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Description of key information

1,6-HDDMA is likely to be readily absorbed by all routes. Due to the low vapour pressure, the dermal route is the primary route of exposure, since inhalation is unlikely. Like other substances of the category, this ester is expected to hydrolyse rapidly by carboxylesterases to methacrylic acid (MAA) and the 1,6-Hexanediol. 1,6-Hexanediol will be transformed to adipic acid and subsequently excreted via the urine or transformed to succinic acid. This metabolite subsequently will be degraded through the tricarboxylic acid cycle and primarily excreted as CO2.

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

Absorption

Oral absorption

The physicochemical properties of 1,6-HDDMA, namely the water solubility, and the molecular weight of 254 g/mol are in a range suggestive of absorption from the gastro-intestinal tract subsequent to oral ingestion, although log Pow around 4.0 indicate that properties are suboptimal for passive diffusion. For chemical safety assessment an oral absorption rate of 50% is assumed as a worst case default value in the absence of other data.

 

Dermal absorption

Based on a QSAR Prediction of Dermal Absorption (extract from Heylings JR, 2013) 1,6-HDDMA is predicted on the basis of its molecular weight and lipophilicity to have a relatively very low ability to be absorbed through the skin. The predicted flux was 0.917μg/cm²/h. However, for chemical safety assessment, a dermal absorption rate of 50% was assumed as worst case default value.

 

Inhalative absorption

Due to the low vapour pressure of 1,6-HDDMA (0.64 Pa at 25°C), exposure via inhalation is unlikely. For chemical safety assessment an inhalative absorption rate of 100% is assumed as a worst case default value in the absence of other data.

 

Distribution

As a rather small molecule with a logPow >0, a wide distribution can be expected. No information on potential target organs is available.

 

Metabolism of Methacrylic esters

Di- and mono-ester hydrolysis

Ester hydrolysis has been established as the primary step in the metabolism of methacrylate esters. In the case of diol di-methacrylate esters the first step would be hydrolysis of one of the ester bonds to produce the corresponding mono-ester followed by subsequent hydrolysis of the second ester bond to produce methacrylic acid (MAA) and the corresponding alcohol1,6-Hexanediol.

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. For multifunctional methacrylates mostly the same would be the case except that because of the lower vapour pressure and hence lower likelihood of inhalation exposure the involvement of the nasal epithelium is less likely.

An elaborate series ofin vitrostudies on carboxyl esterase activity with 7 alkyl methacrylates ranging from methyl methacrylate to octyl methacrylate (with increasing ester size) was used to construct a PB-PK model of in vivoclearance for several tissues (blood, liver, skin and nasal epithelium) from rats and humans (Jones, 2002). Some of these data for rats are summarised below and demonstrate that methacrylate esters are rapidly hydrolysed by carboxylesterases to methacrylic acid (MAA) and the respective alcohol. Clearance of the parent ester from the body is in the order of minutes.

Kinetics data have been reported for the hydrolysis of two multifunctional methacrylates (EGDMA and TREGDMA) by porcine liver carboxylesterasein vitro. For comparison reasons, the results from two lower alkyl methacrylates (EMA and BMA), are also presented in below table (McCarthy and Witz, 1997). The four studied substances showed comparable hydrolysis ratesin vitro.

 

Table: Hydrolysis of Acrylate Esters by Porcine Liver Carboxylesterasein vitro(extract from McCarthy and Witz., 1997)

Ester

Km (mM)

Vmax (nmol/min)

Tetraethyleneglycol dimethacrylate (TREGDMA)

39±15*

2.9±1.0

Ethyleneglycol dimethacrylate (EGDMA)

64±24*

6.9±2.4

Ethyl methacrylate (EMA)

159±90

5.2±2.5

n-Butyl methacrylate (n-BMA)

72±28*

1.8±0.6

*Significantly different (p < 0.05) from ethyl acrylate

 

A recent study, designed to extend an earlier work on lower alkyl methacrylates (Jones 2002, see below) to higher and more complex methacrylate esters, studied thein vitrometabolism of higher and more complex methacrylate esters in rat blood and liver microsomes. This study included three esters of the multifunctional methacrylate category (TREGDMA, EGDMA and 1,4-BDDMA) (DOW, 2013). The results of those studies are summarized in below table.

 

Table: Elimination Rates, Intrinsic Clearance and Half-life in Rat Liver Microsomes and Whole Rat Blood for Five Methacrylate Esters at 0.25 mM Substrate Concentration (DOW, 2013)

 

 

  Liver Microsomes

 

 

  Whole Blood

 

Molecule

Clint

(μl/min/mg)

ke

Half‐Life (min)

Clint(μl/min)

ke

Half‐Life (min)

TREGDMA

116

0.23

3.01

219

0.12

5.68

EGDMA

142

0.28

2.45

796

0.44

1.56

1,4-BDDMA

78

0.16

4.46

304

0.17

4.10

MMA

1192

2.38

0.29

19

0.01

63.00

HEMA

74

0.15

4.62

12

0.01

99.00

ke: elimination rate

Clint: intrinsic clearance (ke x volume of incubation / mg/mL microsomal protein)

MMA: Methyl methacrylate (supporting substance); HEMA: Hydroxyethyl methacrylate (supporting substance)

 

All studied methacrylate esters were rapidly converted to MAA in whole rat blood and rat liver microsomes. Hydrolysis half-lives of the studied category members were in the order of minutes for blood and liver microsomes, respectively.

The incubations in whole rat blood and rat liver microsomes were performed on three separate days with MMA included as a positive control on each day. Rat liver microsome hydrolysis rates for the positive control (MMA) were somewhat variable between days. This was likely due to the rapidity of hydrolysis of MMA. Often, measurable levels of MAA were present even in the zero minute samples and the substrate was completely hydrolyzed by 2 minutes. This made it difficult to accurately calculate hydrolysis rates for MMA in these experiments. However, generally the calculated rates were similar to rates for hydrolysis for MMA reported previously (Jones, 2002; Mainwaring et al., 2001) and confirmed that thein vitrotest systems were enzymatically active for each day of incubation experiments. The other studied methacrylates exhibited rat liver microsome hydrolysis rates approximately 10 fold lower than MMA. From its very rapid degradation to MAA, MMA can be understood as suitable donor substance for MAA as common primary metabolite of all category members.

A second extension of the metabolism study has been performed in 2017 comparing the metabolic rates of 1,3- and 1-4-BDDMA. This study indicated that the two isomers were indeed very similar, while the metabolic rates of the linear diol ester (1,4-BDDMA) appeared to be slightly higher than those of the branched isomer (1,3-BDDMA) (DOW, 2017).

 

Table: Elimination Rates, Intrinsic Clearance and Half-life in Rat Liver Microsomes and Whole Rat Blood; Satellite Study Comparison 1,3-BDDMA and 1,4-BDDMA (DOW, 2017)

 

 

  Liver Microsomes

 

 

  Whole Blood

 

Molecule

Clint

(μl/min/mg)

ke

Half‐Life (min)

Clint(μl/min)

ke

Half‐Life (min)

1,3-BDDMA

116

0.195

3.55

112

0.0559

12.4

1,4-BDDMA

119

0.199

3.48

246

0.123

5.63

 

Supporting information on Alkyl methacrylates

The above mentioned EMA and n-BMA were also studied in an elaborate series ofin vitrostudies on carboxylesterase activity with 7 alkyl methacrylates ranging from methyl methacrylate to octyl methacrylate (with increasing ester size) (Jones, 2002). This was used to construct a PB-PK model ofin vivoclearance for several tissues (blood, liver, skin and nasal epithelium) from rats and humans, which showed that methacrylate mono-esters are rapidly hydrolyzed by carboxylesterases to methacrylic acid (MAA) and the respective alcohol. Whilst there was a trend of increasing half-life of alkyl methacrylates with increasing chain length (up to octyl), clearance of the parent ester from the body was always in the order of minutes.

Although the absolute rate measurements obtained by Jones differ slightly to those determined by McCarthy and Witz, presumably due to differences in experimental conditions such as protein content etc., the rates obtained for the two lower alkyl methacrylates (EMA and BMA) can be used to draw parallels between the work of the two researchers indicating that the kinetics for the hydrolysis of EGDMA and TREGDMA fall within the range observed by Jones for lower alkyl methacrylates. On this basis the parent ester would be expected to have a short systemic half–life within the body being effectively cleared from the blood within the first or second pass through the liver. Hydrolysis of the di- and mono- ester would yield the common metabolite methacrylic acid and the respective alcohol.

 

Subsequent metabolism

 

Methacrylic acid (MAA)

From the available extensive toxicokinetic data on lower alkyl methacrylates it has been established that thecommon primary metabolite methacrylic acidis subsequently cleared predominantly via the liver (valine pathway and the TCA (TriCarboxylic Acid) cycle, respectively; ECB, 2002; OECD SIAR, 2009). Methyl methacrylate (MMA) is rapidly degraded in the body to MAA and can thus be understood as metabolite donor for MAA.

 

Alcohol moiety: 1,6-Hexanediol (1,6-HD)

The metabolism of the alcohols can generally be decribed as multiple oxidizing steps. Alcohol dehydrogenase and aldehyde dehydrogenase enzymes transform the diols to di-carboxyl acids in a sequential manner. Depending on the alcohol, partially incomplete oxidation was observed before excretion.

In the case of 1,6-HD, adipic acid was found as urinary metabolite of 1,6-HD in rabbits, while none of the unchanged diol was isolated from urine. Glucuronic acid conjugation was observed for less than 10% of the applied dose of 2 mmol/kg bw per oral feeding; adipic acid was found as urinary metabolite (Gessner et al., 1960). Tserng and Jin (1990) showed that rat liver homogenates are able to metabolize the C12 dicarboxlic acid (dodecandioc acid) to the C4 succinate and thus into the tricarboxylic cycle via 1,6-HD-CoA byβ-oxidation and subsequent decarboxylation.

 

Glutathione reactivity

A QSAR model for 1,6-HDDMA predicted only slight reactivity with glutathione for the ester and no reactivity for the primary metabolite, methacrylic acid (Cronin, 2012).

 

Studies with methacrylates in vitro confirm low reactivity with GSH, in particular compared to the corresponding acrylates, and have proposed that this is due to steric hindrance of the addition of a nucleophile at the double bond by the alpha-methyl side-group (McCarthy & Witz, 1991, McCarthy et al., 1994, Tanii and Hashimoto, 1982).

 

Table: Apparent Second-Order Rate Constants for the Reaction of Glutathione with Methacrylate Esters (extract from McCarthy et al., 1994)

Ester

App. 2ndorder rate const.

Kapp[L/mol/min]

Tetraethyleneglycol dimethacrylate (TREGDMA)

1.45±1.0

(0.725±0087)*

Ethyleneglycol dimethacrylate (EGDMA)

0.83±0.12

(0.406±0.059)*

Methyl methacrylate (MMA)

0.325±0.059

Ethyl methacrylate (EMA)

0.139±0.022

Butyl methacrylate (BMA)

No appreciable reaction rate

               *Bifunctional esters calculated as two independent esters.

.

In conclusion, ester hydrolysis is considered to be the major metabolic pathway for alkyl and multifunctional methacrylate esters, with GSH conjugation only playing a minor role in their metabolism.

 

 Excretion

As the ester will not survive first pass metabolism in the liver, excretion of the parent compound is of no relevance. The primary methacrylic metabolite, MAA, is cleared rapidly from blood by standard physiological pathways, with the majority of the administered dose being exhaled as CO2, while the alcohol metabolite, 1,6-HD, will be transformed to adipic acid and subsequently excreted via the urine or transformed to succinic acid. This metabolite subsequently will be degraded through the tricarboxylic acid cycle and primarily excreted as CO2.

 

In summary, the metabolism data and modelling results show that 1,6-HDDMA would be rapidly hydrolysed in the rat.

 

Conclusion

Summary and discussion on toxicokinetics

Methacrylate esters are absorbed by all routes while the dermal absorption is limited with the larger members of the category. Due to the low vapour pressure of the multifunctional methacrylates, the dermal route is the primary route of exposure, since inhalation is unlikely. The rate of dermal absorption decreases with increasing ester chain length. All esters are rapidly hydrolyzed by carboxylesterases to methacrylic acid (MAA) and the respective alcohol. In the case of di- and triesters the apparent rate of hydrolysis is highest for the parent ester, but this likely reflects the higher number of hydrolysable target sites instead as opposed to any greater specific activity. Ester hydrolysis can occur in local tissues at the site of contact as well as in blood and other organs by non-specific carboxylesterases. By far the highest enzyme activity has been shown in liver microsomes indicating that the parent ester will be fully metabolized in the liver. Clearance of the parent ester from the body is in the order of minutes. There is a trend towards increasing half-life of the ester in blood with increasing ester chain length, however, none of the esters will survive first pass metabolism in the liver to any significant extent. The primary methacrylic metabolite, MAA, is subsequently cleared rapidly from bloodby standard physiological pathways, with the majority of the administered dose being exhaled as CO2. The respective alcohol moieties will undergo further metabolism in the liver.

1,6 -Hexanediol dimethacrylate is expected to be hydrolyzed rapidly by unspecific carboxyl esterases in the liver into methacrylic acid and 1,6 -Hexanediol. 1,6-Hexanediol will be transformed rapidly by alcolhol dehydrogenases and aldehyd dehydrogenasesto adipic acid and subsequently excreted via the urine or transformed to succinic acid. This metabolite subsequently will be degraded through the tricarboxylic acid cycle and primarily excreted as CO2.

 

Compliance to REACh requirements

The information requirement is covered with reliable in silico predictions on the dermal absorption and glutathione reactivity of the substance itself plus reliablein vitrodata on the primary metabolism of other category substances, reliablein vitro/ in vivostudies on the metabolism of the methacrylic metabolite MAA as well as reliable publication data on the metabolism of the alcohol metabolite 1,6-HD. All mentioned sources are reliable (Reliability 1 or 2) so that the category/ read across approach can be done with a high level of confidence.

 

References

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.

Frederick CB, Udinsky JR, Finch L (1994). The regional hydrolysis of ethyl acrylate to acrylic acid in the rat nasal cavity. Toxicology letters, 70: 49-56.

Jones O (2002). Using physiologically based pharmacokinetic modelling to predict the pharmacokinetics and toxicity of methacrylate esters. A Thesis submitted to Univ. of Manchester for the degree of Doctor of Philosophy.

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

Gessner PK, Parke DV, Williams RT (1960). Studies in Detoxication. 80. The metabolism of glycols. Biochemical Journal, 74: 1-5

McCarthy TJ, Witz G (1997). Structure-activity relationships in the hydrolysis of acrylate and methacrylate esters by carboxylesterase in vitro. Toxicology 116: 153-158. Owner company: Published.

Satoh T, Hosokawa M (1998). The Mammalian carboxylesterases: From models to functions. Annual Review of Pharmacology and Toxicology 38, 257-288. Medicine and Biology 283, 333-335

Tanii H., Hashimoto K.(1982); Structure-Toxicity Relationship of Acrylates and Methacrylates; Toxicol. Lett. 11: 125-129

Tserng K-Y, Jin S-J (1991). Metabolic Conversion of Dicarboxylic Acids to Succinate in Rat Liver

Homogenates. J Biological Chemistry 266, 5, 2924-2929