Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Acute/short term exposure
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
11 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
Acute/short term exposure
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
280 µg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
Overall assessment factor (AF):
10

Workers - Hazard for the eyes

Additional information - workers

Since neither sub-chronic nor chronic repeated dose studies nor skin sensitization studies were available for isobutyl acrylate, DNELs were derived from data from the structural analogue n-butyl acrylate.

 

Butyl acrylate is a chemical intermediate, manufactured and processed within closed systems. The primary routes of industrial exposure to butyl 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) makesrecommendationsto 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 1993 the EU Scientific Committee on Occupational Exposure Limits (SCOEL) recommended an 8 hour OEL (TWA) of 2 ppm (11 mg/m3) for n-butyl 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).

The SCOEL decision is still based on the most actual data, the 2 year inhalation study (Reininghaus et al. 1991).

The critical effect of n-butyl acrylate is atrophy of the olfactory epithelium. In a well conducted study, rats were exposed to 15, 45 and 135 ppm (80, 240 and 720 mg/m³), 6h/d, 5d/w for 2 years (Reininghaus et al, 1991). Dose-related changes were observed in the olfactory epithelium and cornea, with minimal effects in a few animals at the lowest dose, and almost all animals being affected at the high dose. Changes in the eyes were non-significant at the low and medium doses. During a 6-month recovery period, the altered olfactory epithelium was replaced by respiratory epithelium. No treatment-related tumours were reported. The study of Reininghaus et al (1991), establishing a LOAEL of 15 ppm (80 mg/m³) for atrophy of the olfactory epithelium in rats, was considered to be the best available basis for proposing occupational exposure limits. SCOEL considered an uncertainty factor of 5 appropriate to allow for the absence of a NOAEL and of reliable human data. Taking into account the preferred value approach, the recommended 8-hour TWA is 2 ppm (11 mg/m³). A STEL (15 mins) of 10 ppm (53 mg/m³) was proposed to limit peaks of exposure which could result in irritation.

Also the German MAK commission evaluated n-butyl acrylate with a comparable conclusion. They also identified the local irritaion of the olfactory epithelium of the nasal mucous membranes as the most critical effect, occuring even in the lowest concentration tested (15 ppm). According to MAK the database is, however, suitable for estimating the no observed adverse effect concentration from the dose-response relationship according to the benchmark concept. The most sensitive relevant end point is seen as the loss of olfactory and ciliated cells and hyperplasia of the reverse cells after exposure for 24 months. For this effect a benchmark concentration of 2.8 ppm has been established for female animals and 2.7 ppm for males. Taking into consideration the reversibility of these findings in some cases the MAK value for n-butyl acrylate was set at 2 ppm. MAK also assumed that due to the particular nasal anatomy and respiratory physiology of the rat (DeSesso 1993), a higher tissue dose is attained in the olfactory epithelium of the rat than in man. It was therefore expected that man does not react more sensitively than the rat, and the burden in man under the same exposure conditions is more likely to be overestimated.

  • Recommendation from the Scientfic Committee on Occupational Exposure Limits for n-Butylacrylate, SCOEL/SUM/41, 1993
  • Documentation of the German MAK value n-Butyl acrylate (1996)
  • DeSesso JM (1993) The relevance to humans of animal models for inhalation studies of cancer in the nose and upper airways, Oual Assu: Good Pract. Regul Law 2, 213 -231

In addition, an induction-specific DNEL was derived for skin sensitization according toGuidance 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 11.2 % w/v (2800 μg/cm²), indicative of a sensitiser 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 280 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 Pharmacol52: 3-23.
  • ECETOC (2003). Contact Sensitization: classification according to potency. Technical Report No. 87, April 2003.

 

General Population - Hazard via inhalation route

Systemic effects

Acute/short term exposure
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.27 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
Acute/short term exposure
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.28 mg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
Overall assessment factor (AF):
10

General Population - Hazard via oral route

Systemic effects

Acute/short term exposure
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

Since neither sub-chronic nor chronic repeated dose studies nor skin sensitization studies were available for isobutyl acrylate, DNELs were derived from data from the structural analogue n-butyl acrylate.

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 1993 the EU Scientific Committee on Occupational Exposure Limits (SCOEL) recommended an 8 hour OEL (TWA) of 2 ppm (11 mg/m3) for n-butyl 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).

The SCOEL decision is still based on the most actual data, the 2 year inhalation study (Reininghaus et al. 1991).

The critical effect of n-butyl acrylate is atrophy of the olfactory epithelium. In a well conducted study, rats were exposed to 15, 45 and 135 ppm (80, 240 and 720 mg/m³), 6h/d, 5d/w for 2 years (Reininghaus et al, 1991). Dose-related changes were observed in the olfactory epithelium and cornea, with minimal effects in a few animals at the lowest dose, and almost all animals being affected at the high dose. Changes in the eyes were non-significant at the low and medium doses. During a 6-month recovery period, the altered olfactory epithelium was replaced by respiratory epithelium. No treatment-related tumours were reported. The study of Reininghaus et al (1991), establishing a LOAEL of 15 ppm (80 mg/m³) for atrophy of the olfactory epithelium in rats, was considered to be the best available basis for proposing occupational exposure limits. SCOEL considered an uncertainty factor of 5 appropriate to allow for the absence of a NOAEL and of reliable human data. Taking into account the preferred value approach, the recommended 8-hour TWA is 2 ppm (11 mg/m³). A STEL (15 mins) of 10 ppm (53 mg/m³) was proposed to limit peaks of exposure which could result in irritation.

Also the German MAK commission evaluated n-butyl acrylate with a comparable conclusion. They also identified the local irritaion of the olfactory epithelium of the nasal mucous membranes as the most critical effect, occuring even in the lowest concentration tested (15 ppm). According to MAK the database is, however, suitable for estimating the no observed adverse effect concentration from the dose-response relationship according to the benchmark concept. The most sensitive relevant end point is seen as the loss of olfactory and ciliated cells and hyperplasia of the reverse cells after exposure for 24 months. For this effect a benchmark concentration of 2.8 ppm has been established for female animals and 2.7 ppm for males. Taking into consideration the reversibility of these findings in some cases the MAK value for n-butyl acrylate was set at 2 ppm. MAK also assumed that due to the particular nasal anatomy and respiratory physiology of the rat (DeSesso 1993), a higher tissue dose is attained in the olfactory epithelium of the rat than in man. It was therefore expected that man does not react more sensitively than the rat, and the burden in man under the same exposure conditions is more likely to be overestimated.

The OEL of 2 ppm 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 2 ppm, resulting in a DNEL for general population of 0.24 ppm (1.27 mg/m3).

  • Recommendation from the Scientfic Committee on Occupational Exposure Limits for n-Butylacrylate, SCOEL/SUM/41, 1993
  • Documentation of the German MAK value n-Butyl acrylate (1996)
  • DeSesso JM (1993) The relevance to humans of animal models for inhalation studies of cancer in the nose and upper airways, Oual Assu: Good Pract. Regul Law 2, 213 -231

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 11.2 % w/v (2800 μg/cm²), indicative of a sensitiser 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 280 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 Pharmacol52: 3-23.
  • ECETOC (2003). Contact Sensitization: classification according to potency. Technical Report No. 87, April 2003.