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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
415 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC Technical Report No. 110
Overall assessment factor (AF):
18
Modified dose descriptor starting point:
other: The NOAEC for systemic effects (11175 mg/m3) was modified for exposure duration and light exercise to a value of 7487 mg/m3. Please refer to the "discussion" below for more information.
Value:
7 487 mg/m³
Explanation for the modification of the dose descriptor starting point:
No route to route extrapolation is required since a repeated dose inhalation toxicity study is available.
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
6
Justification:
The default extrapolation factor for exposure duration is used: subacute (starting point) to chronic (end point).
AF for interspecies differences (allometric scaling):
1
Justification:
No AF for allometric scaling rat to humans for inhalation required (ECHA, 2012)
AF for other interspecies differences:
1
Justification:
AF for other interspecies difference not required (ECETOC, 2010)
AF for intraspecies differences:
3
Justification:
The (ECETOC) default value for the relatively homogenous group "worker" is used
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required
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:
repeated dose toxicity
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC Technical Report No. 110
Overall assessment factor (AF):
3
Dose descriptor:
other: The NOAEC for local effects (1832 mg/m3) was modified for exposure duration and light exercise to a value of 1227 mg/m3. Please refer to the "discussion" below for more information.
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
1
Justification:
As demonstrated with the close structural analogue methyl methacrylate (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. Please refer to the "discussion" below for more information.
AF for interspecies differences (allometric scaling):
1
Justification:
As recognised by SCOEL for the close structural analogue methyl methacrylate (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 alky methacrylate esters. No adjustment is required.
AF for other interspecies differences:
1
Justification:
As recognised by SCOEL for the close structural analogue methyl methacrylate (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 alky methacrylate esters. No adjustment is required.
AF for intraspecies differences:
3
Justification:
The (ECETOC) default value for the relatively homogenous group "worker" is used
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
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
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC Technical Report No. 110
Overall assessment factor (AF):
24
Modified dose descriptor starting point:
NOAEL
Value:
120 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
There are no relevant experimental data on repeated dermal exposure. A conservative approach is followed by assuming dermal absorption to be equal to oral absorption.
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
2
Justification:
The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point).
AF for interspecies differences (allometric scaling):
4
Justification:
The default allometric scaling factor for the differences between rats and humans is used.
AF for other interspecies differences:
1
Justification:
Interspecies differences including toxicokinetics are fully covered by the allometric scaling. There is no additional evidence for species differences including toxicodynamics. Therefore, no additional factor is used.
AF for intraspecies differences:
3
Justification:
The (ECETOC) default value for the relatively homogenous group "worker" is used.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - workers

General

DNEL derivation for the substance is performed under consideration of the recommendations of ECHA REACH Guidance (2012) and ECETOC (2003). In view of the data used for evaluation, the assessment factor (AS) for dose response relation ship, the AS for quality of whole database factors and the AS for remainign uncertainties are set to a value of 1, and are thus not shown in the calculations presented below.

Acute-systemic effects

The test material is not classified and labelled for acute systemic toxicity, according to Directive 67/548/EEC (DSD) and Regulation (EC) No 1272/2008 (CLP). Thus, DNEL derivation is not required for this endpoint.

Acute/short-term and long-term exposure - local effects

Respiratory irritation

In a 28-day inhalation study with the close structural analogous test substance n-BMA 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 (methyl methacrylate) 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. A much greater percentage of the nasal cavity is lined by olfactory epithelium in rats than in humans. Thus, the rat is more sensitive to the aforementioned effects and the DNEL derived from the animal study represents a worst case scenario.

DNEL derivation:

Taking the aforementioned into consideration, the starting NOAEC 1832 mg/m3 was modifed as follows:

- 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) was used (ECHA 2012).

--> Corrected inhalatory NOAEC for workers = 1832 mg/m3/ (10 m3 / 6.7 m3) = 1227 mg/m3

The worker DNEL (Long-term exposure (inhalation) - local effects) is then calculated using following assessment factors (AF):

AF for differences in duration of exposure: 1

AF for interspecies differences (allometric scaling): 1

AF for interspecies differences:1

AF for intraspecies differences (worker): 3

Taking the above mentioned assessment factors into account, the following worker DNEL (Long-term exposure (inhalation) - local effect) was derived:

1227 mg/m3/ (1x1x1x3) = 409 mg/m3

Skin irritation and skin sensitization:

Based on the available in vivo studies, the test substance is classified as skin irritant (R38) according to the criteria of Directive 67/548/EEC (DSD) and Cat. 2 according to Regulation (EC) No 1272/2008 (CLP). Thus, a qualitative risk assessment is conducted.

Based on the available data, the test substance is not classified as a skin sensitiser according to the criteria of Directive 67/548/EEC (DSD) and Regulation (EC) No 1272/2008 (CLP).  

Eye irritation:

Based on the available in vivo studies, the test substance is classified as eye irritant (R36) according to the criteria of Directive 67/548/EEC (DSD) and Cat. 2 according to Regulation (EC) No 1272/2008 (CLP). Thus, a qualitative risk assessment is conducted.

Long-term exposure (inhalation) - systemic effects

In a sub-acute 28-day inhalation study in rats with the structural analogue n-BMA, the NOAEC for systemic effects was 11175 mg/m3 (1891 ppm) which represents the hightest dose testes in this study.

DNEL derivation: Taking the aforementioned into consideration, the starting NOAEC for systemic effects was modifed as follows:

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

--> Corrected inhalatory NOAEC for workers = 11175 mg/m3/ (10 m3 / 6.7 m3) = 7487 mg/m3

The worker DNEL (Long-term exposure (inhalation) - systemic effects) is then calculated using following asesment factors (AF):

AF for differences in duration of exposure: 6

AF for interspecies differences (allometric scaling): 1

AF for interspecies differences:1

AF for intraspecies differences (worker): 3

Taking the above mentioned assessment factors into account, the following worker DNEL Long-term exposure (inhalation) - systemic effects is 7487 mg/m3/ (6x1x1x3) = 416 mg/m3  

Long-term exposure (dermal exposure) - systemic effects

For the DNEL derivation, the results of the available subchronic 90 -day gavage study were used.

This GLP and guideline compliant study was conducted on the close structural analogue substance n-BMA with the exposure duration available (90 days, oral repeated dose toxicity study in rats). The results of this higher tier study are supported by a 28-day repeated dose toxicity study in rats conducted on the test item in accordance to Japanese testing guidelines and a combined repeated dose and reproductive/developmental toxicity screening test in rats conducted on a close structural analogue substance in accordance to OECD guideline 422.

In thissubchronic 90-day gavage study in rats with the structural analogue 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) were 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.

DNEL derivation:

The worker DNEL Long-term exposure dermal is calculated using following asesment factors (AF):

AF for differences in duration of exposure: 2

AF for interspecies differences (allometric scaling): 4

AF for interspecies differences:1

AF for intraspecies differences (worker): 3

Taking the above mentioned assessment factors into account, the following worker DNEL Long-term exposure dermal - systemic effects was derived as follows:

120 mg/kg bw/day / (2x4x1x3) = 5 mg/kg bw/day

General Population - Hazard via inhalation 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

Local 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 via dermal 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

Local effects

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

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
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:
no hazard identified

Additional information - General Population

Since no exposure of the general population is intended or anticipated, no DNEL has been derived.