2-Propenoic acid, 2-methyl-, C11-14-isoalkyl esters, C13-rich

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics, other

Remarks:

in vivo, in vitro

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
This read-across is based on the hypothesis that source and target substances have similar physicochemical, ecotoxicological and toxicological properties because
• they are manufactured from similar or identical precursors under similar conditions
• they share structural similarities with common functional groups: methacrylate esters
• the metabolism pathway leads to comparable products (methacrylic acid and medium chain alcohol).

Therefore, read-across from the existing physicochemical, ecotoxicity and toxicity studies on the source substances is considered as an appropriate adaptation to the standard information requirements of REACH regulation

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
see “Justification for read-across” attached to IUCLID section 13

3. ANALOGUE APPROACH JUSTIFICATION
see “Justification for read-across” attached to IUCLID section 13

4. DATA MATRIX
see “Justification for read-across” attached to IUCLID section 13

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across: supporting information

Objective of study:

metabolism

Species:

rat

Strain:

Wistar

Sex:

male

Route of administration:

other: in vitro and intravenous in vivo

Type:

metabolism

Results:

rapidly hydrolyzed by ubiquitous carboxylesterases by all routes of exposure

Metabolites identified:

yes

Details on metabolites:

alcohol and methacrylic acid

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 first-pass metabolism of the 

alkyl-methacrylates. 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.

Conclusions:

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. Further, the removal of the hydrolysis product, methacrylic acid, also is very rapid (minutes).

Reference 2

Endpoint:

dermal absorption in vitro / ex vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
This read-across is based on the hypothesis that source and target substances have similar physicochemical, ecotoxicological and toxicological properties because
• they are manufactured from similar or identical precursors under similar conditions
• they share structural similarities with common functional groups: methacrylate esters
• the metabolism pathway leads to comparable products (methacrylic acid and medium chain alcohol).

Therefore, read-across from the existing physicochemical, ecotoxicity and toxicity studies on the source substances is considered as an appropriate adaptation to the standard information requirements of REACH regulation

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
see “Justification for read-across” attached to IUCLID section 13

3. ANALOGUE APPROACH JUSTIFICATION
see “Justification for read-across” attached to IUCLID section 13

4. DATA MATRIX
see “Justification for read-across” attached to IUCLID section 13

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across: supporting information

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 hr-1.
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 hr-1, 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.

Dose:

100 µl/cm²

Parameter:

percentage

Absorption:

0.7 %

Remarks on result:

other: 24 hrs

Remarks:

Rat epidermis

Parameter:

percentage

Absorption:

0.264 %

Remarks on result:

other: 24 hrs

Remarks:

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.

Conclusions:

Lauryl methacrylate is absorbed through rat skin to a low extent, 0.26 % within 24 hours.
The presence of carboxyl esterases in the skin completely hydrolyses the substance, only the resulting metabolite methacrylic acid was demonstrated to pass through.
With respect to human skin, 14 times more efficient permeation through rat skin obtained in an epidermal PB-PK model developed in this study.

Description of key information

As indicated in a dermal absorption study with the source substance Dodecyl methacrylate, the target substance Isotridecyl methacrylate is metabolised during penetration of the skin and not expected to enter the circulation as the parent ester. Gastrointestinal-, respiratory- and dermal absorption to a major extent are not expected due to physicochemical properties and in vitro dermal absorption studies, where methacrylate esters of molecular weight 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.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

No experimental data on Isotridecyl methacrylate are available for the assessment of toxicokinetics is partially based on physicochemical properties. Additionally, studies are available for the source substances 2-Ethylhexyl methacrylate and Dodecyl methacrylate. A detailed justification for read-across is attached to IUCLID section 13.

 

Physico-chemical properties of the substance will enable qualitative judgements of the toxicokinetic (TK) behaviour (Guidance on information requirements and chemical safety assessment Chapter R.7.c, R.7.12 Guidance on Toxicokinetics):

In general, with a calculated log Pow of >6.5 of Isotridecyl methacrylate absorption into the blood form gastrointestinal (GI) absorption, respiratory absorption or skin is not expected. (log Pow values between -1 and 4 are favourable for absorption). With a water solubility of < 1 µg/L the substance is poorly soluble. The molecular weight is 254.42 - 338.58 (mean ca. 285) g/mol, and the substance is not a skin sensitizer.

 

Absorption

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 low water solubility of < 1 µg/L, only very low concentrations of the substance are bioavailable. Therefore, the substance will be absorbed poorly.

GI absorption is not the favoured route of absorption. Only small amounts of the substance may be absorbed by micellular solubilisation due to its very low water solubility.

 

Respiratory absorption – Inhalation

No experimental data are available for respiratory absorption.

The vapour pressure of Isotridecyl methacrylate is 0.06 Pa at 20°C and therefore the volatility is too low for inhalation (substances with low volatility have a vapour pressure of less than 0.5 kPa).

Inhalation is not a relevant route of absorption.

 

Dermal absorption

Isotridecyl methacrylate is a liquid substance with a molecular weight in the range 254.42 - 338.58 (mean ca. 285) g/mol which would favour dermal uptake, but with a very low water solubility of <1 µg/L dermal uptake from the stratum corneum into the epidermis is likely to be too low. With a 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. Uptake into the stratum corneum itself is expected to be slow.

Although Isotridecyl methacrylate has a skin binding structure (methacrylate), it was not. The substance is not skin irritating or corrosive, so that the substance itself will not enhance penetration through damaged skin.

 

Metabolism

No data are available on the metabolism of Isotridecyl methacrylate in vivo.

If it is assumed that Isotridecyl methacrylate will be absorbed through the skin, 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 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). In addition, removal of methacrylic acid from the blood also occurs rapidly (T50 %; see table).

 

Table:

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)

DMA = Dodecyl methacrylate

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.

 

Table: Summary of the peak rates of absorption of MAA and alkyl-methacrylate esters through whole rat and human skin.

		Rat whole skin					Human whole skin
Ester	Molec. Volume	Peak rate of appearance   Parent Ester		Peak rate of appearance   MAA	Period of peak abs. rate	Absorbed dose	Predicted rate of absorption
		µg cm-2h-1 ±SEM		µg cm-2h-1 ±SEM	h	% of applied/ over x hours	µg cm-2h-1
MAA	78.96*			4584** ±344	5-8	70%/24	327.0**
MMA	93.198	360 ±20.9		108** ±4.59	2.5-24	11.3%/24	33.4**
EMA	107.436			190**			13.6**
iBMA	135.646			56**			4.0**
nBMA	135.856			40.9 ±9.4	2-10	0.4%/10	2.9**
6HMA	164.277			20**			1.4**
2EHMA	191.66*			9**			0.6**
OMA	192.696			10.3 ±0.65	8-24	0.24%/24	0.7**
DMA	249.536			11.8 ±2.11	8-24	0.26%/24	0.8**

The values in normal type were obtained experimentally, whilst those in italics are predicted values.

** Values are predicted rates of appearance of total chemical including parent ester and metabolite

 

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 bioavailability of 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 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.

 

Accummulation

In principle, dodecyl methacrylate should be absorbed accumulation in adipose tissue could be expected as the calculated log Pow is 6.68, but before that it is expected be completely metabolised due to the rapid cleavage by esterases as described.

 

Excretion

As absorption is very low respectively not expected and complete metabolism is very fast, excretion of dodecyl methacrylate is hardly relevant.

 

Summary and discussion of toxicokinetics

According to log P > 4, bioaccumulation of Isotridecyl methacrylate is in principle expected. However, with < 1 µg/L the substance is poorly soluble in water. Therefore, the bioavailability of the substance is very low. In vitro studies with rat liver showed fast ester hydrolysis with alkyl methacrylates up to C8-methacrylates. The same rapid metabolism is predicted for Isotridecyl methacrylate particularly as the available concentration in the body will be very low.

 

In experimental studies on dermal absorption, the source substance Dodecyl methacrylate was not detected in the receptor fluid, only the metabolite methacrylic acid. Therefore, it is not expected to enter the circulation as the parent ester.