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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
125 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC Technical Report No. 110
Overall assessment factor (AF):
45
Dose descriptor starting point:
NOAEC
Value:
11 175 mg/m³
Modified dose descriptor starting point:
NOAEC
Value:
5 615 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. Therefore, the worker-DNEL long-term for inhalation route - systemic was derived from the NOAEC of  11175 mg/m³, obtained in the key study “Subacute Inhalation Toxicity: 28-Day Study” in rats (OECD TG 412). The modified NOAEC was calculated as followed:

- standard respiratory volume human = 6.7 m³/8h

- worker respiratory volume = 10 m³/8h

- exposure animal = 6 hr / day

- exposure worker = 8 hr / day

The modified dose descriptor (corrected inhalatory NOAEC) = 11175 mg/m3 * (6.7 m³ (8h)/10 m³ (8h)) * (6 hr / d exposure animal / 8 hr / d exposure worker) = 5615 mg/m³

For more detailed information please refer to section "Additional information - workers".

AF for dose response relationship:
1
Justification:
ECHA REACH Guidance: starting point for the DNEL calculation is a NOAEC, therefore no additional factor is used.
AF for differences in duration of exposure:
6
Justification:
ECHA REACH Guidance: The recommended AF for the extrapolation from sub-acute to chronic exposure is applied.
AF for interspecies differences (allometric scaling):
1
Justification:
ECHA REACH Guidance: no additional factor needed for extrapolation from inhalation to inhalation route
AF for other interspecies differences:
2.5
Justification:
ECHA REACH Guidance: The recommended AF for the interspecies differences is applied.
AF for intraspecies differences:
3
Justification:
In an attempt to evaluate the intraspecies variability within the human population, the distribution of human data for various toxicokinetic and toxicodynamic parameters were examined (Hattis et al 1987, 1999; Hattis and Silver 1994; Renwick and Lazarus, 1998; see ECETOC TR No.86, 2003). These evaluations included data from ‘healthy adults’ of both sexes, as well as limited data from the young and elderly, mixed races and patients with various medical conditions such as cancer and hypertension. The data of Renwick and Lazarus (1998) and Hattis et al (1999) were based exclusively on human data and similar values were obtained within each percentile. Considering that the data analysed by these authors included both sexes, a variety of disease states and ages, the use of the 95thpercentile is considered sufficiently conservative to account for intraspecies variability in the general population. Thus, a default assessment factor of 5 was taken for the general population with a lower factor of 3 (i.e. closer to the 90thpercentile) for the more homogenous worker population.
AF for the quality of the whole database:
1
Justification:
ECHA REACH Guidance: The quality of the whole data base is considered to be sufficient.
AF for remaining uncertainties:
1
Justification:
ECHA REACH Guidance: default factor. 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:
164 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):
7.5
Dose descriptor:
other: The NOAEC for local effects (1832 mg/m3) was modified for light exercise to a value of 1227 mg/m3. Please refer to "Additional information - workers" below for more information.
Value:
1 227 mg/m³
AF for dose response relationship:
1
Justification:
ECHA REACH Guidance: starting point for the DNEL calculation is a NOAEC, 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:
2.5
Justification:
ECHA REACH Guidance: The recommended AF for the interspecies differences is applied.
AF for intraspecies differences:
3
Justification:
In an attempt to evaluate the intraspecies variability within the human population, the distribution of human data for various toxicokinetic and toxicodynamic parameters were examined (Hattis et al 1987, 1999; Hattis and Silver 1994; Renwick and Lazarus, 1998; see ECETOC TR No.86, 2003). These evaluations included data from ‘healthy adults’ of both sexes, as well as limited data from the young and elderly, mixed races and patients with various medical conditions such as cancer and hypertension. The data of Renwick and Lazarus (1998) and Hattis et al (1999) were based exclusively on human data and similar values were obtained within each percentile. Considering that the data analysed by these authors included both sexes, a variety of disease states and ages, the use of the 95thpercentile is considered sufficiently conservative to account for intraspecies variability in the general population. Thus, a default assessment factor of 5 was taken for the general population with a lower factor of 3 (i.e. closer to the 90thpercentile) for the more homogenous worker population.
AF for the quality of the whole database:
1
Justification:
ECHA REACH Guidance: The quality of the whole data base is considered to be sufficient.
AF for remaining uncertainties:
1
Justification:
ECHA REACH Guidance: default factor. The approach used for DNEL derivation is conservative. No further assessment factors are required.
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.8 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):
60
Dose descriptor starting point:
NOAEL
Value:
120 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
168 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. Therefore, the worker-DNEL long-term for dermal route – systemic was derived from the NOAEL of 120 mg/kg bw/day, obtained in the key “Repeated Dose 90-Day Oral Toxicity Study in Rodents (OECD TG 408). The modified NOAEL was calculated as followed: = 120 mg/kg bw/day * (7 d  / wk exposure animal / 5 d / wk exposure worker) = 168 mg/kg bw/day

AF for dose response relationship:
1
Justification:
ECHA REACH Guidance: starting point for the DNEL calculation is a NOAEL, therefore no additional factor is used.
AF for differences in duration of exposure:
2
Justification:
ECHA REACH Guidance: The recommended AF for the extrapolation from sub-chronic to chronic exposure is applied.
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA REACH Guidance: The recommended default allometric scaling factor between rats and humans is used.
AF for other interspecies differences:
2.5
Justification:
ECHA REACH Guidance: The recommended AF for the interspecies differences is applied.
AF for intraspecies differences:
3
Justification:
In an attempt to evaluate the intraspecies variability within the human population, the distribution of human data for various toxicokinetic and toxicodynamic parameters were examined (Hattis et al 1987, 1999; Hattis and Silver 1994; Renwick and Lazarus, 1998; see ECETOC TR No.86, 2003). These evaluations included data from ‘healthy adults’ of both sexes, as well as limited data from the young and elderly, mixed races and patients with various medical conditions such as cancer and hypertension. The data of Renwick and Lazarus (1998) and Hattis et al (1999) were based exclusively on human data and similar values were obtained within each percentile. Considering that the data analysed by these authors included both sexes, a variety of disease states and ages, the use of the 95thpercentile is considered sufficiently conservative to account for intraspecies variability in the general population. Thus, a default assessment factor of 5 was taken for the general population with a lower factor of 3 (i.e. closer to the 90thpercentile) for the more homogenous worker population.
AF for the quality of the whole database:
1
Justification:
ECHA REACH Guidance: The quality of the whole data base is considered to be sufficient.
AF for remaining uncertainties:
1
Justification:
ECHA REACH Guidance: default factor. 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 (2010). 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 remaining uncertainties are set to a value of 1, and are thus not shown in the calculations presented below.

The primary routes of anticipated industrial and professional exposure are via inhalation and skin contact. In industrial settings, ingestion is not an anticipated route of exposure, but has to be considered for the general population (see 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: 2.5

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/ (1x1x2.5x3) = 164 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 exposure duration differences (animal = 6 hr / day, exposure worker = 8 hr / day)

- 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 * (6.7 m³ (8h)/10 m³ (8h)) * (6 hr / day exposure animal / 8 hr / day exposure worker) = 5615 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: 2.5

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/ (6x1x2.5x3) = 125 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 this subchronic 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 starting NOAEC for systemic effects was modifed as follows:

- Correction for exposure duration differences (animal = 7 d/wk, exposure worker = 5 d/wk))

Corrected dermal NOAEC for workers = 120 mg/kg bw/day * (7 d/wk / 5 d/wk ) = 168 mg/kg bw/day

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: 2.5

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:

168 mg/kg bw/day / (2x4x2.5x3) = 2.8 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:
DNEL (Derived No Effect Level)
Value:
1.2 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):
100
Dose descriptor starting point:
NOAEL
Value:
120 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No modification of the value is necessary.

AF for dose response relationship:
1
Justification:
ECHA REACH Guidance: starting point for the DNEL calculation is a NOAEL, therefore no additional factor is used.
AF for differences in duration of exposure:
2
Justification:
ECHA REACH Guidance: The recommended AF for the extrapolation from sub-chronic to chronic exposure is applied.
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA REACH Guidance: The recommended default allometric scaling factor between rats and humans is used.
AF for other interspecies differences:
2.5
Justification:
ECHA REACH Guidance: The recommended AF for the interspecies differences is applied.
AF for intraspecies differences:
5
Justification:
In an attempt to evaluate the intraspecies variability within the human population, the distribution of human data for various toxicokinetic and toxicodynamic parameters were examined (Hattis et al 1987, 1999; Hattis and Silver 1994; Renwick and Lazarus, 1998; see ECETOC TR No.86, 2003). These evaluations included data from ‘healthy adults’ of both sexes, as well as limited data from the young and elderly, mixed races and patients with various medical conditions such as cancer and hypertension. The data of Renwick and Lazarus (1998) and Hattis et al (1999) were based exclusively on human data and similar values were obtained within each percentile. Considering that the data analysed by these authors included both sexes, a variety of disease states and ages, the use of the 95thpercentile is considered sufficiently conservative to account for intraspecies variability in the general population. Thus, a default assessment factor of 5 was taken for the general population with a lower factor of 3 (i.e. closer to the 90thpercentile) for the more homogenous worker population.
AF for the quality of the whole database:
1
Justification:
ECHA REACH Guidance: The quality of the whole data base is considered to be sufficient.
AF for remaining uncertainties:
1
Justification:
ECHA REACH Guidance: default factor. 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

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

The general population is not exposed to the registered substance since it is exclusively used in very restrictive industrial and professional settings.

A DNEL were only assessed for man via environment calculations.

For assessment of exposure "man via the environment" a DNEL (oral, systemic long-term) of 1,2 mg/kg bw/day is assumed based on the NOAEL of 120 mg/kg of the OECD 408 study and an overall assessment factor of 100.

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