Docosyl methacrylate

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics, other

Type of information:

experimental study

Adequacy of study:

key study

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

Qualifier:

no guideline available

Principles of method if other than guideline:

A series of in vitro and PBPK models were used to determine and predict the skin absorption and metabolism of a series of methacrylate monomers. Initial studies were conducted using the rat epidermal membrane model.The results of these studies, when compared to the subsequent rat whole  skin model in vitro experiments clearly indicated that the latter studies were more pertinent to the goals of the studies, particularly since the use of
epidermal membranes appeared to remove the carboxylesterase activity from the skin samples.

GLP compliance:

not specified

Radiolabelling:

no

Species:

rat

Strain:

Wistar

Sex:

male

Route of administration:

other: in vitro and intravenous in vivo

Type:

metabolism

Results:

The studies confirmed that alkyl-methacrylate esters are rapidly hydrolyzed by ubiquitous carboxylesterases. 

A series of in vitro and in vivo studies with a series of methacrylates were used to develop PBPK models that accurately predict the metabolism and fate of these monomers. The studies confirmed that alkyl methacrylate esters are rapidly hydrolyzed by ubiquitous carboxylesterases. First pass (local) hydrolysis of the parent ester has been shown to be significant for all routes of exposure. In vivo measurements of rat liver indicated this organ has the greatest esterase activity. Similar measurements for skin microsomes indicated approximately 20-fold lower activity than for liver. However, this activity was substantial and capable of almost complete firstpass metabolism of the alkylmethacrylates. For example, no parent ester penetrated whole rat skin in vitro for n-butyl methacrylate, octyl methacrylate or lauryl methacrylate tested experimentally with only methacrylic acid identified in the receiving fluid. In addition, model predictions indicate that esters of ethyl methacrylate or larger would be completely hydrolyzed before entering the circulation via skin absorption. This pattern is consistent with a lower rate of absorption for these esters such that the rate 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 hydrolyzed following inhalation exposure. These studies showed that any systemically 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).  

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

 Ester    Vmax       Km        CL    T50%    Cmax    Tmax
----------------------------------------------------------
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
----------------------------------------------------------

Vmax (nM/min/mg) and Km (µM) from rat-liver microsome (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.

Reference 2

Endpoint:

dermal absorption in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

key study

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

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: 780803361

Radiolabelling:

no

Species:

rat

Strain:

Wistar

Sex:

male

Type of coverage:

occlusive

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 PBPK model developed in this study.

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 cm-2 / h.
This rate of absorption is 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 cm-2 / h, 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.

Key result

Time point:

24 h

Dose:

100 µL/cm2

Parameter:

percentage

Absorption:

0.7 %

Remarks on result:

other: Rat epidermis

Key result

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 PBPK model developed in this study.

Description of key information

Bioaccumulation potential:

As indicated in a dermal absorption study, the structural analogue Dodecyl methacrylate is metabolised during penetration of the skin and not expected to enter the circulation as the parent ester.

Gastro intestinal-, respiratory- and dermal absorption are practically not expected due to physico-chemical properties and in vitro dermal absorption studies,  where methacrylate esters of molecular weights equal to or greater than butyl methacrylate were not detected in the receptor fluid and are not expected to enter the circulation as the parent ester. Due to structural analogies the same behaviour can be expected from Docosyl methacrylate.

Absorption rate:

The structural analogue Dodecyl methacrylate appears to be absorbed through rat skin and epidermis to a very low extent of 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. Due to structural analogies the same behaviour can be expected from Docosyl methacrylate.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Docosyl methacrylateis a solid of waxen consistence at 20°C with a molecular weight of 394.67 g/mol. The test item has an estimated water solubility of < 1 µg/L at 20°C. The log Pow is estimated to be 11.59 and the vapour pressure is estimated as1.96E-5 Pa at 25°C. The boiling point is estimated to be >380°C.

Absorption

Absorption is a property of a substance to diffuse across biological membranes.Generally, oral absorption is favored for molecular weights below 500 g/mol andlog Pow values between -1 and 4.In the GI tract absorption of small water-soluble molecules(molecular weight up to around 200 g/mol) occurs through aqueous pores or carriage of such molecules across membranes with the bulk passage of water. With a calculated log Pow of 11.59 Docosyl methacrylate absorption into the blood from gastrointestinal (GI) tract is not expected. With 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 µg/L, only very low concentrations of the substance are bioavailable. Therefore, the substance is considered to be absorbed poorly. Accordingly, no signs of systemic toxicity indicating that absorption has occurred were seen in an acute oral toxicity test up to 2000 mg/kg bw. The low oral toxicity is supported by results of structural analogous as after repeated oral applications with these substances the NOAELs were generally 1000 mg/kg bw/day, the highest dose tested. Therefore, GI absorption is not the favored route of absorption. Only few amounts of the substance may be absorbed by micellular solubilisation due to its very poor water solubility. In addition, the portion available for GI absorption after oral ingestion may be very low due to the widespread occurrence of esterases in the GI tract resulting in fast cleavage of the substance.

 

Absorption via the respiratory route also depends on physico-chemical properties like vapor pressure, log Pow and water solubility. In general, highly volatile substances are those with a vapor pressure greater than 25 kPa or boiling point below 50°C. Substances with log Pow values between -1 and 4 are favored for absorption directly across the respiratory tract epithelium by passive diffusion. Due to its solid waxen consistence, neglectable vapor pressure of1.96E-5 Pa and boiling point of >380°C Docosyl methacrylate is unlikely to be available for inhalation exposure.

 

In general, dermal absorption is favored by small molecular weights and high water solubility of the substance. Log Pow values between 1 and 4 favor dermal absorption, particularly if water solubility is high.

With a very low water solubility of <1 µg/L dermal uptake of Docosyl methacrylate from the stratum corneum into the epidermis is likely to be 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. This is supported by results of Jones, 2002 who investigated the absorption of Lauryl methacrylate (LMA; synonym: Dodecyl methacrylate) and smaller alkyl-methacrylate esters through whole rat skin and rat epidermis in an in vitro system (Jones 2002). The rate of absorption of LMA across the whole rat skin or only rat epidermis was measured using glass diffusion cells following the application of 100 µL/cm2 of LMA to the epidermal surface. The mean rate of absorption was 26.2 µg cm-2 /h for rat epidermis and 7.72 µg cm-2/h for whole rat skin. The total amount of chemical that was absorbed during the time of exposure was 0.7 % (rat epidermis) and 0.26 % (rat whole skin) over 24 hours,respectively.The presence of carboxylesterases completely hydrolyzed the LMA (first pass effect). The appearance of onlymethacrylic acid (MAA) in receptor chambers of diffusion cells, following the application of LMA to the surface of whole rat skin, suggests that the rate of hydrolysis is more rapid than its absorption across the dermal region of the skin. It can be concluded from these results that the ester is completely metabolized during the dermal absorption process.

 

For the alkyl-methacrylate esters, their absorption rates correlate with their molecular volume in the sense that smaller esters permeate membranes more rapidly than larger esters. Therefore, Docosyl methacrylate is expected to be absorbed to a very low extend, if any.

 

Distribution

In general, the smaller the molecule the broader is its distribution. Small water-soluble molecules will diffuse through aqueous channels and pores in the membranes. As the bioavailability of the structural analogue Dodecyl methacrylate 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 limited amount if any of the substance comes into consideration for distribution into 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 can be considered as neglectable.

 

Metabolism

No data are available on the metabolism of Docosyl methacrylatein vivo or in vitro.

The metabolism of higher methacrylate estersstarts with ester hydrolysis resulting in methacrylic acid (MAA) and the corresponding alcohol (Jones, 2002).Wide-spread availablecarboxylesterases mediate this hydrolysis and show a high activity within many tissues and organs (Jones 2002). While the acid is further metabolised via the valine pathway of the citric acid cycle(ECETOC, 1995) thealcohol 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 2-ethylhexyl methacrylate showed rapid metabolism with half lives in rat blood of less than 30 min (Jones, 2002, see table 1).A series of in vitro and in vivo studies with a series of methacrylates were used to develop a PBPK model that accurately predict 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 1). In addition, removal of methacrylic acid from the blood also occurs rapidly (T50 %; see table 1).

 

Table 1: 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	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 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.

 

Taken together, esters were metabolised to MAA, which is the chemical entity associated with toxicity. Therefore, alkyl-methacrylate esters possessing low or no potential for systemic toxicity in rats or humans as a result of their conversion to MAA.

 

Accummulation

In principle, accumulation of Docosyl methacrylate in adipose tissue could be expected as the calculated log Pow is 11.59, but as mentioned above it is expected that the substance is completely metabolized due to rapid cleavage by esterases. Therefore, no accumulation of Docosyl methacrylate is expected.

 

Excretion

In general, urinary excretion in favored by low molecular weight (below 300 g/mol in the rat) and good water solubility. As absorption is very low respectively not expected and complete metabolism is very fast, excretion of unchanged Docosyl methacrylate is hardly relevant.

     

Summary and conclusion

Only a very low oral and dermal absorption of Docosyl methacrylate is expected. Due to its solid waxen state and low vapor pressure Docosyl methacrylate is unlikely to be available for inhalation to a large extent and absorption via inhalation can beneglected. Docosyl methacrylate is expected to be rapidly metabolized resulting in Methacrylic acid (MAA) and the corresponding alcohol Docosan-1-ol. Therefore, Docosyl methacrylate is not expected to enter the circulation as the parent ester and no bioaccumulation will occur.As absorption is very low respectively not expected and complete metabolism is very fast, excretion of unchanged Docosyl methacrylate is hardly relevant.

 

References

[1] Jones, Rhys D.O. (2002), Using Physiologically Based Pharmacokinetic Modelling to Predict the Pharmacokinetics and Toxicity of Methacrylate Esters, thesis submitted to the University of Manchester

[2] ECETOC (European Centre for Ecotoxicology and Toxicology of Chemicals) (1995).

Joint Assessment of Commodity Chemicals. No.30. Methyl Methacrylate. ECETOC.

[3] ECHA (2017), Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance, Version 3.0, June 2017