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EC number: 907-961-3 | CAS number: -
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
Administrative data
Link to relevant study record(s)
- Endpoint:
- basic toxicokinetics
- 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
- 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).
- 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.
Referenceopen allclose all
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.
Description of key information
As indicated in a dermal absorption study with the source substance Dodecyl methacrylate, the target substance Reaction mass of dodecyl methacrylate and tridecyl 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 Reaction mass of dodecyl methacrylate and tridecyl 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 ca. 7 (weighted mean) of Reaction mass of dodecyl methacrylate and tridecyl 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 - 268.42 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 Reaction mass of dodecyl methacrylate and tridecyl 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).
However, in the absense of experimental data, 100% absorption is assumed by default in accordance with the Guidance on information requirements and chemical safety assessment.
Dermal absorption
Reaction mass of dodecyl methacrylate and tridecyl methacrylate is a liquid substance with a molecular weight in the range 254.42 - 268.42 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 of ca. 7 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 Reaction mass of dodecyl methacrylate and tridecyl 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 experimental data are available on the metabolism of Reaction mass of dodecyl methacrylate and tridecyl methacrylate in vivo.
If it is assumed that Reaction mass of dodecyl methacrylate and tridecyl 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 |
Peak rate of appearance |
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 Reaction mass of dodecyl methacrylate and tridecyl 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, Reaction mass of dodecyl methacrylate and tridecyl methacrylate should be absorbed accumulation in adipose tissue could be expected as the calculated log Pow is ca. 7, 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 Reaction mass of dodecyl methacrylate and tridecyl methacrylate is hardly relevant.
Summary and discussion of toxicokinetics
According to log P > 4, bioaccumulation of Reaction mass of dodecyl methacrylate and tridecyl 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 Reaction mass of dodecyl methacrylate and tridecyl 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. This result is also considered relevant for the target substance Reaction mass of dodecyl methacrylate and tridecyl methacrylate.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
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