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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics, other
Remarks:
(Q)SAR
Type of information:
(Q)SAR
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
accepted calculation method
Justification for type of information:
QSAR prediction

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2012
Report Date:
2012

Materials and methods

Principles of method if other than guideline:
Protein/GSH reactivity modelling with OECD Toolbox
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Results and discussion

Any other information on results incl. tables

The algorithm of the OECD toolbox has been used to predict GSH/protein reactiviry.

Test Chemical / Compound Identity

Acronym

SMILES

Molecular Weight

Protein Binding Potency

2-ethylhexyl methacrylate

EHMA

O=C(OCC(CCCC)CC)\C(=C)C

198.3

Slightly reactive (GSH) >> Methacrylates (MA)

ethyl methacrylate

EMA

CCOC(=O)C(=C)C

114.14

Slightly reactive (GSH) >> Methacrylates (MA)

isobutyl methacrylate

iBMA

CC(C)COC(=O)C(=C)C

142.2

Slightly reactive (GSH) >> Methacrylates (MA)

Methacrylic acid

MAA

CC(=C)C(=O)O

100.12

No alert found

Methyl methacrylate

MMA

CC(=C)C(=O)OC

100.12

Slightly reactive (GSH) >> Methacrylates (MA)

n-butyl methacrylate

nBMA

CCCCOC(=O)C(=C)C

142.2

Slightly reactive (GSH) >> Methacrylates (MA)

n-Hexyl methacrylate

n-HMA

CCCCCCOC(=O)C(=C)C

170.25

Slightly reactive (GSH) >> Methacrylates (MA)

ter-Butyl Methacrylate

tBMA

CC(=C)C(=O)OC(C)(C)C

142.2

Slightly reactive (GSH) >> Methacrylates (MA)

Diethylaminoethyl methacrylate

DEAEMA

O=C(OCCN(CC)CC)C(=C)C

185.263

Slightly reactive (GSH) >> Methacrylates (MA)

2-tert-Butylaminoethyl methacrylate

TBAEMA

O=C(OCCNC(C)(C)C)C(=C)C

185.26

Slightly reactive (GSH) >> Methacrylates (MA)

2-Dimethylaminoethyl methacrylate

MADAME

CC(=C)C(=O)OCCN(C)C

157.22

Slightly reactive (GSH) >> Methacrylates (MA)

2-(2-Butoxyethoxy) ethyl methacrylate, Butyldiglycol methacrylate

BDGMA

CCCCOCCOCCOC(=O)C(=C)C

230.3

Slightly reactive (GSH) >> Methacrylates (MA)

2-(2-(2-Ethoxy ethoxy)-thoxyethyl methacrylate

ET3EGMA

O=C(OCCOCCOCCOCC)C(=C)C

246.3

Slightly reactive (GSH) >> Methacrylates (MA)

2-Methoxyethyl methacrylate

MTMA

CC(=C)C(=O)OCCOC

144.08

Slightly reactive (GSH) >> Methacrylates (MA)

2-Ethoxyethyl methacrylate

ETMA

CCOCCOC(=O)C(=C)C

158.09

Slightly reactive (GSH) >> Methacrylates (MA)

Phenoxyethyl Methacrylate

PTMA

CC(=C)C(=O)OCCOC1=CC=CC=C1

206.24

Slightly reactive (GSH) >> Methacrylates (MA)

Allyl methacrylate

AMA

CC(=C)C(=O)OCC=C

126.15

Slightly reactive (GSH) >> Methacrylates (MA)

Benzyl methacrylate

BNMA

CC(=C)C(=O)OCC1=CC=CC=C1

176.21

Slightly reactive (GSH) >> Methacrylates (MA)

Cyclohexyl methacrylate

c-HMA

O=C(OC(CCCC1)C1)C(=C)C

168.23

Slightly reactive (GSH) >> Methacrylates (MA)

Isobornyl methacrylate

IBOMA

CC(=C)C(=O)OC1CC2CCC1(C2(C)C)C

222.32

Slightly reactive (GSH) >> Methacrylates (MA)

Phenyethyl methacrylate

Phenylethyl MA

 CC(=C)C(=O)OCCC1=CC=CC=C1

190.24

Slightly reactive (GSH) >> Methacrylates (MA)

Phenyl methacrylate

PHMA

CC(=C)C(=O)OC1=CC=CC=C1

162.19

Slightly reactive (GSH) >> Methacrylates (MA)

3,3,5-Trimethylcyclohexyl methacrylate

TMCHMA

CC1CC(CC(C1)(C)C)OC(=O)C(=C)C

210.31

Slightly reactive (GSH) >> Methacrylates (MA)

Tridecyl methacrylate

TDMA C13MA

CCCCCCCCCCCCCOC(=O)C(=C)C

268.43

Slightly reactive (GSH) >> Methacrylates (MA)

Isodecyl methacrylate

IDMA

CC(C)CCCCCCCOC(=O)C(=C)C

226.36

Slightly reactive (GSH) >> Methacrylates (MA)

Dodecyl methacrylate

LMA

CCCCCCCCCCCCOC(=O)C(=C)C

254.41

Slightly reactive (GSH) >> Methacrylates (MA)

n-Octyl methacrylate

n-OMA

CCCCCCCCOC(=O)C(=C)C

198.3

Slightly reactive (GSH) >> Methacrylates (MA)

2-Hydroxyethyl methacrylate

HEMA

CC(=C)C(=O)OCCO

130.1

Slightly reactive (GSH) >> Methacrylates (MA)

Hydroxypropyl methacrylate

(propyleneglycol monoester)
= isomer mixture of
< 80 % 2-Hydroxypropyl methacrylate
> 20% 2-Hydroxy-1-methylethyl methacrylate

HPMA

CC(COC(=O)C(=C)C)O



CC(CO)OC(=O)C(=C)C

144.17

Slightly reactive (GSH) >> Methacrylates (MA)

Hydroxypropyl methacrylate

(propyleneglycol monoester)
= isomer mixture of
< 80 % 2-Hydroxypropyl methacrylate
> 20% 2-Hydroxy-1-methylethyl methacrylate

HPMA

CC(CO)OC(=O)C(=C)C

144.17

Slightly reactive (GSH) >> Methacrylates (MA)

N-butoxymethyl methacrylamide

N-BMMA

CCCCOCNC(=O)C(=C)C

157.21

Moderately reactive (GSH) >> 2-Vinyl carboxamides (MA)

N-Methylol methacrylamide

N-MMAA

CC(=C)C(=O)NCO

115.13

Moderately reactive (GSH) >> 2-Vinyl carboxamides (MA)

N,N'-methylenbis(methacrylamide)

 

O=C(NCNC(=O)\C(=C)C)\C(=C)C

154.19

Moderately reactive (GSH) >> 2-Vinyl carboxamides (MA)

N-Dimethylaminopropyl methacrylamide

DMAPMA

CC(=C)C(=O)NCCCN(C)C

170.25

Moderately reactive (GSH) >> 2-Vinyl carboxamides (MA)

Methacrylamide

MAA

CC(=C)C(=O)N

85.1

Moderately reactive (GSH) >> 2-Vinyl carboxamides (MA)

1,12-Dodecanediol dimethacrylate

1,12 DDDMA

O=C(OCCCCCCCCCCCCOC(=O)\C(=C)C)\C(=C)C

338.48

Slightly reactive (GSH) >> Methacrylates (MA)

1,3-Butandiol dimethacrylate

1,3-BDDMA

CC(CCOC(=O)C(=C)C)OC(=O)C(=C)C

226.27

Slightly reactive (GSH) >> Methacrylates (MA)

1,4-Butandiol dimethacrylate

1,4-BDDMA

CC(=C)C(=O)OCCCCOC(=O)C(=C)C

226.27

Slightly reactive (GSH) >> Methacrylates (MA)

1,6-Hexanediol dimethacrylate

1,6 HDDMA

O=C(OCCCCCCOC(=O)\C(=C)C)\C(=C)C

254.32

Slightly reactive (GSH) >> Methacrylates (MA)

Ethylene glycol dimethacrylate

EGDMA

CC(=C)C(=O)OCCOC(=O)C(=C)C

198.22

Slightly reactive (GSH) >> Methacrylates (MA)

Trimethylpropane trimethacrylate

TMPTMA

CCC(COC(=O)C(=C)C)(COC(=O)C(=C)C)COC(=O)C(=C)C

338.4

Slightly reactive (GSH) >> Methacrylates (MA)

Ethoxylated bisphenol A dimethacrylate

2EBADMA

CC(C)(C1=CC=C(C=C1)O)C2=CC=C(C=C2)O.C=CC(=O)O.C(CO)O

ID of reference isomer:
CC(=C)C(=O)OC1=CC=C(C=C1)C(C)(C)C1=CC=C(OC(=O)C(C)=C)C=C1

452.5394

Slightly reactive (GSH) >> Methacrylates (MA)

2,2-bis-[4-(3'-methacryloyloxy-2'-hydroxy)propoxyphenyl] propane

bis-GMA

O=C(OCC(O)COc1ccc(cc1)C(c2ccc(OCC(O)COC(=O)\C(=C)C)cc2)(C)C)\C(=C)C

512.61

Slightly reactive (GSH) >> Methacrylates (MA)

4,4'-Isopropylidenediphenol, oligomeric reaction products with 1-chloro-2,3-epoxy propane, reaction products with methacrylic acid

Bis-GMA NLP (DSM/Akzo/+others)

 

n.d

Slightly reactive (GSH) >> Methacrylates (MA)

Diethyleneglycol dimethacrylate

DEGDMA

CC(=C)C(=O)OCCOCCOC(=O)C(=C)C

242.27

Slightly reactive (GSH) >> Methacrylates (MA)

Glycerol dimethacrylate

GDMA

O=C(OCC(O)COC(=O)\C(=C)C)\C(=C)C

228.24

Slightly reactive (GSH) >> Methacrylates (MA)

7,7,9-(resp. 7,9,9-)trimethyl-4,13-dioxo-3,14-dioxa-5,12-diazahexadecane-1,16-diol-dimethacrylate

HEMATMDI

O=C(OCCOC(=O)NCCC(C)CC(C)(C)CNC(=O)OCCOC(=O)\C(=C)C)\C(=C)C

470,57

Slightly reactive (GSH) >> Methacrylates (MA)

Triethyleneglycol dimethacrylate

TREGDMA

O=C(OCCOCCOCCOC(=O)\C(=C)C)\C(=C)C

286.32

Slightly reactive (GSH) >> Methacrylates (MA)

Tetraethyleneglycol dimethacrylate

TTEGDMA/4EDMA

CC(=C)C(=O)OCCOCCOCCOCCOC(=O)C(=C)C

198.22

Slightly reactive (GSH) >> Methacrylates (MA)

2-hydroxyethyl methacrylate phosphate

HEMA phosphate

CC(=C)C(=O)OCCOP(=O)(O)O

228.14

Slightly reactive (GSH) >> Methacrylates (MA)

Methacrylic anhydride

MAAH

CC(=C)C(=O)OC(=O)C(=C)C

154.16

Slightly reactive (GSH) >> Methacrylates (MA)

Hydroxyethyl ethylene urea methacrylate

MEEUW

O=C1NCCN1CCOC(=O)\C(=C)C

129.16

Slightly reactive (GSH) >> Methacrylates (MA)

Tetrahydrofurfurylmethacrylat

THFMA

O=C(OCC1OCCC1)\C(=C)C

170.21

Slightly reactive (GSH) >> Methacrylates (MA)

2,2-dimethyl-1,3-dioxolan-4-ylmethyl methacrylate

 

CC(=C)C(=O)OCC1COC(O1)(C)C

200.23

Slightly reactive (GSH) >> Methacrylates (MA)

Polyethylengeglycol-200-dimethacrylate

PEG200DMA

for approximation see Tetraethyleneglycol dimathacrylate

no data

Slightly reactive (GSH) >> Methacrylates (MA)

2,2,2-Trifluoroethyl methacrylate

TFMEA 3FM

CC(=C)C(=O)OCC(F)(F)F

336

Slightly reactive (GSH) >> Methacrylates (MA)

N-Trimethylammoniumpropyl methacrylamide-chloride

MAPTAC

CC(=C)C(=O)NCCC[N+](C)(C)C.[Cl-]

220.74

Moderately reactive (GSH) >> 2-Vinyl carboxamides (MA)

2-Trimethylammoniummethyl methacrylate-chloride
2-(Methacryloyloxy)-N,N,N-trimethylethanaminium chloride

TMAEMC
DMCMA

CC(=C)C(=O)OCC[N+](C)(C)C.[Cl-]

207.7

Slightly reactive (GSH) >> Methacrylates (MA)

         
         
         
         

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): other: low reactivity with GSH
A dataset with methacrylic acid derivatives has been assessed using the reactivity profiler in the OECD QSAR Toolbox. This profiler contains structural alerts derived from an analysis of experimental reactivity data as measured using glutathione (the Schultz assay). The profiler assigns chemicals to one of five potency classes (non-reactive, slightly reactive, moderately reactive, highly reactive and extremely reactive) based on the experimental results.

The majority of the chemicals, including HEMA, are slightly reactive. For methacrylates it is well known that the addition of an alkyl group on the alpha-carbon significantly reduces reactivity in the Michael addition reaction.

There are also a group of vinyl carboxamides (methacrylamide derivatives) that have been flagged as being moderately reactive. It should be noted, however, that in the underlying QSAR data in the TB there is no information regarding the effect of an alpha substituent for this class of chemical. In reality this means that no chemicals were tested with glutathione that contained an alpha alkyl substituent thus the prediction is being made based on the un-substituted parent (acrylamide; thus the over-cautious prediction). The investigator indicated that they are likely to be pretty unreactive in reality.
Executive summary:

A dataset with methacrylic acid derivatives has been assessed using the reactivity profiler in the OECD QSAR Toolbox. This profiler contains structural alerts derived from an analysis of experimental reactivity data as measured using glutathione (the Schultz assay). The profiler assigns chemicals to one of five potency classes (non-reactive, slightly reactive, moderately reactive, highly reactive and extremely reactive) based on the experimental results.

 

The majority of the chemicals, including HEMA, are slightly reactive. For methacrylates it is well known that the addition of an alkyl group on the alpha-carbon significantly reduces reactivity in the Michael addition reaction.

 

There are also a group of vinyl carboxamides (methacrylamide derivatives) that have been flagged as being moderately reactive. It should be noted, however, that inthe underlying QSAR data in the TB there is no information regarding the effect of an alpha substituent for this class of chemical. In reality this means that no chemicals were tested with glutathione that contained an alpha alkyl substituent thus the prediction is being made based on the un-substituted parent (acrylamide; thus the over-cautious prediction). The investigator indicated that they are likely to be pretty unreactive in reality.