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Description of key information

Gastro intestinal-, respiratory- and dermal absorption to a major extent are not expected due to physico-chemical properties and in vitro dermal absorption study of the structural analogue dodecyl methacrylate. Dodecyl methacrylate appears to be absorbed through rat skin and epidermis to a low extent, 0.26 % in 24 hrs. It is fully metabolized to methacrylic acid during the passage (first-pass effect). As indicated by a PB-PK model used in this study, human skin is 14 times less permeable to dodecyl methacrylate than rat skin.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

Physical chemical properties

The test substance is a liquid UVCB containing isomers with a molecular weight of 324.54 g/mol. The calculated log Pow value is 9.1 at 25 °C and the solubility in water is < 24 µg/L at 20 °C. No data on hydrolysis and surface tension are available since the substance is poorly soluble. The vapour pressure of the substance is 0.0000109 hPa at 20 °C. These physico-chemical properties of the substance will enable qualitative judgements of the toxicokinetic behaviour (Guidance on information requirements and chemical safety assessment Chapter R.7.c, R.7.12 Guidance on Toxicokinetics).

GI absorption

No experimental data are available for GI absorption. Substances with a molecular weight below 500, high water solubility and a log Pow between -1 and 4 are favourable for absorption. With a log Pow > 4 passive diffusion through membranes is not expected but the substance may form micelles and be absorbed into the lymphatic system. However, due to the very poor water solubility of < 1 mg/L, only very low concentrations of the substance are bioavailable. In addition, no signs of systemic toxicity indicating that absorption has occurred were seen in an acute oral toxicity test up to 2000 mg/kg bw. Furthermore an oral repeated dose study is available for the structural analogue N-Dodecyl methacrylate (CAS 142-90-5) and no treatment related effects were observed in this study which could indicate that the substance may be absorbed.

Respiratory absorption – Inhalation

No experimental data are available for respiratory absorption. The vapour pressure of C 17 Methacrylate is only 0.0000109 hPa and therefore inhalation is not a relevant route of absorption.

Dermal absorption

C 17 Methacrylate is a liquid with a molecular weight below 500 g/mol which would favour dermal uptake, but with a very low water solubility <1 µg/l dermal uptake from the stratum corneum into the epidermis is likely to be very low. With log Pow > 6 the rate of transfer between the stratum corneum and the epidermis will be slow and will limit absorption across the skin. Uptake into the stratum corneum itself is expected to be slow.

In addition, no signs of systemic toxicity indicating absorption were observed in an acute dermal toxicity study on C17 Methacrylate with doses up to 5000 mg/kg bw.

For the structural analogue dodecyl methacrylate the dermal absorption (steady-state flux) has been estimated by calculation using the principles defined in the Potts and Guy prediction model (Heylings JR, 2013) (Table 1). Based on a molecular weight of 254.41 g/mol and a Kow of 6.68, the predicted flux of dodecyl methacrylate is 0.003 μg/cm²/h; thus, the relative dermal absorption is minimal. In addition, in an in vitro skin absorption study Lauryl methacrylate (70 % Dodecyl methacrylate and 25 % tetradecyl methacrylate) was applied to skin of male Wistar rats. The 24 hour absorption was determined to be 0.264%. In conclusion, absorption of dodecyl methacrylate via the skin will be limited and subsequently it can be concluded that dermal absorption of C 17 Methacrylate is likely to be minimal.

Table 1: Terms used for categorising absorption of chemicals through human skin:

Kp (cm/h)

 

Absorption Rate (µg/cm²/h)

 

Relative Absorption Rate Category

 

 

Predicted Absorption from Normal Exposure

1E-02 – 1E-01

>500

Very fast

Very high

1E-03 – 1E-02

100-500

Rapid - Fast

High

1E-04 – 1E-03

10-50

50-100 

Slow - Moderate

Moderate - Rapid

Moderate

1E-05 – 1E-04

0.1-10

Very slow - Slow

Low

1E-06 – 1E-05

0.001-0.1

Extremely - Very slow

Minimal

<1E-06

<0.001

Extremely slow

Negligible

Metabolism

No data are available on the metabolism of C 17 Methacrylate in vivo.

The prominent pathway for the metabolism of higher methacrylate esters starts with ester hydrolysis resulting in methacrylic acid and the corresponding alcohol (Jones, 2002); (McCarthy and Witz, 1997). While the acid is further metabolised via the valine pathway of the citric acid cycle (ECETOC, 1995; European Union, 2002) the alcohol may be further metabolised by the two standard metabolic pathways for fatty alcohols (1. oxidation: fatty alcohol -> aldehyde -> acid, and subsequently CoA-mediated fatty acid metabolism - or - 2.: glucuronidation of the alcohol and excretion). Alkyl esters of methacrylic acid up to C8 (2-ethylhexyl methacrylate) showed rapid metabolism with half lives in rat blood of less than 30 min (Jones, 2002):

A series of in vitro and in vivo studies with a series of methacrylates were used to develop a PBPK model that accurately predicts the metabolism and fate of these monomers. The studies confirmed that alkyl methacrylate esters are rapidly hydrolysed in the organism by ubiquitous carboxylesterases. First pass (local) hydrolysis of the parent esters has been shown to be significant for all routes of exposure. In vivo measurements of rat liver indicated this organ as with the greatest esterase activity. Similar measurements for skin microsomes indicated an approximately 20-fold lower activity than for liver. Nevertheless, this activity was substantial and capable of almost complete first-pass metabolism of the alkyl methacrylates applied on skin. For example, no parent ester penetrated whole rat skin in vitro for n-butyl methacrylate, octyl methacrylate or lauryl methacrylate. When tested experimentally, only methacrylic acid was identified in the receiving fluid. In addition, model predictions indicate that esters of ethyl methacrylate or larger would be completely hydrolysed before entering the circulation via skin absorption. This pattern is consistent with a lower rate of absorption for these esters indicating that the rate of metabolism is within the metabolic capacity of the skin. Parent ester also was hydrolyzed by S9 fractions from nasal epithelium and was predicted to be effectively hydrolysed following inhalation exposure.

These studies showed that any systematically absorbed parent ester will be effectively removed during the first pass through the liver (CL as % LBF, see table). In addition, removal of methacrylic acid from the blood also occurs rapidly (T50 %; see table 2).

Table 2: Rate constants for the ester hydrolysis by rat-liver microsomes and predicted systemic fate kinetics from methacrylates following i.v. administration:

Ester

Vmax

Km

CL

(%LBF)

T50%(min)

Cmax(MAA)

(mg L-1)

Tmax(MAA)

(min)

MAA

-

-

51.6%

-

-

-

MMA

445.8

164.3

98.8%

4.4

14.7

1.7

EMA

699.2

106.2

99.5%

4.5

12.0

1.8

i-BMA

832.9

127.4

99.5%

11.6

7.4

1.6

n-BMA

875.7

77.3

99.7%

7.8

7.9

1.8

HMA

376.4

34.4

99.7%

18.5

5.9

1.2

2EHMA

393.0

17.7

99.9%

23.8

5.0

1.2

OMA

224.8

11.0

99.9%

27.2

5.0

1.2

MAA = Methacrylic acid (CAS 79-41-4); MMA = Methyl methacrylate (CAS 80-62-6); EMA = Ethyl methacrylate (CAS 97-63-5); i-BMA = Isobutyl methacrylate (CAS 97-86-9); n-BMA = n-Butyl methacrylate (CAS 97-88-1); HMA = Hexyl methacrylate (CAS 142-09-6); 2EHMA = 2-Ethylhexyl methacrylate (CAS 688-84-6); OMA = Octyl methacrylate (CAS 2157-01-9)

Vmax (nM/min/mg) and Km (µM) from rat-liver microsomes (100 µg/ml) determinations; CL = clearance as % removed from liver blood flow, T50% = Body elimination time (min) for 50% parent ester, Cmax = maximum concentration (mg/L) of MAA in blood, Tmax = time (min) to peak MAA concentration in blood from model predictions.

GSH conjugation, the second potential pathway, has only been observed with small alkyl methacrylates (methyl methacrylate/MMA, ethyl methacrylate/EMA) but was no longer measurable with butyl methacrylate. Moreover, GSH conjugation was only detectable with MMA and EMA at high concentrations which are only achievable under laboratory conditions (Elovaara et al., 1983, Mc Carthy et al., 1994).

Distribution

As the expected bioavailability is very low that means neither GI- and respiratory absorption nor dermal absorption to a more than minimal extent are expected and complete metabolism is predicted, only a very low amount of the substance comes into consideration for distribution in blood or plasma and accumulation in organs and tissues. In theory the lipophilic molecule is likely to distribute into cells and then the intracellular concentration may be higher than extracellular concentration particular in fatty tissues, but this is of secondary importance as the bioavailability of the substance is very low.

Accumulation

In principle, C 17 Methacrylate accumulation in adipose tissue could be expected as the calculated log Pow is 9.1, but before that it is expected to be completely metabolized due to rapid cleavage by esterases as described above.

Excretion

As absorption is very low respectively not expected and complete metabolism is very fast, excretion of the parent compound is not to be expected.