2-hydroxyethyl methacrylate

Repeated dose toxicity: oral

Administrative data

Endpoint:

chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Justification for type of information:

READ ACROSS APPROACH: BIOTRANSFORMATION TO COMMON COMPOUNDS
Like other short chain alkyl-methacrylate esters, HEMA is initially hydrolyzed by non-specific carboxylesterases to methacrylic acid (MAA) and the structurally corresponding alcohol ethylene glycol (EG) in several tissues. Thus, MAA and EG are considered as primary metabolites of the methacrylic and alcoholic moieties of HEMA, respectively. For more details see chapter Toxicokinetics and the attached Read Across Justification (2022) and Category document (2019).

Cross-reference

Reason / purpose for cross-reference:

read-across source

Reference

Endpoint:

chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

equivalent or similar to guideline

Guideline:

other: not known

Principles of method if other than guideline:

Chronic, repeated dose study with exposure via drinking water

GLP compliance:

no

Limit test:

no

Specific details on test material used for the study:

source: Rohm & Haas company, Philadelphia
stabilized with 10 ppm monomethylether of t-butylhydroquinone

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: "young" (unspecified)
The  animals were individually housed and provided food (finely ground Purina Dog Chow Kibbled Meal; questionable information in the publication) ad libitum
- rats were individually caged and weighed once a week

Route of administration:

oral: drinking water

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

The rats were individually caged and weighed once a week. The diet consisted of finely ground Purina Dog Chow Kibbled Meal consumed ad libitum. Fluid consumption values were determined over a 3-day period at the end of 1 and 4 weeks,
monthly through 6 months, and on even months thereafter. Food consumptions were measuered over 3-day periods at the same intervals.
The low and medium concentrations in the water were selected with the expectation that the diet equivalents would approximate 10 and 100 ppm. The high concentration was selected following preliminary tests that indicated
that this level would significantly depress fluid consumption.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Polarographic analysis of monomer content

Duration of treatment / exposure:

104 weeks (2 years)

Frequency of treatment:

Daily, ad libitum

Dose / conc.:

6 ppm

Remarks:

raised after 5 months to 7 ppm

Dose / conc.:

60 ppm

Remarks:

raised after 5 months to 70 ppm

Dose / conc.:

2 000 ppm

Dose / conc.:

12 other: ppm (on the basis of fluid and food consumption observations)

Remarks:

corresponding to roughly 0.6 mg/kg/bw (based on a conversion factor of 20 (Derelanko, M.J.,
2000)corresponding to roughly 0.6, 6 and 165 mg/kg/bw (based on a conversion factor of 20
(Derelanko, M.J., 2000)

Dose / conc.:

120 other: ppm (on the basis of fluid and food consumption observations)

Remarks:

corresponding to roughly 6 mg/kg/bw (based on a conversion factor of 20 (Derelanko, M.J., 2000)

Dose / conc.:

3 000 other: ppm (on the basis of fluid and food consumption observations)

Remarks:

corresponding to roughly 165 mg/kg/bw (based on a conversion factor of 20 (Derelanko, M.J., 2000)

No. of animals per sex per dose:

25

Control animals:

yes, concurrent no treatment

Details on study design:

Twenty-five male and female albino (Wistar) rats were administered 6, 60 or 2000 ppm of methyl methacrylate in the drinking water. The concentrations of the low- and mid-dose groups were increased to 7 and 70 ppm at the beginning of the fifth month of the study. The animals were individually housed and provided food ad libitum.  
Prior to the start of the study, it was apparent that methyl methacrylate was volatilizing at the tip of the water bottles. A special design was employed to reduce the volatilization and measurements showed that the methyl methacrylate concentrations remained within 15% of nominal for 72 hours.
The low and medium concentrations in the water were selected with the expectation that the diet equivalents would approximate 10 and 100 ppm. The high concentration was selected following preliminary tests that indicated that this level would significantly depress fluid consumption.

Observations and examinations performed and frequency:

Body weights were measured prior to study initiation, at weeks 1, 3, 6, 13, 26, 52, 78 and 104. Food and water consumption was measured over a three day period at the end of one and four weeks, monthly through month six and during even months thereafter. Hematological measurements, including hematocrit, hemoglobin, total white and differential white cell counts, were obtained from five rats from each sex in each treatment level at three month intervals. Pooled urine samples were collected from five rats per sex from each treatment group every three months to evaluate urinary concentrations of reducing substances and proteins.
Semiquantitative tests for urinary concentrations of reducing substances and protein were performed on urines pooled from 5 rats/sex per group at three month intervals. At two years, survivors were sacrificed and organ to body weight measurements were made for heart, spleen, kidney, liver and testes

Sacrifice and pathology:

At two years, survivors were sacrificed and organ to body weight measurements were made for heart, spleen, kidney, liver and testes.
Tissues preserved from all animals on study included heart, lung, kidney, liver, urinary bladder, spleen, gastrointeric, skeletal muscle, bone marrow, skin, brain, thyroid, adrenal, pancreas, pituitary and gonad. Histopathology was conducted on all tissues collected except from animals in the low dose group.

Clinical signs:

not specified

Mortality:

mortality observed, non-treatment-related

Description (incidence):

There is no difference in the number of 2-year suvivors observed in any of the dose groups.

Conc. female male
control 16/25 13/25
6 ppm 18/25 18/25
60 ppm 18/25 15/25
200 ppm 15/25 13/25

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Sex Fluid conc. (ppm) / Start / Average weight of rats (g)
Week 1 Week 3 Week 6 Week 13 Week 26 Week 52 Week 78 Week 104
Female 0 60 92 145 194 243 284 340 366 388
6b 60 92 145 191 240 281 325 349 371
60c 60 90 142 190 239 286 341 373 360
2000 60 83* 133 172 231 259 307 315 331
Male 0 63 100 186 283 403 483 562 561 563
6b 63 99 179 283 393 470 548 554 516
60c 63 102 187 285 406 468 550 571 533
2000 63 87* 168* 271 397 474 550 558 518

b The concentration was raised to 7 ppm at the start of 5th month
c The concentration was raised to 70 ppm at the start of 5th month
* p<= 0.05

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Sex Fluid conc. (ppm) Fluid consumption (ml/rat/day) Food consumption (g/rat/day) Diet equivalent of fluid conc. (ppm)
Female 0 32.2±4.9 15.6±2.2 -
6b 32.2±4.5 15.3±2.0 13.9±1.5
60c 24.5±5.3* 13.8±1.8* 3530±430
Male 0 35.8±4.6 19.6±3.4 -
6b 35.3±4.8 19.6±2.8 12.2±1.2
60c 34.0±4.2 20.4±2.6 115±3
2000 31.3±4.9* 19.6±3.3 3210±220

b The concentration was raised to 7 ppm at the start of 5th month
c The concentration was raised to 70 ppm at the start of 5th month
* p<= 0.05

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

effects observed, treatment-related

Description (incidence and severity):

Sex Fluid conc. (ppm) Fluid consumption (ml/rat/day) Food consumption (g/rat/day) Diet equivalent of fluid conc. (ppm)
Female 0 32.2±4.9 15.6±2.2 -
6 32.2±4.5 15.3±2.0 13.9±1.5
60 30.3±5.1 15.4±2.1 132±5
2000 24.5±5.3* 13.8±1.8* 3530±430
Male 0 35.8±4.6 19.6±3.4 -
6 35.3±4.8 19.6±2.8 12.2±1.2
60 34.0±4.2 20.4±2.6 115±3
2000 31.3±4.9* 19.6±3.3 3210±220

b The concentration was raised to 7 ppm at the start of 5th month
c The concentration was raised to 70 ppm at the start of 5th month
* p<= 0.05

Fluid consumption data was obtained at 16 observation periods during the study. The overall data obtained indicate a significant depression in fluid consumption by rats receiving 2000 ppm of the test material, although the degree ofthis tended to regress toward the end of the study.

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Description (incidence and severity):

Hematologic values varied within normal ranges in ali' groups of rats throughout the study

Clinical biochemistry findings:

not examined

Urinalysis findings:

no effects observed

Description (incidence and severity):

Urine concentrations of protein and reducing substances showed no trends that appeared relatable to treatment.

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, non-treatment-related

Description (incidence and severity):

Organ to body weight ratios obtained at sacrifice of 2-year survivors differed from the controls only in significantly increased kidney ratios in female rats receiving 2000 ppm of methyl methacrylatc (controls 0.0082 ± 0.0019; treated 0.0094 ± 0.0011).

Gross pathological findings:

not examined

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

Histopathologic findings showed no abnormalities or lesions, in kind or incidence, not explicable on the basis of naturally occurring ones in this strain of rat at this age.

Histopathological findings: neoplastic:

not specified

Details on results:

Body weight depression observed at 2000 ppm did not persist beyond the first few weeks of the study. Significant depression of fluid consumption was observed at 2000 ppm, although this tended to regress at the end of the study. Individual observations of depressed food consumption tended to parallel periods of depressed growth. These effects were considered as temporary non-adverse effects.
There were significantly increased kidney weight ratios for female rats at 2000 ppm. Since no substance-related effects were reported from histopathologic examinations in the kidneys, this effect is not considered as biologically relevant.

Dose descriptor:

NOAEL

Effect level:

>= 124.1 mg/kg bw/day (actual dose received)

Sex:

male

Basis for effect level:

other: based on fluid consumption and body weight (see attached document)

Dose descriptor:

NOAEL

Effect level:

>= 162 mg/kg bw/day (actual dose received)

Sex:

female

Basis for effect level:

other: based on fluid consumption and body weight (see attached document)

Dose descriptor:

NOAEL

Effect level:

>= 2 000 other: ppm nominal

Sex:

male/female

Basis for effect level:

other: corresponding to ca. 3300 ppm in the diet on the basis of fluid and food consumption observations

Critical effects observed:

not specified

Conclusions:

No relevant effects were observed up to the highest dose tested (2000 ppm, limited by palatability) in a 2 years study in rats by oral administration in drinking water.
No statistical differences were noted in the mortality of the animals exposed to methyl methacrylate and those in the control group. A statistically significant decrease in body weight was observed in the
first week for the female rats and in weeks one through three in the male rats administered 2000 ppm methyl methacrylate. Water consumption was reduced in the animals from the high-dose group; ho
wever, it was reported that this finding tended to regress towards the end of the study. Food consum ption was not affected by the administration of methyl methacrylate in the drinking water.
Hematologic values varied within normal ranges in all groups of rats throughout the study, and urine concentrations of protein and reducing substances showed no trends that appeared relatable to
treatment.
Organ to body weight ratios obtained at sacrifice of 2-year survivors differed from the controls only in significantly increased kidney ratios in female rats receiving 2000 ppm of methyl methacrylate
(controls 0.0082 ± 0.0019; treated 0.0094 ± 0.0011). Histopathologic findings showed no abnormalities or lesions, in kind or incidence, not explicable on
the basis of naturally occurring ones in this strain of rat at this age. Diet equivalents of the test materials were calculated from the fluid and food consumption data.
In these calculations, corrections were not made for evaporation losses of the test materials from the drinking water, the orders of magnitude of which are given under methods described above
(maximum 15%). Allowing for such losses, it would appear that the concentrations of test materials in the drinking water were equivalent to approximately 10, 100, and 3000 ppm in the diet.

Executive summary:

A two years toxicity study was performed in 1964 to study the tolerance of animals to chronic ingestion of methyl methacrylate.

Twenty-five male and female Wistar rats were administered three doses of methyl methacrylate in the drinking water for two years (Borzelleca et al. 1964). Initial doses of 6, 60 or 2000 ppm were partially raised to 7, 70 and 2000 ppm after 5 months.

A special design was employed to reduce the volatilization and measurements which showed that the methyl methacrylate concentrations remained within 15% of the nominal concentration for 72 hours. Body weight depression was also observed at 2000 ppm but it did not persist beyond the first few weeks of the study. Significant depression of liquid consumption was observed at 2000 ppm, although this tended to regress at the end of the study. Individual observations of depressed food consumption tended to parallel periods of depressed growth. There were significantly increased kidney ratios for female rats at 2000 ppm. These effects were believed to be a consequence of reduced food intake and reduced body weights, and in the absence of any histopathology, were considered as not biologically relevant. Therefore the NOAEL is considered to be >= 2000 ppm, corresponding to 124.1 mg/kg bw/day and 164 mg/kg bw/day, for males and females, respectively, on the basis of treatment specific fluid consumption rates and body weights.

 

No relevant effects were observed after exposure of rats in drinking water up to the highest dose tested (2000 ppm, limited by palatability).

Materials and methods

Test material

Test material information

Constituent 1

Reference substance name:

2-hydroxyethyl methacrylate

EC Number:

212-782-2

EC Name:

2-hydroxyethyl methacrylate

Cas Number:

868-77-9

Molecular formula:

C6H10O3

IUPAC Name:

2-hydroxyethyl methacrylate

Details on test material:

IUCLID4 Test substance: no data

Results and discussion

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

>= 161.3 mg/kg bw/day (actual dose received)

Based on:

other: HEMA

Sex:

male

Basis for effect level:

other: liquid consumption and body weight

Remarks on result:

other: Effect level calculated based on the study result with read across substance MMA: 0.00124 mol

2

Dose descriptor:

NOAEL

Effect level:

>= 213.2 mg/kg bw/day (actual dose received)

Based on:

other: HEMA

Sex:

female

Basis for effect level:

other: liquid consumption and body weight

Remarks on result:

other: Effect level calculated based on the study result with read across substance MMA: 0.00164 mol

Applicant's summary and conclusion

Conclusions:

Chronic toxicity (2 years) by oral application of HEMA was predicted by read across with the methyl methacrylate, the metabolite donor of methacrylic acid (MAA) in a 2-years drinking water study in rats. NOAEL (male) corresponding to HEMA was >= 161.3 mg/kg bw/day (actual dose received) and 213.2 mg/kg bw/day (actual dose received) for females both based on liquid consumption and body weight gain.
No relevant effects of MMA were observed up to the highest dose tested (2000 ppm, limited by palatability) in a 2 years study in rats by oral administration in drinking water.
No statistical differences were noted in the mortality of the animals exposed to methyl methacrylate and those in the control group. A statistically significant decrease in body weight was observed in the first week for the female rats and in weeks one through three in the male rats administered 2000 ppm methyl methacrylate. Water consumption was reduced in the animals from the high-dose group; however, it was reported that this finding tended to regress towards the end of the study. Food consum ption was not affected by the administration of methyl methacrylate in the drinking water.
Hematologic values varied within normal ranges in all groups of rats throughout the study, and urine concentrations of protein and reducing substances showed no trends that appeared relatable to
treatment.
Organ to body weight ratios obtained at sacrifice of 2-year survivors differed from the controls only in significantly increased kidney ratios in female rats receiving 2000 ppm of methyl methacrylate
(controls 0.0082 ± 0.0019; treated 0.0094 ± 0.0011). Histopathologic findings showed no abnormalities or lesions, in kind or incidence, not explicable on
the basis of naturally occurring ones in this strain of rat at this age. Diet equivalents of the test materials were calculated from the fluid and food consumption data.
In these calculations, corrections were not made for evaporation losses of the test materials from the drinking water, the orders of magnitude of which are given under methods described above
(maximum 15%). Allowing for such losses, it would appear that the concentrations of test materials in the drinking water were equivalent to approximately 10, 100, and 3000 ppm in the diet.

Executive summary:

Hydroxyethyl methacrylate rapidly hydrolyses in vivo into its metabolites methacrylic acid and ethylene glycol Chronic toxicity (2 years) by oral application of HEMA was predicted by read across with the methyl methacrylate, the metabolite donor of methacrylic acid (MAA) in a 2-years drinking water study in rats

A two years toxicity study was performed in 1964 to study the tolerance of animals to chronic ingestion of methyl methacrylate.

Twenty-five male and female Wistar rats were administered three doses of methyl methacrylate in the drinking water for two years (Borzelleca et al. 1964). Initial doses of 6, 60 or 2000 ppm MMA were partially raised to 7, 70 and 2000 ppm MMA after 5 months.

A special design was employed to reduce the volatilization and measurements which showed that the methyl methacrylate concentrations remained within 15% of the nominal concentration for 72 hours. Body weight depression was also observed at 2000 ppm MMA but it did not persist beyond the first few weeks of the study. Significant depression of liquid consumption was observed at 2000 ppm, although this tended to regress at the end of the study. Individual observations of depressed food consumption tended to parallel periods of depressed growth. There were significantly increased kidney ratios for female rats at 2000 ppm. These effects were believed to be a consequence of reduced food intake and reduced body weights, and in the absence of any histopathology, were considered as not biologically relevant. Therefore the NOAEL is considered to be >= 2000 ppm MMA, corresponding to 124.13mg/kg bw/day and 164 mg/kg bw/day (MMA), for males and females, respectively, on the basis of treatment specific fluid consumption rates and body weights, corresponding to NOAEL for HEMA of >= 161.3 mg/kg bw/day (males) and  >= 213.2 mg/kg bw/day (females)

No relevant effects were observed after exposure of rats in drinking water up to the highest dose tested (2000 ppm, limited by palatability).