tert-butyl methacrylate

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

dermal absorption in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2002

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

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

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:

- Supplier: Ineos Acrylics
- Name of test material (as cited in study report): n-butyl methacrylate
- Physical state: liquid
- Analytical purity: 99%
- Purity test date: no data
- Lot/batch No.: Acrylics 98/15

Radiolabelling:

no

Species:

rat

Strain:

Wistar

Sex:

male

Type of coverage:

open

Vehicle:

unchanged (no vehicle)

Duration of exposure:

48 hours

Doses:

100 µL/cm²

Details on in vitro test system (if applicable):

The absorption of nBMA was evaluated through rat and human epidermis and through rat whole skinin an in vitro system.

SKIN PREPARATION
- Source of skin: epidermal membrane absorption studies: male rats of the Wistar-derived strain (supplied by Charles River UK Ltd, Margate, Kent, UK.); whole skin absorption studies: male Fisher F344 rats (supplied by Harlan Olac); human skin for epidermal membrane absorption studies: extraneous tissue was removed from human abdominal whole skin samples
- Ethical approval if human skin: obtained post mortem in accordance with local ethical guidelines
- Type of skin: human and rat skin
- Preparative technique:
Wistar rat skin: 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.
Fisher rat skin: 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.
Human skin: The skin samples were immersed in water at 60°C for 40-45 seconds and the epidermis was carefully peeled away from the dermis. Each epidermal membrane was given an identifying number and stored frozen on aluminium foil until required for use.
- Thickness of skin (in mm): Discs of approximately 3.3 cm in diameter; thickness not specified
- Membrane integrity check: yes; The donor and receptor chambers of the cells were filled with physiological saline (approx 0.9% w/v sodium chloride in water) and placed in a water bath maintained at 32ºC ± 1ºC. Membrane integrity was determined by measuring their electrical resistance. Membranes that were found to have a measured resistance that was below 2.5 kΩ (rat) or 10 kΩ (human) were regarded as having a lower integrity than normal and were not used. Following the completion of the integrity assessment, the contents of the donor and receptor chambers were discarded
- Storage conditions: frozen

PRINCIPLES OF ASSAY
- Diffusion cell: glass diffusion cell
- Receptor fluid: 50% ethanol in water (rat and human epidermis experiments) or physiological saline (0.9% w/v sodium chloride in water) (whole rat skin experiment)
- solubility in receptor fluid: Those esters that were tested are sufficiently
soluble in the ethanol/water receptor fluid, however, only the smaller esters – MMA & nBMA – are anything more than slightly soluble in saline
- Static system: yes; dose rate 100 μl cm-2; occluded for the duration of the exposure period (up to 48 h)
- Flow-through system: no
- Occlusion: yes

Signs and symptoms of toxicity:

not examined

Dermal irritation:

not examined

Absorption in different matrices:

Absorption of nBMA through rat epidermis:
The fastest rate of absorption (mean) of nBMA through rat epidermis was measured to be 1543 µg cm-2 hr-1, which occurred between 0 and 6 hrs following the application of the chemical. The rate of absorption diminished from this time onwards, as indicated by a flattening of the curve. The total amount absorbed was calculated as 11% by 6 hours and 18.3% after 24 hours, at which point no more samples were taken.

Absorption of nBMA through human epidermis:
The rate of absorption of n-butyl methacrylate was linear over the duration of the experiment and was calculated to be 76.7 µg cm-2 hr-1. Just over 2% of the applied dose was absorbed over the exposure period.

Absorption of nBMA through whole (viable) rat skin
Only methacrylic acid (MAA) appeared in the receptor chambers of skin that had had n-butyl methacrylate applied to the surface. This would imply that all of the nBMA that is absorbed through the skin is hydrolysed by carboxylesterases that are present in this tissue. The peak rate of appearance of MAA, which occurred between 2 and 10 hrs, was calculated to be 40.9 µg cm-2 hr-1. There is a lag-time present between 0 and 2 hrs. This experiment did not extend beyond ten hours, and the percentage dose removed from the donor reservoir was 0.4%.

Dose:

100 µL/cm²

Parameter:

percentage

Absorption:

18 %

Remarks on result:

other: 24 hours

Remarks:

Rat epidermis

Dose:

100 µL/cm²

Parameter:

percentage

Absorption:

2 %

Remarks on result:

other: 24 hours

Remarks:

Human epidermis

Dose:

100 µL/cm²

Parameter:

percentage

Absorption:

0.4 %

Remarks on result:

other: 10 hours

Remarks:

Whole (viable) rat skin

Conversion factor human vs. animal skin:

Human epidermis appears to be 20 times less permeable to nBMA than rat epidermis.

The results of the whole-skin penetration studies and the model predictions for 

other methacrylate esters are presented in the table.

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

 Ester     Ester      MAA     Period    %               Peak       Peak       Peak    Applied
                                         Absorp. Dose/
                                 (hours) length of exposure
-----------------------------------------------------------
MAA                    4584    5 - 8       70%/24 h 
MMA        360         108     2.5 - 24    11.3%/24 h
EMA                    190**                              
i-BMA                   56**                              
n-BMA                   41     2 - 10      0.4%/10 h
HMA                     20**                              
2EHMA                    9**                              
OMA                     10     8 - 24      0.24%/24 h
LMA                     12     8 - 24      0.26%/24 h
-----------------------------------------------------------

Ester Peak = rate of appearance of the parent ester (µg/cm2/hr) 
MAA Peak = rate of appearance of the hydrolysis product, MAA (µg/cm2/hr)
Period Peak Absorp. = Time (hours) after application for peak absorption
% Applied Dose = total % absorbed
** Predicted rates of MAA from model estimates.

Conclusions:

nBMA readily absorbs through rat and human epidermis and through whole rat skin. Human epidermis appears to be 20 times less permeable to 2-EHMA than rat epidermis.

Executive summary:

The absorption of nBMA was evaluated through rat and human epidermis and through whole (viable) rat skin in an in vitro system. Glass diffusion cells are employed to measure the amount of n-BMA that is received into a receptor chamber with respect to time, following the application of 100 µl/cm² of nBMA to the epidermal surface. The mean rate of absorption was 1540, 76.7 and 40.9 (appearance of MAA) µg cm-2 hr-1 and the total amount of chemical that was absorbed during the time of exposure was 18 (over 24 hours), 2 (over 24 hours) and 0.4% (over 10 hours), respectively. nBMA appears readily absorbed through rat and human epidermis, but human epideremis is 20 times less permeable to nBMA than rat epidermis.

Reference 2

Endpoint:

basic toxicokinetics, other

Remarks:

A series of in vitro and in vivo studies were used to develop PBPK models

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2002

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:

absorption

metabolism

Principles of method if other than guideline:

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.
A physiologically based pharmacokinetic model has been formulated to predict the pharmacokinetics and systemic disposition of alkylmethacrylate esters in rats and humans. Physiological (species specific) model parameters were obtained from the literature, while chemical specific model parameters were derived mainly from in vitro experiments. These in vitro experiments, which utilised rat and human tissues, included methods for estimating (1) the in vivo clearance from the liver, blood and skin, (2) the rates of absorption through skin and (3) the biological partition coefficients of the alkyl-methacrylate esters. A limited number of in vivo studies in the rat served to validate the PBPK model.

GLP compliance:

not specified

Specific details on test material used for the study:

Methacrylic acid from Ineos Acrylics (Lot 98/42; purity > 99%),
methyl methacrylate from Ineos Acrylics (Lot 98/15; purity > 99%),
ethyl methacrylat from Atofina (Lot 011666); purity: > 99%),
i-butyl methacrylate from Ineos Acrylics (Lot 98/15; purity 99%),
n-butyl methacrylate from Ineos Acrylics (Lot 98/15; purity 99%),
hexyl methacrylate from Röhm GmbH (Lot 78070243; purity > 98%),
2-ethylhexyl methacrylate from Röhm GmbH (Lot 78080370; purity > 98%),
octyl methacrylate from Röhm GmbH (Lot 22-902-13914-28; purity > 98%)

Radiolabelling:

no

Species:

rat

Strain:

Fischer 344

Sex:

male

Route of administration:

other: in vitro and intavenous in vivo

Type:

clearance

Results:

Systemically absorbed parent ester will be effectively removed during the first pass through the liver (%LBF) resulting in their relatively rapid elimination from the body (T50%).

Type:

absorption

Results:

Alkyl-methacrylate esters are rapidly absorbed

Type:

metabolism

Results:

Alkyl-methacrylate esters are hydrolyzed at exceptionally high rates to methacrylic acid. These studies showed that any systemically absorbed parent ester will be effectively removed during the first pass through the liver.

Metabolites identified:

yes

Details on metabolites:

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. In addition, removal of methacrylic acid from the blood also occurs rapidly.

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.

 

 

Table 2: Rate constants for ester hydrolysis by human-liver microsome samples

 Ester    Vmax (nM/min*mg) Km (mM) CL (µL/min*mg)    
-----------------------------------------------
MMA       1721      4103     419   
EMA        936      1601     584  
i-BMA       80       441     181
n-BMA      211       158    1332
HMA        229 66 3465
2EHMA       53        48    1109
OMA        243 38 6403

----------------------------------------------------------

CL is calculated from the mean Vmax and Km

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). For n-BMA the half-life was 7.8 minutes and 99.7 % was removed by first-pass metabolism in the liver.

Executive summary:

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). For n-BMA the half-life was 7.8 minutes and 99.7 % was removed by first-pass metabolism in the liver.

Description of key information

Short description of key information on bioaccumulation potential result: 
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 and the respective alcohol. Further, the removal of the hydrolysis product, methacrylic acid, also is very rapid (minutes). For n-BMA the half-life was 7.8 minutes and 99.7 % was removed by first-pass metabolism in the liver.

Short description of key information on absorption rate: 
The absorption of nBMA was evaluated through rat and human epidermis and through whole (viable) rat skin in an in vitro system. The mean rate of absorption was 1540, 76.7 and 40.9 (appearance of MAA) µg cm-2 hr-1 and the total amount of chemical that was absorbed during the time of exposure was 18 (over 24 hours), 2 (over 24 hours) and 0.4% (over 10 hours), respectively. nBMA appears readily absorbed through rat and human epidermis, but human epidermis is 20 times less permeable to nBMA than rat epidermis.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - dermal (%):

2

Additional information

Basic absorption, distribution,metabolism and excretion (ADME), toxicokinetics

Data availability:

 

For t-BMA is no data available for metabolism in vitro and in vivo. As a member of a category of lower methacrylate esters there is sufficient data available to confirm applicability of this data across all members of the category.

 

There is some basic information available for the structural analogue n-BMA for metabolism in vitro and in vivo, as well as dermal absorption through rat and human skin. Furthermore, n-BMA is a member of a category of lower methacrylate esters, of which there are extensive data available for the methyl ester (MMA) and this has been reviewed in the EU Risk Assessment (2002). Sufficient data is available to confirm applicability of this data across all members of the category and this has been reviewed in the OECD SIAR (2009). Data on MAA, the common metabolite, has been reviewed in the EU Risk Assessment (2002). The following text relies on these reviews

Trends/Results

The OECD SIAR on short chain methacrylate esters concluded that: “Other short chain alkyl-methacrylate esters, like MMA, are initially hydrolysed by non-specific carboxylesterases to methacrylic acid and the structurally corresponding alcohol in several tissues (ECETOC 1995, 1996b)". In many regards, therefore, n-BMA behaves similarly to its close structural analogue MMA.

Taken from the EU Risk Assessment on MMA; “after oral or inhalation administration, methyl methacrylate is rapidly absorbed and distributed. In vitro skin absorption studies in human skin indicate that methyl methacrylate can be absorbed through human skin, absorption being enhanced under occluded conditions. However, only a very small amount of the applied dose (0.56%) penetrated the skin under unoccluded conditions (presumably due to evaporation of the ester from the skin surface (Syngenta/CEFIC, 1993))".

Absorption

The absorption of n-butyl methacrylate was evaluated through rat and human epidermis and through whole (viable) rat skin in an in vitro system (Jones, 2002). Glass diffusion cells are employed to measure the amount of n-BMA that is received into a receptor chamber with respect to time, following the application of 100 µl/cm² of nBMA to the epidermal surface. The mean rate of absorption was 1540, 76.7 and 40.9 (appearance of MAA) µg cm-2 hr-1 and the total amount of chemical that was absorbed during the time of exposure was 18 (over 24 hours), 2 (over 24 hours) and 0.4% (over 10 hours), respectively.

N-BMA, like all members of the Lower Alkyl (C1-C8) Methacrylates category can be absorbed following ingestion with the shorter esters being absorbed more rapidly through the skin than the longer esters. The volatile esters in the category are efficiently scrubbed from the inhaled air in the upper respiratory tract after inhalation.

MMA was reviewed under the EU Risk Assessment Program while the other esters were addressed under the OECD SIDS program, but this did not address absorption. The EU Risk Assessment on MMA concluded that; “after oral or inhalation administration, methyl methacrylate is rapidly absorbed and distributed.In vitroskin absorption studies in human skin indicate that methyl methacrylate can be absorbed through human skin, absorption being enhanced under occluded conditions. However, only a very small amount of the applied dose (0.56%) penetrated the skin under unoccluded conditions (, presumably due to evaporation of the ester from the skin surface (CEFIC, 1993)). After inhalation exposure to rats 10 to 20% of the substance is deposited in the upper respiratory tract where it is metabolized (by non-specific esterases to the acid, MAA (Morris, 1992)).

-Dermal

Jones (2002) studied the permeability of separated rat and human skin to alkyl methacrylate esters as part of a PhD thesis on development of a PBPK model to predict the pharmacokinetics and toxicity of methacrylate esters. Data on MMA, nBMA and 2-EHMA indicate that rat skin is more permeable to the absorption of these esters than human skin and there is a steep decline in the rate of penetration across the category from MMA to the larger ester, 2-EHMA. The rate of penetration of EMA was predicted to be between that of MMA and nBMA and that of iBMA comparable to nBMA.

 

Table: Summary of the results for the peak rates of absorption of alkyl methacrylate esters through rat & human epidermis (adapted from Jones, 2002)

 

Ester

Rat epidermis

Human epidermis

 

	Peak rate of absorption (μg/cm²/hr) ±SEM	Period of peak absorption rate (hours)	% age of applied dose absorbed over x hours	Peak rate of absorption (μg/cm²/hr) ±SEM	Period of peak absorption rate (hours)	% age of applied dose absorbed over x hours
MMA	5888±223	2-8	46% / 16h	453±44.5	4-24	10% / 24h
EMA	4421	-	-	253	-	-
i-BMA	1418	-	-	80	-	-
n-BMA	1540±69	0-6	18% / 24h	76.7±9.8	0-24	2% / 24h
HMA	147	-	-	25	-	-
2EHMA	234±4.8	0-30	7.8% / 30h	22.7.7±3.7	3-24	0.6% / 24h
OMA	159±15	0-24	-	7.8	-	-

 

 

Metabolism

 

After inhalation exposure to rats 10 to 20% of the substance is deposited in the upper respiratory tract where it is metabolized (by non-specific esterases to the acid, MAA (Morris, 1992)). Activities of local tissue esterases of the nasal epithelial cells appear to be lower in man than in rodents (Green, 1996 later published as Mainwaring, 2001). Toxicokinetics seem to be similar in man and experimental animal. After arthroplasty using methyl methacrylate-based cements, exhalation of unchanged ester occurs to a greater extent than after i. v., i. p. or oral administration. After oral or parenteral administration methyl methacrylate is further metabolised by physiological pathways with the majority of the administered dose being exhaled as CO₂ (Bratt and Hathway, 1977; ICI, 1977a). Conjugation with GSH or NPSH plays a minor role in methyl methacrylate metabolism and only occurs at high tissue concentrations (McCarthy and Witz, 1991; Elovaara et al., 1983) ”.

Methacrylic acid and the corresponding alcohol are subsequently cleared predominantly via the liver (valine pathway and the TCA (TriCarboxylic Acid) cycle, respectively). The carboxylesterases are a group of non-specific enzymes that are widely distributed throughout the body and are known to show high activity within many tissues and organs, including the liver, blood, GI tract, nasal epithelium and skin (Satoh & Hosokawa, 1998; Junge & Krish, 1975; Bogdanffy et al., 1987; Frederick et al., 1994). Those organs and tissues that play an important role and/or contribute substantially to the primary metabolism of the short-chain, volatile, alkyl-methacrylate esters are the tissues at the primary point of exposure, namely the nasal epithelia and the skin, and systemically, the liver and blood.

Methacrylate esters can conjugate with glutathione (GSH) in vitro, although they show a low reactivity, since the addition of a nucleophile at the double bond is hindered by the alpha-methyl side-group (McCarthy & Witz, 1991, McCarthy et al., 1994, Tanii and Hashimoto, 1982). Data with n-BMA indicate that GSH conjugation is negligible (McCarthy et al. 1994). Hence, ester hydrolysis is considered to be the only significant metabolic pathway for n-BMA.  Therefore, ester hydrolysis is considered to be the major metabolic pathway for alkyl-methacrylate esters, with GSH conjugation only playing a minor role in their metabolism, and then possibly only when very high tissue concentrations are achieved.

 

Table: GSH reactivity of methacrylate esters

Ester	GSH reactivity*(meas.) logKGSH	GSH reactivity* (predicted.) logKGSH	GSH reactivity assessment**	GSH reactivity*** (predicted.) logKGSH
MMA	-1.14	-0.73	slight	-0.62
EMA	-1.24	-0.88	slight	-0.79
i-BMA	-0.44	-0.82	slight	-0.74
n-BMA			slight	-0.78
HMA			slight
2EHMA			slight
Metabolites
MAA			No alert found

*as quoted by Schwöbel et al., 2010
**as calculated by Cronin, 2012 using the method of Schwöbel et al., 2010
***as calculated by Tindale, 2015 according to the method of (Fujisawa and Kadoma, 2012)

 

 

Studies completed after the MMA RA have confirmed that all short chain alkyl-methacrylate esters are rapidly hydrolysed by ubiquitous carboxylesterases (see table below, adapted from Jones; 2002). First pass (local) hydrolysis of the parent ester has been shown to be significant for all routes of exposure. For example, no parent ester can be measured systemically following skin exposure to EMA and larger esters (including n-BMA), as the lower rate of absorption for these esters is within the metabolic capacity of the skin (Jones, 2002). Parent ester will also be effectively hydrolysed within the G. I. tract and within the tissues of the upper respiratory tract (particularly the olfactory tissue). Systemically absorbed parent ester will be effectively removed during the first pass through the liver (%LBF; see table below) resulting in their relatively rapid elimination from the body (T50%; see table below).

 

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

Ester	Rat liver microsomes (100µg ml-1) Vmax               Km    (nM min-1mg-1)  (µM)		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

 

HMA–hexyl methacrylate; OMA–octyl methacrylate. Fate kinetics determined using the “well-stirred” model; CL%LBF–Clearance as percentage removed from liver blood flow i.e. first pass clearance; T_50%- time taken for 50% of parent ester to have been eliminatedfrom the body; C_max–maximum concentration of MAA in circulating blood; T_max–time in minutes to peak MAA concentration in blood “Jones, 2002”

 

In terms of MAA, the common metabolite for these esters, another study using intravenous injection of MAA in rats demonstrated very rapid clearance from the blood (half-life < 5min), suggestive of rapid subsequent metabolism (Jones, 2002).

 

Conclusion

 

n-BMA, the analogous substance t-BMA, as well as other short chain esters and MAA are absorbed by all routes. The rate of absorption decreases with increasing ester chain length so it will be absorbed less rapidly than MMA. All esters are rapidly hydrolysed in local tissues as well as in blood by non-specific esterases to methacrylic acid (MAA) and the respective alcohol. There is a trend towards increasing half-life of the ester in blood with increasing ester chain length. The half life of n-BMA is still, however, in the order of minutes (7.8). The primary metabolite, MAA, is subsequently cleared rapidly from blood and, as indicated by studies with MMA, this metabolism is by standard physiological pathways, with the majority of the administered dose being exhaled as CO2. On the basis of the rapid metabolism and short half-lives a systemic accumulation of the esters and their metabolites is not expected.

Like with MMA, local effects resulting from the hydrolysis of the ester to MAA might be expected following inhalation exposure. In the case of MMA this has been shown to be due to the localised concentration of non-specific esterases in nasal olfactory tissues. In subacute inhalation studies with n-BMA the NOAEC for this lesion is 310 ppm compared with the NOAEC of 25 ppm for MMA, indicating lower reactivity in the nose. In the case of MMA SCOEL concluded that “Extensive PBPK modelling work has predicted that on kinetic grounds for a given level of exposure to MMA human nasal olfactory epithelium will be at least 3 times less sensitive than that of rats to the toxicity of MMA” (SCOEL, 2005). This would suggest that humans are also less sensitive than rodents to the local inhalation effects of n-BMA.

Overall there is a high level of confidence in the toxicokinetic and toxicodynamic assessment for these chemicals based upon in vitro and in vivo studies in rodents and human tissues. This is further supported by clear trends across the category consistent with predicted trends based on recognised QSAR based models. In terms of the overall relevance of the findings in animals to humans there is a high degree of confidence since the same toxicokinetic/dynamic processes are known to occur in humans. In the case of dermal exposure there is robust in vitro data based upon measurements in animal and human skin supported by an established QSAR model that shows that dermal absorption, and therefore risk, of these esters is lower in humans than in rodents. In the case of inhalation exposure well recognised morphological and physiological differences between rodents and humans have been confirmed for the methyl ester to indicate a lower sensitivity of humans than rodents to the local effects in the upper respiratory tract. This is consistent with findings in limited studies in clinical volunteers and by cross-sectional studies in workers with long-term exposure to concentrations of MMA vapour well in excess of the effect concentration in rodents. There is a high level of confidence that the findings for MMA can be equally applied to the ethyl ester. This is based upon the close structural similarity and physico-chemical properties supported by robust PBPK observations and effect data in animals.

In the case of the butyl esters there is a high degree of confidence that data on the linear, n- butyl ester can be read across to the branched esters based upon the very similar physical chemical properties, Michael addition reactivity, half-life within the body and ultimate metabolic fate, both of the parent ester as well as the alcohol metabolites.

In conclusion therefore, there is a high level of confidence in the toxicokinetic assessment for the category of Lower Alkyl (C1-C8) Methacrylates.

 

References quoted from the EU ESR on MMA and other documents, but not copied into the IUCLID dataset:

 

Bogdanffy MS, Randall HW, Morgan KT (1987) Biochemical quantitation and histochemical localization of carboxylesterase in the nasal passages of the Fischer-344 rat and B6C3F1 mouse. Toxicology and Applied Pharmacology 88: 183-194

 

Bratt H,(1977). Fate of methyl methacrylate in rats. Brit. J. Cancer 36, 114-119.

 

CEFIC (1993). Methyl methacrylate: in vitro absorption through human epidermis: Ward RJ and Heylings JR, Zeneca Central Toxicology Lab., Unpublished study on behalf of CEFIC Methacrylates Toxicology Committee, Brussels

 

European Chemicals Bureau (2002). European Union - Risk Assessment Report on Methacrylic Acid. European Union - Risk Assessment Report, Vol. 25, Doc. No. EUR 19837 EN

 

European Chemicals Bureau (2002). European Union - Risk Assessment Report on Methyl methacrylate. European Union - Risk Assessment Report, Vol. 22. Doc. No. EUR 19832 EN

 

ECETOC (1995) Joint Assessment of Commodity Chemicals No 30 ; Methyl Methacrylate, CAS No. 80-62-6. European Centre for Ecotoxicology and Toxicology of Chemicals, Avenue Van Nieuwenhuyse 4, (Bte 6) B-1160,. ISSN-0773-6339-30

 

ECETOC (1996a) Joint Assessment of Commodity Chemicals No 35 ; Methacrylic acid, CAS No. 79-41-4. European Centre for Ecotoxicology and Toxicology of Chemicals, Avenue Van Nieuwenhuyse 4, (Bte 6) B-1160,. ISSN-0773-6339-35

 

Elovaara E, Kivistoe H, Vainio H (1983).Effects of methyl Methacrylate on non-protein thiols and drug metabolizing enzymes in rat liver and kidneys. Arch. Toxicol. 52, 109-121.Hext PM., Pinto PJ, Gaskell BA. (2001) Methyl methacrylate toxicity in rat nasal epithelium: investigation of the time course of lesion development and recovery from short term vapour inhalation. Toxicology 156: 119-128

 

FrederickCB (1998). Interim report on interspecies dosimetry comparisons with a hybrid computational fluid dynamics and physiologically-based pharmacokinetic inhalation model. Rohm and Haas Co.,.

 

ICI (1977). The biological fate of methylmethacrylate in rats; Rep. CTL/R/396 by Hathaway DE and Bratt H; Zeneca, Alderly Park, Macclesfield, Cheshire.

 

Junge W, Krisch K (1975) The carboxylesterases/amidases of mammalian liver and their possible significance. Critical Reviews in Food Science and Nutrition, 371-434.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

 

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

 

Morris JB (1992). Uptake of Inspired Methyl Methacrylate and Methacrylic Acid Vapors in the Upper Respiratory Tract of the F344 Rat. Prepared by of, Univ. for US Methacrylate Producers Association (MPA).Washington, DC

 

OECD (2004) SIDS Initial Assessment Report for18: Short-Chain Alkyl Methacrylates; http://webnet.oecd.org/hpv/UI/handler.axd?id=1da0a7af-3b11-45b7-865f-acad8b19c6c3