2-Propenoic acid, 2-propylheptyl ester

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

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:

44 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

other: German MAK commission

Dose descriptor:

other: OEL

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:

652.5 µg/cm²

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

Overall assessment factor (AF):

10

Dose descriptor starting point:

other: EC3

Additional information - workers

General

Most acrylates are chemical intermediates, manufactured and processed within closed systems. The primary route of industrial exposure to 2-propylheptyl acrylate is skin contact and inhalation. In an industrial setting, ingestion is not an anticipated route of exposure. DNEL derivation for the test item is performed under consideration of the recommendations of ECHA (2010). Since neither sub-chronic nor chronic repeated dose studies were available for 2-propylheptyl acrylate, DNELs were derived by readacross to the structural analogue 2-ethylhexyl acrylate as it has similar toxicological, physico-chemical and ecotoxicological properties compared to the test substance.

Systemic DNEL

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.

Short term DNELs are not required as the acute toxicity of 2-propylheptylester is low. The test substance is not classified and labelled for acute systemic toxicity, according to Directive 67/548/EEC (DSD) and Regulation (EC) No 1272/2008 (CLP), based on the test data for acute oral, dermal and inhalation toxicity.

Longterm, local DNEL

There exists no standard test method for the assessment of respiratory irritation. 2-propylheptyl acrylate has shown a skin irritating potential, whereas no irritation to the eye was observed. The structural analogue 2-ethylhexyl acrylate is classified as irritating to skin and respiratory tract. These data indicate a potential for respiratory irritation of 2-propylheptyl acrylate. Thus a qualitative risk assessment must be conducted. In 2007 the German MAK commission determined a scientific OEL (observed effect level) for long term local effects for 2-ethylhexyl acrylate of 5 ppm (38 mg/m3), which was confirmed as a German OEL by the regulatory authorities in 2008. The evaluation is based on the subchronic inhalation study (BASF AG, 1989) with a NOAEC for local effects (as most sensitive parameter) at 10 ppm, at the next higher concentration of 30 ppm only marginal to mild irritation / degeneration of the olfactory epithelium in the nasal cavity was observed. The grading of those effects was the same as observed in the control animals, only the incidence was slightly increased. Based on the mild and focal effects observed at the LOAEC of 30 ppm, also no dysfunctions of the olfactory epithelium are expected at these concentrations. Because rats are obligate nose breathers, and considering physiological parameters such as respiratory minute volume and surface area of the nasal cavity / olfactory epithelium, it was calculated that the exposure of the olfactory epithelium of the rat under experimental conditions was not less than anticipated worker exposure based on increased respiratory rate under work load. Since no short term inhalation studies are available with 2-ethylhexyl acrylate the MAK commission took data available with acrylic acid, methyl-, ethyl- and butyl acrylate which showed that only a mild enhancement of the local irritation effects were observed over time. An intraspecies factor may be justified if an effect is linked to enzyme polymorphism however, in cases of unspecific local irritation; especially where the effects are only sequels of pH-shifts or protein denaturation, there is not much variation to be expected. According to the MAK evaluation, based on studies with ethyl acrylate examining the enzymatic activity of carboxylic esterases in the respiratory and olfactory epithelium in rats, cynomolgus monkeys and men, it can be assumed that the ester cleavage is faster in rats than in men and monkeys (Frederick et al. 2002). Also other studies with succinic-, glutaric and adipinic acid esters showed a faster ester cleavage in the olfactory epithelium of rats compared with men and monkeys (Bogdanffy and Frame 1994), comparable results are known with methyl methacrylate (Mainwaring et al 2001). Acrylic acid is responsible for the nasal lesions caused by acrylates. It was calculated for 2 – 5 ppm ethyl acrylate that the acrylic acid burden of the olfactory epithelium in rats is by a factor 18 higher than it would be in the human olfactory epithelium (Frederick et al. 2002). Based on this data the MAK commission came to the conclusion that the olfactory epithelium of humans is less exposed than those of rats to acrylates. On the basis of the subchronic NOAEC of 10 ppm the MAK-value of 2-ethylhexyl acrylate was determined to be 5 ppm (MAK evaluation 2-ethylhexyl acrylate, 2007). This national OEL is taken as DNEL longterm local, as 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 requirements and chemical safety assessment, Chapter R.8: Characterisation of dose (concentration)-response for human health (December 2010). The DNEL of 5 ppm for 2-ethylhexyl acrylate was acceptable for its structural analogue 2-propylheptyl acrylate due to their toxicological and physico-chemical similarities, corresponding to a DNEL of 44 mg/m3.

References

BASF AG (1989) Report: Inhalation toxicity of 2-ethylhexyl acrylate as vapor in rats (3 months study), Project-no. 50I081/8502.

Bogdanffy MS, Fame SR (1994), Olfactory mucosal toxicity, Integration of morphological and biochemical data in mechanistic studies; Dubasuc esters as an example. Inhalation Toxicology 6, 205-219.

Frederick CB, Lomax LG, Black KA, Finch L, Scribner HE, Kimbel JS, Morgan KT, Subramaniam PR, Morris JB (2002) Use of a hybrid computational fluid dynamics and physiologically based inhalation model for interspecies dosimetry comparisons of ester vapors. Toxicol. Appl. Pharmacol., 183, 23-40.

Mainwaring G, Foster JR, Lund V, Green T (2001) Methyl methacrylate toxicity in rat nasal epithelium: studies of the mechanism of action and comparisons between species. Toxicology 158, 109-118.

MAK evaluation 2-ethylhexyl acrylate, Toxikologische arbeitsmedizinische Begründung von MAK-Werten, 42. Lieferung 2007.

Skin sensitisation

2-propylheptyl acrylate has been identified as a skin sensitiser in a local lymph node assay (BASF SE, 2008). The corresponding DNEL was derived from an EC3 value of 26.1% w/v. This value is equivalent to 6525 µg/cm2. With an EC3 of 1000 – 10000 µg/cm2 2-propylheptyl acrylate is classified as weak sensitiser. 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.

Step 1: Selection of the relevant dose descriptor (starting point):

The EC 3 value of 6525 µg/cm2 is the relevant dose descriptor.

Step 2: Modification into a correct starting point:

Not applicable

Step 3: Use of assessment factors: 10

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 recognised 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.

In conclusion, long term local dermal DNEL, workers = 652.5 µg/m2

References

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

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Acute/short term exposure

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Acute/short term exposure

DNEL related information

General Population - Hazard via oral route

Systemic effects

Acute/short term exposure

DNEL related information

Additional information - General Population

Since neither sub-chronic nor chronic repeated dose studies were available for 2-propylheptyl acrylate, DNELs were derived by read across to the structural analogue 2-ethylhexyl acrylate. End-use consumer products contain only trace amounts of acrylic acid and esters (as a result of polymerization). Therefore consumer exposure to acrylate monomers is likely to be low (SRI, 2001). General population is not exposed to 2-propylheptyl acrylate by inhalation or dermal exposure. The release of the substance in the environment (water, air) is extremely low. Therefore no inhalation and no dermal DNEL were derived for general population. An oral DNEL was not calculated for general population as secondary poisoning is not applicable. Although the substance has a log Pow above 3.0, it is readily biodegradable. Therefore the substance does not accumulate in food chains and an oral long-term DNEL does not need to be derived.