Icosyl acrylate

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

2015

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Objective of study:

metabolism

Qualifier:

no guideline followed

GLP compliance:

not specified

Radiolabelling:

no

Positive control reference chemical:

methyl methacrylate

Metabolites identified:

yes

Incubation in rat liver S9 mix

The hydrolysis rate of 2 -Propenoic acid, C16 -alkyl ester is nearly parallel with that of 2 -Propenoic acid, C18 -alkyl ester. A slow but continously increase of acrylic acid was seen after 60 min, maximum degradation of 20% until the end of exposere time.

 

Incubation in rat plasma

A decrease of 2 -Propenoic acid, C16 -18 -alkyl ester of 50 % was seen in the first 10 min, until the end of the exposure time (120 min) the decrease of the alkyl esters was 75%. A continuous increase in acrylic acid of 25% is visible over the duration of the experiment.

Reference 2

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

2015

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Objective of study:

metabolism

Qualifier:

no guideline followed

GLP compliance:

not specified

Radiolabelling:

no

Positive control reference chemical:

methyl methacrylate

Metabolites identified:

yes

Incubation in rat liver S9 mix

The hydrolysis of 2 -Propenoic acid, C18 -22 -alkyl esters shows that the hydrolysis rate of 2 -Propenoic acid, C18 -alkyl ester, is in parallel with but a bit faster than that of 2-Propenoic acid, C20-alkyl ester and 2 -Propenoic acid, C22. Until the end of the exposure time a degradation rate of 20% was seen for 2 -Propenoic acid. C18 -22 -alkyl ester. Only a low formation of acrylic acid was seen.

Incubation in rat plasma

In the first 10 min a fast decrease of 2-Propenoic acid, C18-22 alkyl esters was seen. Until the end of the exposure time (120 min) the decrease of the 2 -Propenoic acid, C18 -22- alkyl esters was about 50%. Only a low formation of acrylic acid was seen after 60 min.

Reference 3

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

2015

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Objective of study:

metabolism

Qualifier:

no guideline followed

GLP compliance:

not specified

Radiolabelling:

no

Metabolites identified:

yes

Details on metabolites:

As the amount of the acrylate (2-Propenoic acid, C12-14-alkyl esters) decreases, the amount of acrylic acid increases in correlation.

Incubation in rat liver S9 mix

The hydrolysis of 2 -Propenoic acid, C12 -14 -alkyl esters shows that the hydrolysis rate of 2 -Propenoic acid, C12 -alkyl ester is in parallel with but a little bit faster than that of 2 -Propenoic acid, C14 -alkyl ester. The amount of acrylic acid increased in correlation with the decrease of 2 -Propenoic acid, C12 -14 -alkyl esters.

Incubation in rat plasma

After 120 minutes a reduction of 2 -Propenoic acid, C12 -14 -alkyl esters of almost 100 % is observed. At the same time the acrylic acid increased by 50 %.

Reference 4

Endpoint:

basic toxicokinetics

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

2002

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Objective of study:

metabolism

GLP compliance:

no

Species:

rat

Strain:

Fischer 344

Sex:

male

Route of administration:

other: in vitro and intravenous in vivo

Details on absorption:

Using a reliable experimental method, the in vivo and in vitro investigations as well as the PBPK models developed from the data showed that alkyl-methacrylate esters are rapidly absorbed and are hydrolyzed at exceptionally high rates to methacrylic acid by high capacity, ubiquitous carboxylesterases.

Details on excretion:

The removal of the hydrolysis product, methacrylic acid, also is very rapid (minutes). For 2-EHMA the half-life was 23.8 minutes and 99.9 % was removed by first-pass metabolism in the liver.

Reference 5

Endpoint:

dermal absorption in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

2002

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 428 (Skin Absorption: In Vitro Method)

GLP compliance:

no

Radiolabelling:

no

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

Collection and preparation of rat skin for epidermal membrane absorption studies:
Skin was used from male rats of the Wistar-derived strain (supplied by Charles River UK Ltd, Margate, Kent, UK.) aged 28 days ± 2 days. Fur from the dorsal and flank region was carefully shaved using animal clippers, ensuring that the skin was not damaged. The clipped area was excised and any subcutaneous fat removed. The skins were soaked for approximately 20 hours in 1.5M sodium bromide then rinsed in distilled water. The epidermis was carefully peeled from the dermis. Each epidermal membrane was given an identification number and stored frozen on aluminium foil until required for use.
 
Collection and preparation of rat skin for whole skin absorption studies:
Skin was taken from male Fisher F344 (supplied by Harlan Olac) rats weighing between 200 and 250 g. Fur from the dorsal and flank region was carefully shaved using animal clippers, ensuring that the skin was not damaged. The clipped area was excised and any subcutaneous fat removed. Each skin membrane was given an identification number and immediately assembled into diffusion cells and their integrity checked.

Type of coverage:

open

Vehicle:

unchanged (no vehicle)

Duration of exposure:

48 hrs

Doses:

100 µL/cm²

Details on study design:

The absorption of Lauryl methacrylate was evaluated through rat epidermis and intact skin in an in vitro system. Values for human skin absorption were extrapolated on the basis of a 14 times more efficient permeation through rat skin obtained in an epidermal PB-PK model developed in this study.

Details on in vitro test system (if applicable):

Assembly of the diffusion cells:
The type of glass diffusion cell has an exposed membrane area of 2.54 cm². Discs of approximately 3.3 cm in diameter were cut from the prepared skin and membrane from at least three individuals (two in the case of human skin) were mounted, dermal side down, in diffusion cells held together with individually numbered clamps.

Signs and symptoms of toxicity:

not examined

Dermal irritation:

not examined

Absorption in different matrices:

Absorption of Lauryl methacrylate through rat epidermis:

The substance is readily absorbed through rat epidermis at a constant mean rate of 26.2 µg/cm²/hr.
This rate of absorption are virtually constant over the duration of the experiment.
The total amount of chemical that was absorbed during the time of exposure was 0.7 % of the applied dose.

Absorption of Lauryl methacrylate through whole rat skin:

Like the smaller esters investigated, Lauryl methacrylate was also metabolised to methacrylic acid as it was absorbed through whole rat skin. the peak rate of appearance of methacrylic acid was calculated to be 11.8 µg/cm²/hr, which occurred between 8 and 24 hours.
0.264 % of the Lauryl methacrylate was depleted from the donor reservoir over the 24 hr exposure period.

Time point:

24 h

Dose:

100 µL/cm²

Parameter:

percentage

Absorption:

0.7 %

Remarks on result:

other: Rat epidermis

Time point:

24 h

Dose:

100 µL/cm²

Parameter:

percentage

Absorption:

0.264 %

Remarks on result:

other: whole rat skin

Conversion factor human vs. animal skin:

With respect to human skin, 14 times more efficient permeation through rat skin obtained in an epidermal PB-PK model developed in this study.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Absorption:

All members of the category are not expected to be readily absorbed by oral, inhalation and dermal routes based on the experimental data and predictions from physico-chemical properties. The available repeated dose toxicity studies for oral route/reproductive toxicity show that the long-chain acrylate esters, either as parents and/or their metabolites, are not likely absorbed based on the lack of significant systemic effects observed.

 

Based on the molecular weights varying from 240 to > 350 g/mol, the high log Pow between 6.13 to 11.04 and very low water solubility values, the long-chain acrylate esters are not very likely to be absorbed in the gastrointestinal (GI) tract. The high log Pow indicates that the substances will not diffuse well across plasma membranes. In addition, gastro-intestinal absorption will not be triggered by passage via passive diffusion through aqueous pores or carriage with the bulk passage of water, which is favoured for small (molecular weight < 200 g/mol), water soluble substances. Therefore, only very low concentrations of these substances are bioavailable. The substances may be taken up by micellular solubilisation since this mechanism may be of particular importance for highly lipophilic compounds (log Pow > 4), particularly those that are poorly soluble in water. Overall, limited gastrointestinal absorption is expected for the target substance and the source substances based on their physicochemical properties. Moreover, almost no systemic effects were seen in acute and repeated dose toxicity studies after oral administration of mixture of C12-14 acrylates or mixture of C18-22 acrylates demonstrating and supporting that long-chain alkyl esters are not very well absorbed in the gastrointestinal tract, and if absorbed reveal a low systemic toxicity.

 

Higher acrylate esters exhibit a low volatility (vapour pressure of hPa). Therefore, only a very minimal amount of the substance is available for inhalation and thus, absorption by inhalation can be almost excluded. Moreover, absorption will be limited due to the low water solubility and high Pow of the substances. In addition, fine dust is not formed by this compound. Consequently, inhalation exposure due to fine dust or particles is also unlikely.

 

Thelong-chain acrylate estersare liquid or solid with very low water solubility (< 0.1 mg/L) and molecular weights between 240 and 350 g/mol, therefore dermal uptake from the stratum corneum into the epidermis is likely to be low. With log Pow > 6.5 the rate of transfer between the stratum corneum and the epidermis will be slow and will limit absorption across the skin. In addition, the substances showed no effects when tested for acute dermal toxicity or skin irritation.

These characteristics are in line with information obtained with the structural related substance Dodecyl methacrylate (C12, also known as Lauryl methacrylate): Experiments on this structural related substance with rat skin have demonstrated that the long-chain methacrylate esters in principle are dermally absorbed at very low amounts (0.26 % over 26 h). As a tendency confirmed with experiments on esters up to a chain length of C8, absorption decreased with increasing ester chain length. Due to the slow diffusion as well as the metabolic competency of the skin, the ester underwent complete hydrolysis to methacrylic acid and the long-chain alkyl alcohol. It is suggested that the rate of hydrolysis is more rapid than its absorption across the dermal region of the skin. It can be concluded that the ester is completely metabolized during the dermal absorption process (Jones, 2002). Furthermore, dermal absorption modelling performed with Dermwin (EPIsuite) also shows such a trend.

Dermal absorption rates for long-chain acryl esters generated with Dermwin model (EPIsuite).

 

Substance	Absorption rate (mg/cm2)	Kp (cm/h)
C12	0.00042	0.831
C14	0.000242	0.579
C16	0.000141	0.403
C18	0.0000802	0.28
C20	0.0000454	0.195
C22	0.0000256	0.136

 

Based on the physicochemical properties of higher acrylate esters they are unlikely to be widely distributed systemically throughout the extracellular compartments of the body after absorption. Particularly due to the low water solubility and the high log Pow values, a long biological half-life in tissues might be expected, but is almost excluded due to the poor absorption and the metabolic cleavage. Thus, the target substance and the source substances have no bioaccumulation potential and only a limited amount of any of these substances come into consideration for distribution into blood or plasma and accumulation in organs and tissues. Furthermore, the experimental data from the repeated dose toxicity study with C12-14 acrylate ester mixture has not shown any significant organ-specific toxicity which further supports the hypothesis of poor distribution throughout the body.

 

Metabolism:

This category is based on the hypothesis that the acrylate esters have similar toxicological properties and they have a common rapid metabolism pathway described by two primary routes: carboxylesterase mediated hydrolysis of the ester linkage to acrylic acid and the corresponding alcohol; and conjugation of AA-ester with glutathione.  

Primary hydrolysis products

 

Acrylate esters	Primary hydrolysis products
2-Propenoic Acid, C12-C14 alkylesters (Laurylacrylate 1214)	Acrylic acid, dodecanol and tetradecanol
Dodecyl acrylate (C12)	Acrylic acid and dodecan-1-ol
Tetradecyl acrylate (C14)	Acrylic acid and tetradecan-1-ol
2-Propenoic acid, C16-C18 alkylesters (Stearylacrylate)	Acrylic acid, hexadecan-1-ol and octadecan-1-ol
Hexadecyl acrylate (C16)	Acrylic acid and hexadecan-1-ol
Octadecyl acrylate (C18)	Acrylic acid and octadecan-1-ol
2-Propenoic acid, C18-22-alkyl esters	Acrylic acid, octadecan-1-ol and docosan-1-ol
Icosyl acrylate (C20)	Acrylic acid and icosan-1-ol
Docosyl acrylate (C22)	Acrylic acid and docosan-1-ol

 

 The alcohols associated with the esters being formed after hydrolysis are dodecan-1-ol (CAS No. 112-53-8), tetradecan-1-ol (CAS No. 112-72-1), hexadecan-1-ol (CAS No. 36653-82-4),octadecan-1-ol(CAS No. 112-92-5), docosan-1-ol (CAS No. 661-19-8), and icosan-1-ol (CAS No. 112-92-5 ). These alcohols are not considered to impact on the read-across approach within the category. Due to the rapid metabolism of the acrylate esters as demonstrated in the in vitro assays, the systemic toxicity exerted from the parental acrylate esters is also considered to be of minimal relevance (Roos, 2015).

 

However, the available toxicological studies of the category members for systemic toxicity endpoints suggest the similarity in toxicological properties. Therefore, any potential variation in toxicity associated with differences in the ester chain length is considered to be negligible. It is therefore concluded that AA is the common product of metabolism that is partly responsible for systemic toxicity for all substances within the category.

 

The major route of metabolism of acrylate esters has been shown to involve the rapid cleavage of the ester bond by carboxylic esterases (Figure 2; ECETOC, 1998; WHO, 1997), resulting in internal exposure to AA. Following carboxylesterase-catalysed hydrolysis to AA and the corresponding alcohol, a subsequent metabolic pathway involves metabolism of AA to carbon dioxide (CO2) via the propionate degradation pathway. The respective alcohols are metabolised via either a catalase peroxidative pathway or the alcohol dehydrogenase pathway. There is a trend towards increasing half-life of the esters in blood with increasing alcohol chain length (Roos, 2015). But systemically absorbed parent esters will be effectively removed during first pass through the liver resulting in their relatively rapid elimination from the body.

 

Half-lives and degradation rates for acrylate esters in presence of rat S9 fraction or plasma (Roos, 2015)

Substance	CAS No.	S9 Rat  (t1/2min.)	Plasma  (t1/2min.)
MA	96-33-3	-	34.62
EA	140-88-5	1.40	-
nBA	141-32-2	0.84	8.45
iBA	106-63-8	0.74	8.15
tBA	1663-39-4	-	-
2EHA	103-11-7	1.15	6.48
2-Propenoic Acid, C12-C14 alkylesters	84238-60-8	22.5 - 34,78	14.93 - 21.44
Dodecyl acrylate (C12)	2156-97-0	ND	ND
Tetradecyl acrylate (C14)	21643-42-5	ND	ND
2-Propenoic acid, C16-C18 alkylesters	90530-21-5	34.26 - 68.96	70.00-79.75
Hexadecyl acrylate (C16)	13402-02-3	ND	ND
Octadecyl acrylate (C18)	4813-57-4	ND	ND
2-Propenoic acid, C18-22-alkyl esters	85085-17-2	-	-
Icosyl acrylate (C20)	48076-38-6	ND	ND
Docosyl acrylate (C22)	18299-85-9	ND	ND

 

 

Acrylate esters are also expected to undergo conjugation with GSH to form thioesters (Frederick et al., 1992), with the main urinary conjugate identified as N-acetyl-S-(2-carboxyethyl)cysteine.The conjugates are then converted to mercapturic acids and excreted in the urine (Silver and Murphy, 1981; Miller, 1981).Inhibition of the hydrolytic pathway with a carboxylase inhibitor results in increased metabolism via the GSH conjugation route.Some minor impact is exerted by the positive inductive effect of the alcohol sub-group, but the incremental impact on electrophilicity rapidly decreases with increasing alcohol chain length. Therefore, for direct electrophilic reactions the alcohol group will only have a minor, rather monotonic influence with increasing chain length.

McCarthy et al. (1994) reported that increased alcohol chain length moderately affected the apparent second-order rate constant for the spontaneous reaction of acrylate esters with GSH in the in vitro study but did not affect potency relative to cellular GSH depletion. The structural alerts generated using QSAR Toolbox v4.3 show the similarity in electrophilic reactivity for all the category members.

Also, the low absorption of the long-chain acrylate esters can be considered a limiting factor for the formation of thioestersand GSH depletion.

Generally, metabolism will render the molecule more polar and harmless, leading to faster excretion. No conversion into a metabolite that is more toxic than the parent is expected as no increases in toxicity were noted in the presence of metabolic activation during the in vitro tests.