Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
415.9 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC 2010
Overall assessment factor (AF):
27
Modified dose descriptor starting point:
NOAEC
Value:
11 175 mg/m³
AF for dose response relationship:
1
Justification:
The NOAEC is reliable. No adjustment is required.
AF for differences in duration of exposure:
6
Justification:
Sub-acute to chronic (ECHA 2008)
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling rat to humans as inhalation (ECHA 2008).
AF for other interspecies differences:
1
Justification:
The substances are metabolised 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.
AF for intraspecies differences:
3
Justification:
Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricarboxylic acid cycle) makes a lower variability likely, hence the AF of 5 by ECETOC (2010) is sufficiently conservative for workers.
AF for the quality of the whole database:
1
Justification:
The key study was conducted according to modern regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
1.5
Justification:
Modification of starting point, value of AF is rounded. Exact overall AF is 26.87. For details see "Discussion".
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
409 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC 2010
Overall assessment factor (AF):
4.5
Dose descriptor:
NOAEC
AF for dose response relationship:
1
Justification:
The NOAEC is reliable. No adjustment is required.
AF for differences in duration of exposure:
1
Justification:
As demonstrated with MMA once the olfactory lesion is formed there is little or no increase in sensitivity with sub-acute to chronic exposure. No adjustment for studies of longer duration is required.
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling rat to humans as inhalation (ECHA 2008).
AF for other interspecies differences:
1
Justification:
The substances are metabolised 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.
AF for intraspecies differences:
3
Justification:
Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricarboxylic acid cycle) makes a lower variability likely, hence the AF of 5 by ECETOC (2010) is sufficiently conservative for workers.
AF for the quality of the whole database:
1
Justification:
The key study was conducted according to modern regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
1.5
Justification:
Modification of starting point, value of AF is rounded. Exact overall AF is 4.48. For details see "Discussion".
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC 2010
Overall assessment factor (AF):
24
Modified dose descriptor starting point:
NOAEL
Value:
120 mg/kg bw/day
AF for dose response relationship:
1
Justification:
The NOAEC is reliable. No adjustment is required.
AF for differences in duration of exposure:
2
Justification:
The NOAEC is based on a 13-week study. AF for extrapolation from Sub-chronic to chronic (ECHA 2008).
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling rat to humans AF 4 (ECHA 2008).
AF for other interspecies differences:
1
Justification:
The substances are metabolised 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.
AF for intraspecies differences:
3
Justification:
The substances are metabolised 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.
AF for the quality of the whole database:
1
Justification:
The key study was conducted according to modern regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1 % in mixture (weight basis)
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
Overall assessment factor (AF):
1
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1 % in mixture (weight basis)
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
Overall assessment factor (AF):
1

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - workers

Since n-BMA 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 an ALC of 4901 ppm (29000 mg/m³; mixed exposure to vapour/aerosol) by inhalation, the dermal and inhalation DNELs derived for long-term exposure are considered sufficiently protective of acute exposure.

Acute, short-term exposure - local effects:

LLNA data are not available for n-BMA, so, an induction-specific DNEL was not derived for skin sensitization. Because n-BMA appears to be a sensitiser of low potency, the default threshold for contact allergy is assumed appropriate.

Long-term exposure (inhalation) - local effects

In a 28-day inhalation study the only treatment-related histopathological finding was localised bilateral degeneration of olfactory epithelium lining the dorsal meatus of the nasal cavity at 952 and 1891 ppm (5626 and 11175 mg/m³) in both sexes. Based on histopathological changes seen in the nasal cavities, the no-observable adverse effect concentration (NOAEC) for local effects was 310 ppm (1832 mg/m³). By analogy to the close structural analogue, MMA, the pattern of the critical effects of inhalation of n-BMA 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) with MMA, 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 mouth, 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 normalised 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.

Methacrylate esters are rapidly absorbed, metabolised and excreted from the body (see toxicokinetics).In the inhalation studies with MMA local degeneration of the olfactory epithelia was observed in a very similar way in acute (6hrs) at 100ppm, through to chronic (2-yr) studies at 100ppm. There was no progression with regard to concentration threshold, severity or extent of tissues involved in the lesion.Because n-BMA is unlikely to accumulate significantly further following chronic exposure, comparable to the other esters, the target organs identified in the subchronic study with n-BMA are likely to be indicative of local effects after chronic exposure.

There are no useful human data available for n-BMA.

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEC6h/rat:>1832 mg/m3(310 ppm)

NOAEC for rats, 6 hr/day, 5 days/week for 4 weeks

Step 2) Modification of starting point

1


 

 

 

 

10 m3/6.7 m3

- As demonstrated with MMA the olfactory lesion is present within 6 hrs of exposure and no increase in sensitivity exists with longer exposure. Hence no correction of exposure duration in study (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 2008).

Step 3) Assessment factors

 

 

Interspecies

1

The olfactory lesion is produced by local enzymatic cleavage of the ester to the acid (MAA). Furthermore, as recognised by SCOEL for the close structural analogue, MMA, “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. The same assumptions apply to other short chain alkyl methacrylate esters. No adjustment is required.

Intraspecies

3

Default AF (ECETOC, 2010)

Exposure duration

1

As demonstrated with MMA once the olfactory lesion is formed there is little or no increase in sensitivity with sub-acute to chronic exposure. No adjustment for studies of longer duration is required.

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.

DNEL

Value

based on NOAEC6h/rats>1832 mg/m3(310 ppm)

Using a total factor (POD modifier and AF) of 4.48 (1 x 10/6.7 x 1 x 1 x 3 x1 x 1 x 1 )a DNELlong-term,workerof 409 mg/m3(69.23 ppm) is derived.

 

Long-term exposure (inhalation) - systemic effects

In a sub-acute 28-day inhalation study in rats with n-BMA, the NOAEC for systemic effects was 11175 mg/m3(1891 ppm).

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEC6h/rat:11175 mg/m3(1891 ppm)

NOAEC for rats,6 hr/day, 5 days/week for 4 weeks

Step 2) Modification of starting point

8/6


 

10 m3/6.7 m3

- Correction of exposure duration in study (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 2008).

Step 3) Assessment factors

 

 

Interspecies

1

No allometric scaling rat to humans as inhalation (ECHA 2008). 2.5 for remaining differences not justified (ECETOC, 2010).

Intraspecies

3

Default AF (ECETOC, 2010)

Exposure duration

6

Sub-acute to chronic(ECHA 2008)

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.

DNEL

Value

based on NOAEC6h/rats 11175 mg/m3(1891 ppm)

Using a total factor (POD modifier and AF) of 26.87 (1 x 10/6.7 x 1 x 3 x 6 x 1 x 1 )a DNELlong-term,worker of 415.9 mg/m3(66.7 ppm) is derived.

 

Long-term exposure (oral/dermal exposure) - systemic effects

In a subchronic 90-day gavage study in rats with n-BMA, the lead effect observed was lesions in the olfactory region of the nose (typically observed as a local lesion following inhalation exposure). It is not clear at this stage whether the lesion is a true systemic effect (exposure to the ester via the circulatory system) or a local (via indirect regurgitation/inhalation/ etc.). Considering the short half life of n-BMA in blood (99.7 % removed in first pass by the liver, Jones 2002) it is unlikely that these effects were of systemic origin, but were rather local effects as a consequence of the dosing technique. Consequently, it is likely that the olfactory lesions are the result of inhalation exposure (i.e. local effect) as an indirect consequence of the dosing procedure rather than by systemic exposure. For assessment purposes, as the relevant exposure is likely to occur by inhalation, the DNEL derived for this route will be protective against this effect.

Other toxicologically relevant signs of general systemic toxicity (limited to including effects on the liver activity (increased liver weight, prolonged prothrombin time, lower serum globulin and triglyceride levels in males and/or females) and kidneys weight (increased absolute weight in females) was observed at higher doses. The NOAEL for toxicologically relevant signs of general systemic toxicity was 120 mg/kg body weight/day in both males and females.

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEC:120 mg/kg bw/d

NOAEC for rats, for 13 weeks

Step 2) Modification of starting point

1


No adjustment is necessary.

Step 3) Assessment factors

 

 

Interspecies

4

Allometric scaling rat to humans AF 4 (ECHA 2008). 2.5 for remaining differences not justified (ECETOC, 2010).

Intraspecies

3

Default AF (ECETOC, 2010)

Exposure duration

2

The NOAEC is based on a 13-week study. AF for extrapolation from Sub-chronic to chronic (ECHA 2008).

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.

DNEL

Value

NOAEC:120 mg/kg bw/d

Using a total factor (POD modifier and AF) of 24 (1 x 1 x 4 x 3 x 2 x 1 x 1)a DNELlong-term,workerof 5.0mg/kg bw/d is derived.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
66.5 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC 2010
Overall assessment factor (AF):
168
Modified dose descriptor starting point:
NOAEC
Value:
11 175 mg/m³
AF for dose response relationship:
1
Justification:
The NOAEC is reliable. No adjustment is required.
AF for differences in duration of exposure:
6
Justification:
Sub-acute to chronic (ECHA 2008).
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling rat to humans as inhalation (ECHA 2008).
AF for other interspecies differences:
1
Justification:
The substances are metabolised 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.
AF for intraspecies differences:
5
Justification:
Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricarboxylic acid cycle) makes a lower variability likely, hence the AF of 5 by ECETOC (2010) is sufficiently conservative for general population.
AF for the quality of the whole database:
1
Justification:
The key study was conducted according to modern regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
5.6
Justification:
Modification of starting point. For details see section "Discussion" below.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
366.4 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC 2010
Overall assessment factor (AF):
5
Dose descriptor:
NOAEC
AF for dose response relationship:
1
Justification:
The NOAEC is reliable. No adjustment is required.
AF for differences in duration of exposure:
1
Justification:
As demonstrated with MMA once the olfactory lesion is formed there is little or no increase in sensitivity with sub-acute to chronic exposure. No adjustment for studies of longer duration is required.
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling rat to humans as inhalation (ECHA 2008).
AF for other interspecies differences:
1
Justification:
The substances are metabolised 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.
AF for intraspecies differences:
5
Justification:
Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricarboxylic acid cycle) makes a lower variability likely, hence the AF of 5 by ECETOC (2010) is sufficiently conservative for general population.
AF for the quality of the whole database:
1
Justification:
The key study was conducted according to modern regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC 2010
Overall assessment factor (AF):
40
Modified dose descriptor starting point:
NOAEL
Value:
120 mg/kg bw/day
AF for dose response relationship:
1
Justification:
The NOAEC is reliable. No adjustment is required.
AF for differences in duration of exposure:
2
Justification:
The NOAEC is based on a 13 -week study. AF for extrapolation from Sub-chronic to chronic(ECHA 2008).
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling rat to humans AF 4 (ECHA 2008).
AF for other interspecies differences:
1
Justification:
The substances are metabolised 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.
AF for intraspecies differences:
5
Justification:
Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricarboxylic acid cycle) makes a lower variability likely, hence the AF of 5 by ECETOC (2010) is sufficiently conservative for general population.
AF for the quality of the whole database:
1
Justification:
The key study was conducted according to modern regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1 % in mixture (weight basis)
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
Overall assessment factor (AF):
1
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1 % in mixture (weight basis)
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
Overall assessment factor (AF):
1

General Population - Hazard via oral route

Systemic effects

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

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - General Population

Since n-BMA 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 an ALC of 4901 ppm (29000 mg/m³; mixed exposure to vapour/aerosol) by inhalation, the dermal and inhalation DNELs derived for long-term exposure are considered sufficiently protective of acute exposure.

Acute, short-term exposure - local effects:

LLNA data are not available for n-BMA, so, an induction-specific DNEL was not derived for skin sensitization. Because n-BMA appears to be a sensitiser of low potency, thedefault threshold for contact allergy is assumed appropriate.

Long-term exposure (inhalation) - local effects

The point of departure is the NOAEC for olfactory lesions in the nasal cavity of 1832 mg/m3(310 ppm) observed in a sub-acute 28-day inhalation study in rats with n-BMA. For further details see local effects, workers.

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEC6h/rat:>1832 mg/m3(310 ppm)

NOAEC for rats,6 hr/day, 5 days/week for 4 weeks

Step 2) Modification of starting point

1


 

 

 

 

 

- As demonstrated with MMA the olfactory lesion is present within 6 hrs of exposure and no increase in sensitivity exists with longer exposure. Hence no correction of exposure duration in study (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 not required (ECHA 2008).

Step 3) Assessment factors

 

 

Interspecies

1

The olfactory lesion is produced by local enzymatic cleavage of the ester to the acid (MAA). Furthermore, as recognised by SCOEL for the close structural analogue, MMA, “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. The same assumptions apply to other short chain alkyl methacrylate esters.No adjustment is required.

Intraspecies

5

Non-specific decarboxylesterase enzymes responsible for the development of the nasal lesion are common and as it is a local effect it is unlikely to vary significantly between individuals (ECETOC2010)

Exposure duration

1

As demonstrated with MMA once the olfactory lesion is formed there is little or no increase in sensitivity with sub-acute to chronic exposure. No adjustment for study duration is required.

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.

DNEL

Value

based on NOAEC6h/rats>1832 mg/m3(310 ppm)

 Using a total factor (POD modifier and AF) of 5 (1 x 1 x 1 x 1 x 5 x1 x 1 x 1)a DNELlong-term,general populationof366.4 mg/m3(62 ppm) is derived.

 

Long-term exposure (inhalation) - systemic effects

In a sub-acute 28-day inhalation study in rats with n-BMA, the NOAEC for systemic effects was 11175 mg/m3(1891 ppm).

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEC6h/rat:11175 mg/m3(1891 ppm)

NOAEC for rats,6 hr/day, 5 days/week for 4 weeks

Step 2) Modification of starting point

24/6


7/5

 

 

- Correction for study duration (6hrs) to default general population exposure (24 hrs/day) is required.

- Correction for worker week of 5 days to 7 days for general population

-Correction for activity driven differences of respiratory volumes in workers compared to workers in rest (10 m3/6.7 m3) is not required (ECETOC 2008).

Step 3) Assessment factors

 

 

Interspecies

1

2.5 for remaining differences not justified (ECETOC, 2010).

Intraspecies

5

Default AF for General Population (ECHA 2008)

Exposure duration

6

Sub-acute to chronic(ECHA 2008)

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.

DNEL

Value

based on NOAEC6h/rats 11175 mg/m3(1891 ppm)

 Using a total factor (POD modifier and AF) of 168 (8/6 x 24/8 x 7/5 x 5 x 6 x 1 x 1 )a DNELlong-term,general populationof 66.5 mg/m3(11.3 ppm) is derived.

 

Long-term exposure (oral/dermal exposure) - systemic effects

The POD is the NOAEL for toxicologically relevant signs of general systemic toxicity of 120 mg/kg body weight/day in both males and females in a subchronic 90-day gavage study in rats with n-BMA. For further details see “Long-term exposure (oral/dermal exposure) - systemic effects, workers”.

                                                                                                                                                                                                                                                        

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEC:120 mg/kg bw/d

NOAEC for rats,for 13 weeks

Step 2) Modification of starting point

1


No adjustment is necessary.

Step 3) Assessment factors

 

 

Interspecies

4

Allometric scaling rat to humans AF 4 (ECHA 2008). 2.5 for remaining differences not justified (ECETOC, 2010).

Intraspecies

5

Default AF (ECETOC, 2010)

Exposure duration

2

The NOAEC is based on a 13-week study. AF for extrapolation fromSub-chronic to chronic(ECHA 2008).

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.

DNEL

Value

NOAEC:120 mg/kg bw/d

 Using a total factor (POD modifier and AF) of 40 (1 x 1 x 4 x 5 x 2 x 1 x 1)a DNELlong-term,general_populationof 3.0mg/kg bw/d is derived.