Registration Dossier

Diss Factsheets

Administrative data

Workers - 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:
DNEL (Derived No Effect Level)
Value:
18 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
other: 2004 EU Scientific Committee on Occupational Exposure Limits (SCOEL) value
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:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.49 mg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
10
Dose descriptor starting point:
other: NOAEL
AF for dose response relationship:
1
AF for interspecies differences (allometric scaling):
1
Justification:
A number of other organizations were able to empirically show that the EC3 value (in µg/cm2) also closely correlates with the NOEL from human sensitization tests designed to confirm lack of induction (Api et al., 2006, Api et al., 2008, ECETOC TR87, 2003). Therefore, it seems appropriate to use the EC3, expressed as dose per skin area, as a surrogate for the human sensitization threshold without the modification by uncertainty factors.
AF for other interspecies differences:
1
AF for intraspecies differences:
10
Justification:
It is recognized that a general DNEL must take into account that the threshold for skin sensitization varies between individuals. This may be due to differences in parameters such as genetic effects, sensitive subpopulations, inherent barrier function, age, gender, and ethnicity (Api et al., 2008). Whereas the latter three are recognized to have some effect on the sensitization threshold, it is generally recognized that genetic differences, the inherent barrier function and especially sensitive subpopulations play a major role (Api et al., 2008). The barrier function of the skin may be compromised which in turn may lead to a greater susceptibility of the individual. At the same time the barrier function is thought to be very similar from infancy to adulthood. The influence of the genetic setting is not well understood, however, may be plausible in the light of the immunological effect under consideration. The term sensitive subpopulations refers mostly to individuals who have previously been sensitized to other substances which may increase the susceptibility to further sensitizers (Api et al., 2006, Api et al., 2008). All of these effects make up the intraspecies factor, a factor of 10 is thought to adequately address the combined influence of these effects.
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

Methyl acrylate is a chemical intermediate, manufactured and processed within closed systems. The primary routes of industrial exposure to methyl acrylate are skin contact and inhalation. In an industrial setting, ingestion is not an anticipated route of exposure.

Long-tern exposure systemic DNELs were not calculated because of the lack of long-term systemic effects. Dose-level selection for long-term studies was limited by severity of local effects on the upper respiratory tract.

DNEL derivation:

The EU Scientific Committee on Occupational Exposure Limits  (SCOEL) makes recommendations to the Commission on 'health-based' OELs. An OEL of this type may be established in those cases where a review of the total available scientific database leads to the conclusion that it is possible to identify a clear threshold dose below which exposure to the chemical in question is not expected to lead to adverse effects. The European Commission uses the scientific advice from SCOEL to make proposals for occupational exposure limits. Limits based solely on scientific considerations are considered as adaptations to technical progress, and are incorporated in proposals for Commission directives within the framework of the chemical agents directive and are indicative.

In September 2004 the EU Scientific Committee on Occupational Exposure Limits (SCOEL) recommended an 8 hour OEL (TWA) of 5 ppm (18 mg/m3) for methyl acrylate. This reommended OEL is taken as DNEL, it is based on actual and well documented  toxicological information and evaluation of health effects, in which the approach how it is derived is scientifically justified and is therefore in accordance with ECHA Guidance on information requirments and chemical safety assessment, Chapter R.8: Characterisation of dose (concentration)-response for human health (May 2008).

There are no human data available which are adequate for proposing occupational exposure limits.

The study of Reininghaus et al. (1991), establishing a LOAEL of 15 ppm (54 mg/m3), for slight irritation of the olfactory epithelium in rats, was considered to be the best available basis for proposing occupational exposure limits.

In this well-conducted 2 year study Sprague-Dawley rats (86 rats per sex and group) developed no systemic effects at concentrations of 15, 45 and 135 ppm Methylacrylate (54, 161 or 483 mg/m3). In the cornea a dose-related increase in neovascularization and parenchymal cloudiness was observed in male and female animals. However, little importance can be attached to this finding because it is a result of anatomical and geriatric features of the rat which are not found in man. The rat eye is spherical and the cornea highly domed so that external factors have more effect on the rat than on the human eye. The lacrimal glands of some strains including the Sprague-Dawley rat, are often subject to age-related changes. This is also to be seen in the author's own historical data for the Wistar rat. The changes lead to inadequate lacrimation which means that the cornea of such animals is no longer adequately protected. Any additional adverse external influences, such as the irritation caused by methyl acrylate, can then result in (dose dependent) corneal changes. Furthermore, the neovascularization of the cornea in rats exposed to methyl acrylate is known to be a reversible non-specific reaction to chronic irritation. Thus the alterations in the lacrimal glands and cornea which developed in rats under the conditions described above are not to be expected in man. Corneal damage has not been reported in workers in factories producing methyl acrylate (DFG 1993). The critical effect was irritation of the nasal mucosa. Dose-related changes occurred in the nasal mucosa at the level of the dorsal lamella of the second endoturbinate. At the lowest concentration tested (15 ppm, 54 mg/m3) slight atrophy of the neurogenic part of the olfactory epithelium was observed in a few male rats. At 45 and 135 ppm, almost all exposed rats developed a partial loss of the columnar cell layer, with an accompanying stratified reserve-cell hyperplasia . No treatment-related changes were detected in the posterior nasal cavity, which is mainly lined with olfactory epithelium. No irritative changes were observed in the larynx, trachea or lungs of the exposed rats. The LOAEL of this study for basal-cell hyperplasia (critical effect) is 15 ppm with a very steep concentration-response-curve at higher concentrations (Reininghaus et al., 1991). Calculation of a benchmark dose (BenchMark dose Software from US EPA, Version 1.3.2, dichotomous logistic model with 0.95 confidence level) gave a BMDL of 14 ppm. In contrast to methylacrylate, the concentration-response-curve for butylacrylate was flat, resulting in a BMDL of 6 ppm, which is in accordance with the 8-h TWA of 2 ppm.

In view of the mild nature of this localized lesion, observed in a well-conducted study and

the very steep concentration-response-curve beyond 15 ppm, the Scientific Committee of Occupational Exposure Limits considered an uncertainty factor of 2 appropriate to allow for the absence of a NOAEL and of human data. This is in accordance with the calculated BMDL of 14 ppm. Taking into account the preferred value approach, the recommended 8-hour TWA is 5 ppm (18 mg/m3). A short term exposure limit (STEL) (15 mins) of 10 ppm (36 mg/m3) was proposed to limit peaks of exposure which could result in irritation.

  • Recommendation from the Scientfic Committee on Occupational Exposure Limits for Methylacrylate, SCOEL/SUM/46, September 2004

In addition, an induction-specific DNEL was derived for skin sensitization according to Guidance on information requirements and chemical safety assessment, Chapter R.8 (ECHA, May 2008) based on the EC3 value from an LLNA study (BAMM 2006). The EC3 value was reported to be 19.6 % w/v (4900 µg/cm²), indicative of a sensitizer of weak potency (ECETOC 2003). The EC3 value (in µg/cm2) can be considered as the NOAEL for induction, based on the Guidance on information requirements and chemical safety assessment, Chapter R.8.

Interspecies:

A number of other organizations were able to empirically show that the EC3 value (in µg/cm2) also closely correlates with the NOEL from human sensitization tests designed to confirm lack of induction (Api et al., 2006, Api et al., 2008, ECETOC TR87, 2003). Therefore, it seems appropriate to use the EC3, expressed as dose per skin area, as a surrogate for the human sensitization threshold without the modification by uncertainty factors.

Intraspecies:

It is recognized that a general DNEL must take into account that the threshold for skin sensitization varies between individuals. This may be due to differences in parameters such as genetic effects, sensitive subpopulations, inherent barrier function, age, gender, and ethnicity (Api et al., 2008). Whereas the latter three are recognized to have some effect on the sensitization threshold, it is generally recognized that genetic differences, the inherent barrier function and especially sensitive subpopulations play a major role (Api et al., 2008). The barrier function of the skin may be compromised which in turn may lead to a greater susceptibility of the individual. At the same time the barrier function is thought to be very similar from infancy to adulthood. The influence of the genetic setting is not well understood, however, may be plausible in the light of the immunological effect under consideration. The term sensitive subpopulations refers mostly to individuals who have previously been sensitized to other substances which may increase the susceptibility to further sensitizers (Api et al., 2006, Api et al., 2008). All of these effects make up the intraspecies factor, a factor of 10 is thought to adequately address the combined influence of these effects.

The DNEL for skin sensitization was calculated to be 490 µg/cm2/day.

  • Api AM, Basketter DA, Cadby PA, Cano M-F, Graham E, Gerberick F, Griem P, McNamee P, Ryan CA, Safford B (2006). Dermal Sensitization Quantitative Risk Assessment (QRA) for fragrance ingredients. Technical dossier. March 15, 2006 (revised May 2006).
  • Api AM, Basketter, DA, Cadby PA, Cano M-F, Ellis G, Gerberick GF, Griem P, McNamee PM, Ryan CA, Safford R (2008). Dermal sensitization quantitative risk assessment (QRA) for fragrance ingredients. Reg Toxicol Pharmacol 52: 3-23.
  • ECETOC (2003). Contact Sensitization: classification according to potency. Technical Report No. 87, April 2003.

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:
DNEL (Derived No Effect Level)
Value:
2.1 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
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:
DNEL (Derived No Effect Level)
Value:
0.49 mg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
Overall assessment factor (AF):
10

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 end-use consumer products contain only trace levels of acrylic acid and esters (as a result of polymerization), consumer exposure to acrylate monomers is likely to be low (SRI, 2001).

  • SRI, 2001 . CEH Marketing Research Report, Acrylic Acid and Esters, 606 .4000A, Chemical Economics Handbook -SRI International .

Long-tern exposure systemic DNELs were not calculated because of the lack of long-term systemic effects. Dose-level selection for long-term studies was limited by severity of local effects on the upper respiratory tract.

DNEL derivation:

The EU Scientific Committee on Occupational Exposure Limits  (SCOEL) makes recommendations to the Commission on 'health-based' OELs. An OEL of this type may be established in those cases where a review of the total available scientific database leads to the conclusion that it is possible to identify a clear threshold dose below which exposure to the chemical in question is not expected to lead to adverse effects. The European Commission uses the scientific advice from SCOEL to make proposals for occupational exposure limits. Limits based solely on scientific considerations are considered as adaptations to technical progress, and are incorporated in proposals for Commission directives within the framework of the chemical agents directive and are indicative.

In September 2004 the EU Scientific Committee on Occupational Exposure Limits (SCOEL) recommended an 8 hour OEL (TWA) of 5 ppm (18 mg/m3) for methyl acrylate. This reommended OEL is taken as DNEL, it is based on actual and well documented  toxicological information and evaluation of health effects, in which the approach how it is derived is scientifically justified and is therefore in accordance with ECHA Guidance on information requirments and chemical safety assessment, Chapter R.8: Characterisation of dose (concentration)-response for human health (May 2008).

There are no human data available which are adequate for proposing occupational exposure limits.

The study of Reininghaus et al. (1991), establishing a LOAEL of 15 ppm (54 mg/m3), for slight irritation of the olfactory epithelium in rats, was considered to be the best available basis for proposing occupational exposure limits.

In this well-conducted 2 year study Sprague-Dawley rats (86 rats per sex and group) developed no systemic effects at concentrations of 15, 45 and 135 ppm Methylacrylate (54, 161 or 483 mg/m3). In the cornea a dose-related increase in neovascularization and parenchymal cloudiness was observed in male and female animals (Table 1). However, little importance can be attached to this finding because it is a result of anatomical and geriatric features of the rat which are not found in man. The rat eye is spherical and the cornea highly domed so that external factors have more effect on the rat than on the human eye. The lacrimal glands of some strains including the Sprague-Dawley rat, are often subject to age-related changes. This is also to be seen in the author's own historical data for the Wistar rat. The changes lead to inadequate lacrimation which means that the cornea of such animals is no longer adequately protected. Any additional adverse external influences, such as the irritation caused by methyl acrylate, can then result in (dose dependent) corneal changes. Furthermore, the neovascularization of the cornea in rats exposed to methyl acrylate is known to be a reversible non-specific reaction to chronic irritation. Thus the alterations in the lacrimal glands and cornea which developed in rats under the conditions described above are not to be expected in man. Corneal damage has not been reported in workers in factories producing methyl acrylate (DFG 1993). The critical effect was irritation of the nasal mucosa. Dose-related changes occurred in the nasal mucosa at the level of the dorsal lamella of the second endoturbinate. At the lowest concentration tested (15 ppm, 54 mg/m3) slight atrophy of the neurogenic part of the olfactory epithelium was observed in a few male rats. At 45 and 135 ppm, almost all exposed rats developed a partial loss of the columnar cell layer, with an accompanying stratified reserve-cell hyperplasia (Table 1). No treatment-related changes were detected in the posterior nasal cavity, which is mainly lined with olfactory epithelium. No irritative changes were observed in the larynx, trachea or lungs of the exposed rats. The LOAEL of this study for basal-cell hyperplasia

(critical effect) is 15 ppm with a very steep concentration-response-curve at higher concentrations (Reininghaus et al., 1991). Calculation of a benchmark dose (BenchMark dose Software from US EPA, Version 1.3.2, dichotomous logistic model with 0.95 confidence level) gave a BMDL of 14 ppm. In contrast to methylacrylate, the concentration-response-curve for butylacrylate was flat, resulting in a BMDL of 6 ppm, which is in accordance with the 8-h TWA of 2 ppm.

In view of the mild nature of this localized lesion, observed in a well-conducted study and the very steep concentration-response-curve beyond 15 ppm, the Scientific Committee of Occupational Exposure Limits considered an uncertainty factor of 2 appropriate to allow for the absence of a NOAEL and of human data. This is in accordance with the calculated BMDL of 14 ppm. Taking into account the preferred value approach, the recommended 8-hour TWA is 5 ppm (18 mg/m3). A short term exposure limit (STEL) (15 mins) of 10 ppm (36 mg/m3) was proposed to limit peaks of exposure which could result in irritation.

This value is regarded to be safe for workers; according to the ECHA Guidance document the intraspecies factor is by a factor 2 higher for general population than for worker. Also the possible exposure time may be by a factor 3 (8 hrs. vs. 24 hrs) and by a factor 1.4 (5 days/week vs. 7 days/week) longer. Therefore an additional AF of 8.4 is added to the OEL value of 5 ppm, resulting in a DNEL for general population of 0.60 ppm ( 2.1 mg/m3).

  • Recommendation from the Scientfic Committee on Occupational Exposure Limits for Methylacrylate, SCOEL/SUM/46, September 2004

In addition, an induction-specific DNEL was derived for skin sensitization according to Guidance on information requirements and chemical safety assessment, Chapter R.8 (ECHA, May 2008) based on the EC3 value from an LLNA study (BAMM 2006). The EC3 value was reported to be 19.6 % w/v (4900 µg/cm²), indicative of a sensitizer of weak potency (ECETOC 2003). The EC3 value (in µg/cm2) can be considered as the NOAEL for induction, based on the Guidance on information requirements and chemical safety assessment, Chapter R.8.

Interspecies:

A number of other organizations were able to empirically show that the EC3 value (in µg/cm2) also closely correlates with the NOEL from human sensitization tests designed to confirm lack of induction (Api et al., 2006, Api et al., 2008, ECETOC TR87, 2003). Therefore, it seems appropriate to use the EC3, expressed as dose per skin area, as a surrogate for the human sensitization threshold without the modification by uncertainty factors.

Intraspecies:

It is recognized that a general DNEL must take into account that the threshold for skin sensitization varies between individuals. This may be due to differences in parameters such as genetic effects, sensitive subpopulations, inherent barrier function, age, gender, and ethnicity (Api et al., 2008). Whereas the latter three are recognized to have some effect on the sensitization threshold, it is generally recognized that genetic differences, the inherent barrier function and especially sensitive subpopulations play a major role (Api et al., 2008). The barrier function of the skin may be compromised which in turn may lead to a greater susceptibility of the individual. At the same time the barrier function is thought to be very similar from infancy to adulthood. The influence of the genetic setting is not well understood, however, may be plausible in the light of the immunological effect under consideration. The term sensitive subpopulations refers mostly to individuals who have previously been sensitized to other substances which may increase the susceptibility to further sensitizers (Api et al., 2006, Api et al., 2008). All of these effects make up the intraspecies factor, a factor of 10 is thought to adequately address the combined influence of these effects.

The DNEL for skin sensitization was calculated to be 490 µg/cm2/day.

  • Api AM, Basketter DA, Cadby PA, Cano M-F, Graham E, Gerberick F, Griem P, McNamee P, Ryan CA, Safford B (2006). Dermal Sensitization Quantitative Risk Assessment (QRA) for fragrance ingredients. Technical dossier. March 15, 2006 (revised May 2006).
  • Api AM, Basketter, DA, Cadby PA, Cano M-F, Ellis G, Gerberick GF, Griem P, McNamee PM, Ryan CA, Safford R (2008). Dermal sensitization quantitative risk assessment (QRA) for fragrance ingredients. Reg Toxicol Pharmacol 52: 3-23.
  • ECETOC (2003). Contact Sensitization: classification according to potency. Technical Report No. 87, April 2003.