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Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
30 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
30 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance

Local effects

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

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:
high hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

General

DNEL derivation for the test item is performed under consideration of the recommendations of ECHA, Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterization of dose-response for human health (Version: 2.1, November 2012).

Acrylic acid is an important intermediate for polymer industry and is produced in large quantities within the European Union.

Acrylic acid serves as an industrial intermediate product, i.e. it is either processed directly into a polyacrylate or polymerized via the intermediate stage of an acrylate ester. Furthermore, acrylic acid is used as an ingredient and occurs as residual monomer in consumer products like adhesives, paints, binding agents and printing inks.

1.Inhalation

In 2006 the German MAK commission determined a scientific OEL for acrylic acid of 10 ppm (30 mg/m3), which was confirmed as a German OEL by the regulatory authorities in 2007 and the European Scientific Committee for Occupational Exposure Limits in 2008. The MAK value is defined as the maximum concentration of a substance (a gas, vapor) in the workplace air which generally does not have known adverse effects on the health of workers nor causes unreasonable annoyance, even when a person is repeatedly exposed during long periods, usually for 8 hours daily but assuming on average a 40-hour working week.

The most critical effect of acrylic acid is its strong irritation property; it causes severe burns to skin and eyes in animals and severe irritation in the respiratory tract. The corrosive properties of the substance are demonstrated in a dose dependent manner. In humans acrylic acid causes skin corrosion and irritation of the respiratory tract.

Within the MAK documentation following considerations to evaluate the OEL for acrylic acid were made:

In a 90-day study, a NOAEC of 25 ppm was obtained for rats after 6-hour inhalation per day, whereas slight damage to the olfactory epithelium was observed in mice even at 5 ppm.

Investigations with an anatomical model of the nasal cavity of an adult rat showed that only 7 -10 % of the airflow inhaled passes over the olfactory epithelium (Keyhani et al. 1995). Similar investigations with a rat nose model showed that between 13.2 % and 21.7 % of the inspiratory airflow reaches the affected olfactory epithelium in the dorsal medial meatus, depending on the flow rate and the direction of the nostrils (upwards or downwards). At the normal inspiratory rate of 288 mL/min for the F344 rat examined, the rates were 14.6 % if the nostrils pointed downwards and 17 % if they pointed upwards (Kimbell et al. 1997).

After an acrylic acid concentration of 131 ppm was drawn through the upper respiratory passages of tracheotomized F344 rats at a flow rate of 200 mL/min, 97 % of the substance was found to be deposited in the respiratory tract (Morris and Frederick 1995).

The local tissue dose of inhaled acrylic acid in the nasal cavity of humans and rats was estimated by means of a CFD-PBPK model (computational fluid dynamics and physiologically based pharmacokinetic dosimetry model) by way of comparison. Steady-state simulations of the anterior nasal cavity of rats and the human nasal cavity were carried out in a 3-dimensional model. The release of acrylic acid vapour onto the mucous membranes of the upper respiratory tract was determined region for region in the simulations. Calculations were carried out with respiratory minute volumes of 0.1, 0.3 and 0.5 L/minute for rats and 11.4 and 18.9 L/minute for humans. Two compartments with olfactory epithelia (dorsal meatus and ethmoid region) were included for rats while only one compartment was included for the human model since humans have no ethmoid. The model included the effect of the buffer capacity of the mucus on the degree of ionization of the acid and the diffusion of the ionized and non-ionized species. The model also incorporated local physicochemical processes, partition coefficients, and the metabolism of acrylic acid, flow conditions and respiratory parameters. Deposition of 50 % was calculated for the human nasal cavity using this model; compared with the 97 % measured in rats (Morris and Frederick 1995) this is plausible in view of the somewhat wider respiratory passages of the human nose (Frederick et al. 1998). The amounts deposited of a number of substances were also well predicted for rats (Frederick et al. 2001). In further calculations using this model, similar effects on the olfactory epithelium were estimated after acrylic acid concentrations of 4.4 and 25 ppm for rats (respiratory minute volume 0.250 L/minute) and humans (respiratory minute volume 13.9 L/minute) (Andersen et al. 2000; Frederick et al. 2001). However, since the values of important model parameters (e.g. gas phase diffusivity, diffusivity in mucus, diffusivity in squamous epithelium, tissue diffusivity and blood flow through the nasal epithelium) are not based on measurements, but on model simulations and assumptions, the conclusions drawn from the model are to not absolutely reliable. Assuming uniform distribution over the surface of the nasal cavity the ratio for the amounts of acrylic acid deposited in the olfactory epithelium of rats and humans per time unit is about 1 to 3. Taking into account the different airflow that passes over the olfactory epithelium of both species, the effect on the olfactory epithelium is about 1 to 1.6 (Table 1). This calculation considers the respiratory minute volume increased under workplace conditions as the worst-case assumption. In view of the log Powof 0.46 (EU 2002) for acrylic acid, it must be assumed, however, that a larger fraction is deposited in the anterior region of the nose than in the posterior region. Since the olfactory epithelium of the rat is located in the posterior region of the nasal cavity and accounts for almost 50 % of the surface area of the nasal cavity (in humans only 4 %; Frederick et al. 1998), i.e. most of the olfactory epithelium is closer to the portal of entry in rats, more acrylic acid will reach the olfactory epithelium in rats than in humans. It can therefore be assumed that the concentrations to which the olfactory epithelium is exposed are not higher in humans than in rats.

Within the MAK documentation it was estimated that the exposure level of the olfactory epithelium in humans at an increased respiratory minute volume (about 21 L/minute = 10 m3/8 hours) is not higher than that in rats (resting tidal volume) and is lower than that in mice. Since irritation of the olfactory epithelium does not substantially increase with time and since inter-individual differences are probably slight as acrylic acid does not have to be metabolized, the MAK value for acrylic acid has been established at 10 ppm (=30 mg/m3). Because irritation is the critical effect, acrylic acid has been classified by MAK in Peak limitation category I, and since there are no studies to establish an excursion factor, a basic excursion factor of 1 has been fixed.

The MAK value of 30 mg/m3 was determined as systemic and local DNEL via inhalation for workers (long and short term).

Table 1.Comparison of the exposure level of the olfactory epithelium in rats and humans; exposure to acrylic acid concentrations of 25 ppm (75 µg/L) (MAK Commission)

 

Rat

Human

respiratory minute volume

0.175 L/min for 250 g rat (EPA 1988)

10 m3/8 h= 20.8 L/min

inhaled acrylic acid amount/min

13.1 µg

1563 µg

surface of the nasal cavity

13.79 cm2(Frederick et al. 1998)

245.9 cm2(Frederick et al. 1998)

surface of the olfactory epithelium

6.72 cm2(Frederick et al. 1998)

13.2 cm2(Frederick et al. 1998)

deposition in the nasal cavity

97 % (Morris and Frederick 1995)

about 50 % (Frederick et al. 1998)

average dose on the nasal surface (assuming uniform distribution in the nose)

13.1 µg/min/13.79 cm2× 0.97
= 0.92 µg/cm2/min

1563 µg/min/245.9 cm2× 0.5
= 3.18 µg/cm2/min

airflow over the olfactory epithelium

about 15 % (Frederick et al. 1998)

about 7 % (Frederick et al. 1998)

ratio of the exposure of the olfactory epithelium taking into account the different airflow over the olfactory epithelium (rat = 1)

1

3.18/0.92 × 7 %/15 % = 1.6

2. Dermal

Long term& acute, systemic DNEL- dermal exposure (workers)

The substance classified for skin corrosion (Cat.1A) and cause damage to eyes (Cat.1). Therefore, the systemic effects are secondary due to local effects. The available data do not allow a quantitative approach since the substance exerts its effects by a threshold mode of action. Therefore, a qualitative risk characterization should be performed for this endpoint in order to guarantee ‘adequately control of risks’, it is necessary to stipulate risk management measures that prevent skin corrosion. In two dermal carcinogenicity studies in three mice strains (C3H/HeJ, C3H/HeN Hsd BR and Hsd:(ICR)BR), the frequency of skin tumors was not elevated compared to the vehicle controls.

Long term & acute, local DNEL- dermal exposure (workers)

According to the REACH guidance on information requirements and chemical safety assessment, Part E: Risk Characterization, a qualitative risk characterization should be performed for this endpoint. This qualitative approach has to be implemented to deal with the eye as well as skin irritating properties of the substance. As a result, a high hazard is derived. In order to guarantee "adequately control of risks", it is necessary to stipulate risk management measures that prevent skin, eye and mucous membrane exposure. Results of the a study with three strains of mice receiving acrylic acid dermally at levels of 4, 1 and 0% for 13 weeks caused comparable skin irritation to ICR, C3H and B6C3F1 mice at the 4% dose level. Minimal skin reactions were observed in all strains at the 1% dose level. Gross lesions other than skin reactions were incidental to treatment. Microscopic findings characterized as proliferative, degenerative or inflammatory changes were seen predominantly at the 4% level in all strains, occasionally at the 1% level and only rarely in controls. Body weights of all strains at all dose levels were similar.

Hazard to the eye-local effects (worker)

The test item is classified for eye damage (Cat.1, H318) according to Regulation (EC) No 1272/2008 (CLP).

 

References

ECHA (2012). Guidance on information requirements and chemical safety assessment. Chapter R.8:

Characterisation of dose [concentration]-response for human health. Version 2.1, November 2012

ECHA (2016). Guidance on information requirements and chemical safety assessment. Part E: Risk Characterisation, Version 3.0, May 2016

The MAK-Collection Part I: MAK Value Documentations, Vol. 26.DFG, Deutsche Forschungsgemeinschaft, Acrylic Acid

Andersen M, Sarangapani R, Gentry R, Clewell H, Covington T, Frederick CB (2000) Application of a hybrid CFD-PBPK nasal dosimetry model in an inhalation risk assessment: an example with acrylic acid.Toxicol Sci 57: 312–325

Frederick CB, Bush ML, Lomax LG, Black KA, Finch L, Kimbell JS, Morgan KT, Subramaniam RP, Morris JB, Ultman JS (1998) Application of a hybrid computational fluid dynamics and physiologically based inhalation model for interspecies dosimetry extrapolation of acidic vapors in the upper airways.Toxicol Appl Pharmacol 152: 211–231

Frederick CB, Gentry PR, Bush ML, Lomax LG, Black KA, Finch L, Kimbell JS, Morgan KT, Subramaniam RP, Morris JB, Ultman JS (2001) A hybrid computational fluid dynamics and physiologically based pharmacokinetic model for comparison of predicted tissue concentrations of acrylic acid and other vapors in the rat and human nasal cavities following inhalation exposure.Inhal Toxicol 13: 359–376

Keyhani K, Scherer PW, Mozell MM (1995) Numerical simulation of airflow in the human nasal cavity.J Biomech Eng 117: 429–441

Kimbell JS, Gross EA,,RB, Morgan KT (1997) Computer simulation of inspiratory airflow in all regions of the F344 rat nasal passages.Toxicol Appl Pharmacol 145: 388–398

Morris JB, Frederick CB (1995) Upper respiratory tract uptake of acrylate esters and acid vapors. Inhal.Toxicol 7: 557–574

General Population - Hazard via inhalation route

Systemic effects

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

Local effects

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

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:
high hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.4 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Dose descriptor starting point:
NOAEL
Value:
40 mg/kg bw/day
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:
The default extrapolation factor for exposure duration is used.
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:
2.5
Justification:
The default value for interspecies differences is used.
AF for intraspecies differences:
10
Justification:
The default value for the more heterogenous group "general population" 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:
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:
ECHA REACH Guidance
Overall assessment factor (AF):
0.33
DNEL extrapolated from long term DNEL

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - General Population

General

DNEL derivation for the test item is performed under consideration of the recommendations of ECHA, Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterization of dose-response for human health (Version: 2.1, November 2012).

1. Inhalation

In 2006 the German MAK commission determined a scientific OEL for acrylic acid of 10 ppm (30 mg/m³), which was confirmed as a German OEL by the regulatory authorities in 2007 and the European Scientific Committee for Occupational Exposure Limits in 2008. This value is regarded to be safe for workers; according to the ECHA Guidance document the intra-species 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 10 ppm, resulting in a DNEL for general population of 1.2 ppm (3.6 mg/m3). The DNEL value of 3.6 mg/m3 was determined for systemic and local DNEL via inhalation for general population (long and short term).

2. Dermal

Long term& acute, systemic DNEL- dermal exposure (general population)

The substance classified for skin corrosion (Cat.1A) and cause damage to eyes (Cat.1). Therefore, the systemic effects are secondary due to local effects. The available data do not allow a quantitative approach since the substance exerts its effects by a threshold mode of action. Therefore, a qualitative risk characterization should be performed for this endpoint in order to guarantee ‘adequately control of risks’, it is necessary to stipulate risk management measures that prevent skin corrosion. In two dermal carcinogenicity studies in three mice strains (C3H/HeJ, C3H/HeN Hsd BR and Hsd:(ICR)BR), the frequency of skin tumors was not elevated compared to the vehicle controls.

Long term & acute, local DNEL- dermal exposure (general population)

According to the REACH guidance on information requirements and chemical safety assessment, Part E: Risk Characterization, a qualitative risk characterization should be performed for this endpoint. This qualitative approach has to be implemented to deal with the eye as well as skin irritating properties of the substance. As a result, a high hazard is derived. In order to guarantee "adequately control of risks", it is necessary to stipulate risk management measures that prevent skin, eye and mucous membrane exposure. Results of the a study with three strains of mice receiving acrylic acid dermally at levels of 4, 1 and 0% for 13 weeks caused comparable skin irritation to ICR, C3H and B6C3F1 mice at the 4% dose level. Minimal skin reactions were observed in all strains at the 1% dose level. Gross lesions other than skin reactions were incidental to treatment. Microscopic findings characterized as proliferative, degenerative or inflammatory changes were seen predominantly at the 4% level in all strains, occasionally at the 1% level and only rarely in controls. Body weights of all strains at all dose levels were similar.

3.Oral

Long term, systemic DNEL – exposure by oral route (general population)

In a subchronic study with Fischer 344 rats following administration of acrylic acid in the drinking water for 90 days, the NOAEL was determined to be 83 mg/kg bw/day. Following chronic exposure to acrylic acid in the drinking water, the NOAEL for male Wistar rats was 40 mg/kg bw/day, and for female rats 375 mg/kg bw/day.

Step 1: Relevant dose descriptor (NOAEL): 40 mg/kg bw/day

Step 2: Overall AF= 100

Interspecies AF, allometric scaling (rat to human): 4

Interspecies AF, remaining differences: 2.5

Intraspecies AF (general population): 10

Dose-response relationship AF: 1

Exposure duration AF: 1

In conclusion, long term systemic oral DNEL, general population= 0.4 mg/kg bw/day.

Acute, systemic DNEL- exposure by oral route (general population)

Due to the acute oral toxicity observed for the test item (LD50 >1000 < 2000 mg/kg bw), the substance is considered to be classified for acute oral toxicity Cat.4 under Regulation (EC) No. 1272/2008. In the ECHA Guidance it is stated that “[..], the acute DNEL can by default be set as 1-5 times the long-term DNEL”. Therefore, the DNEL for acute systemic oral, worker was extrapolated according to the ECHA Guidance by applying the AF of 0.33.

DNEL, long-term systemic dermal (0.4 mg/kg bw/day)/ AF (0.33)

DNEL, short-term systemic oral = 1.2 mg/kg bw/day

Hazard to the eye-local effects (worker)

The test item is classified for eye damage (Cat.1, H318) according to Regulation (EC) No 1272/2008 (CLP).

 

References

ECHA (2012). Guidance on information requirements and chemical safety assessment. Chapter R.8:

Characterisation of dose [concentration]-response for human health. Version 2.1, November 2012

ECHA (2016). Guidance on information requirements and chemical safety assessment. Part E: Risk Characterisation, Version 3.0, May 2016

The MAK-Collection Part I: MAK Value Documentations, Vol. 26. DFG, Deutsche Forschungsgemeinschaft, Acrylic Acid