNEL related information

Acute/short term exposure

DNEL related information

Local effects

Long term exposure

DNEL related information

Acute/short term exposure

DNEL related information

Workers - Hazard for the eyes

Local effects

Additional information - workers

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

DNEL related information

Acute/short term exposure

DNEL related information

Local effects

Long term exposure

DNEL related information

Acute/short term exposure

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

DNEL related information

Acute/short term exposure

DNEL related information

Local effects

Long term exposure

DNEL related information

Acute/short term exposure

DNEL related information

General Population - Hazard via oral route

Systemic effects

Long term exposure

DNEL related information

Acute/short term exposure

DNEL related information

General Population - Hazard for the eyes

Local effects

Additional information - General Population