Methacrylic anhydride

Repeated dose toxicity: oral

Administrative data

Endpoint:

chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study well documented, meets generally accepted scientific principles, acceptable for assessment.

Data source

Reference

Reference Type:

publication

Title:

Studies on the Chronic Oral Toxicity of Monomeric Ethyl Acrylate and Methyl Methacrylate.

Author:

Borzelleca JF, Larson PS, Hennigar GR, Huf EG, Crawford EM, Blackwell, Smith R

Year:

1964

Bibliographic source:

Toxicol. Appl. Pharmacol. 6: 29-36

Materials and methods

Test guideline

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

Test material

Test material information

Constituent 1

Reference substance name:

Methacrylic anhydride

EC Number:

212-084-8

EC Name:

Methacrylic anhydride

Cas Number:

760-93-0

Molecular formula:

C8H10O3

IUPAC Name:

2-methylprop-2-enoyl 2-methylprop-2-enoate

Test material form:

liquid

Specific details on test material used for the study:

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

Test animals

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

Administration / exposure

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

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

6 ppm

Remarks:

raised after 5 months to 7 ppm

Doses / concentrations 2

Dose / conc.:

60 ppm

Remarks:

raised after 5 months to 70 ppm

Doses / concentrations 3

Dose / conc.:

2 000 ppm

Doses / concentrations 4

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)

Doses / concentrations 5

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)

Doses / concentrations 6

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.

Examinations

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.

Sacrifice and pathology:

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. 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.

Results and discussion

Results of examinations

Haematological findings:

no effects observed

Description (incidence and severity):

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

Urinalysis findings:

no effects observed

Description (incidence and severity):

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

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).

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.

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.

Effect levels

1

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)

2

Dose descriptor:

NOAEL

Effect level:

>= 164 mg/kg bw/day (actual dose received)

Sex:

female

Basis for effect level:

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

3

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

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Mortality:

A summary of the mortality data for methyl methacrylate is presented below.

Dose group (ppm)            Male           Female
Negative              (0)          12/25           9/25
                           6/7           7/25           7/25
          60/70          10/25           7/25
           2000          12/25          10/25

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 consumption 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.

Applicant's summary and conclusion

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.

Executive summary:

A two years toxicity study was performend in 1964 to study the tolerance of animals to chronic ingestion of methyl methacrylate. No relevant effects were observed after exposure of rats in drinking water up to the highest dose tested (2000 ppm, limited by palatability)..