2,3-epoxypropyl methacrylate

Carcinogenicity

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: oral

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

1990

Reliability:

1 (reliable without restriction)

Guideline:

other: see attached IARC monograph on glycidol

GLP compliance:

not specified

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

water

Duration of treatment / exposure:

103 weeks

Frequency of treatment:

5 days per week

Remarks:

Doses / Concentrations:
0, 37.5 and 75 mg/kg/d
Basis:
nominal in water

No. of animals per sex per dose:

50

Dose descriptor:

T25

Effect level:

57 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Note that the effect level for glycidol (T25=29.7 mg/kg/d) was corrected for the difference in molecular weight between glycidol and glycidyl methacrylate by multipying the number by 142.17/74.08

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

Groups of 50 male and 50 female Fischer 344 rats, eight weeks of age, were administered

0, 37.5 or 75 mg/kg bw of glycidol (purity, 94%, with the main impurities being

those listed in Section 3.1.1) in distilled water by gavage on five days per week for 103

weeks. Survival of rats was significantly lower in the treated groups in both males and

females than in the control groups, with the mean survival being 92, 82 and 66 weeks

for the control, mid- and high-dose males, respectively, and 97, 85 and 78 weeks for the

female dose groups. As shown in Table 3 of the IARC monograph, respectively in the main

table in the abstract of the NTP report, there was a statistically significant increase in

the incidence of mesotheliomas of the tunica vaginalis/peritoneum in males at both 37.5

and 75 mg/kg bw. There was a statistically significant increase in the incidence of

fibroadenoma and adenocarcinoma of the mammary gland in female rats, and of

mammary fibroadenoma in male rats at both doses in each case. The incidences in the

forestomach of squamous-cell papilloma and of squamous papilloma or carcinoma

combined were significantly increased in female rats at both doses and in male rats at

the high dose. Gliomas of the brain were significantly increased in both sexes at the high

dose. Other tumour types with increased incidence included squamous-cell papillomas

or carcinomas of the mouth or tongue, adenomas or carcinomas of the clitoral gland and

leukaemia in female rats; and Zymbal gland carcinomas, thyroid follicular-cell

adenomas or carcinomas, skin tumours and adenomatous polyps or adenocarcinomas of

the intestine combined in male rats (National Toxicology Program TR 374, 1990).

For the calculation of the T25, female rat mammary gland adenocarcinoma's were considered since 1) these have a high relevance for human carcinogenicity and 2) these were statistically significantly increased at both 37.5 and 75.0 mg/kg bw/d.

The dose of 37.5 mg/kg/d was corrected for 5 days dosing/wk instead of 7 days (factor 5/7), for 103 weeks dosing instead of 104 (factor 103/104) and for the purity of the glkycidol used (94% instead of 100%: factor 94/100).

The percentage of this type of cancer at 37.5 mg/kg/d was 11 rats out of 48 rats or 23%, while the percentage at 0 mg/kg/d was 1 rat out of 50 rats or 2%. The net percentage increase was thus 21%.

This leads to a T25 for glycidol of 37.5*5/7*103/104*94/100*25/21= 29.7 mg/kg/d

This number was corrected to a T25 for GMA for molecular weight differences:

29.7 * 142.17/74.08 = 57 mg/kg/d

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

T25

57 mg/kg bw/day

Study duration:

chronic

Species:

rat

Justification for classification or non-classification

Based on the available study (read across from glycidol since glycidyl methacrylate is rather rapidly metabolised to glycidol) glycidyl methacrylate must be classified under REACH and CLP as Carcinogenic Category 1B (H350).

Additional information

There are reports on chronic exposure studies with GMA, but each one has significant methodologic deficiencies such that the conclusion is that there are no acceptable chronic studies with GMA. Consequently aRead Across for GMA was used. Rationale: although the kinetics of carboxylesterase-mediated hydrolysis of GMA appear to be species dependent, the primary metabolite of GMA found in humans, rats and rabbits is glycidol. Chronic bioassay data were located for glycidol in rats and mice.

 

The results of studies on carcinogenicity after oral administration of glycidol are summarised as follows:

Groups of 50 male and 50 female Fischer 344 rats, eight weeks of age, were administered 0, 37.5 or 75 mg/kg bw of glycidol (purity, 94%) in distilled water by gavage on five days per week for 103 weeks. Survival of rats was significantly lower in the treated groups in both males and females than in the control groups, with the mean survival being 92, 82 and 66 weeks for the control, mid- and high-dose males, respectively, and 97, 85 and 78 weeks for the female dose groups. As shown in Table 3 of the IARC monograph, respectively in the main table in the abstract of the NTP report, there was a statistically significant increase in the incidence of mesotheliomas of the tunica vaginalis/peritoneum in males at both 37.5 and 75 mg/kg bw. There was a statistically significant increase in the incidence of fibroadenoma and adenocarcinoma of the mammary gland in female rats, and of mammary fibroadenoma in male rats at both doses in each case. The incidences in the forestomach of squamous-cell papilloma and of squamous papilloma or carcinoma combined were significantly increased in female rats at both doses and in male rats at the high dose. Gliomas of the brain were significantly increased in both sexes at the high dose. Other tumour types with increased incidence included squamous-cell papillomas or carcinomas of the mouth or tongue, adenomas or carcinomas of the clitoral gland and leukaemia in female rats; and Zymbal gland carcinomas, thyroid follicular-cell adenomas or carcinomas, skin tumours and adenomatous polyps or adenocarcinomas of the intestine combined in male rats. According to the National Toxicology Program Review Panel, there was clear evidence of carcinogenicity in male and female Fischer 344 rats. (National Toxicology Program TR374, 1990; IARC, 2000).

 

Groups of 50 male and 50 female B6C3F1 mice, nine weeks of age, were administered 0, 25 or 50 mg/kg bw of glycidol (94% purity, with the primary impurity, as determined by gas chromatography, being diglycidyl ether at a concentration of 2.8%, and 3-methoxy-1,2-propanediol (1.2%), 2,6-dimethanol-1,4-dioxane (1.1%), 3-chloro-1,2-propanediol (0.4%) and methanol (0.1%) as lesser impurities) in distilled water by gavage on five days per week for 103 weeks. The survival of female mice at the high dose was significantly lower after week 101 than in the controls. As shown in Table 2 of the IARC monograph, there was a significantly increased incidence of Harderian gland adenomas and adenocarcinomas combined in the high-dose males and in the high- and mid-dose females, and of Harderian gland adenocarcinomas in the high-dose males. In male mice only, the incidences of adenomas and carcinomas of the liver, squamous-cell papillomas of the forestomach and skin and alveolar/bronchiolar adenomas of the lung were significantly increased at the high dose; in females only, the incidences of mammary gland adenocarcinomas and of subcutaneous sarcomas and fibrosarcomas combined were significantly increased at the high dose. There was also a slight increase in uterine glandular carcinomas in female mice (National Toxicology Program TR374, 1990; IARC, 2000).

For the calculation of the T25 for the parent study on glycidol, female rat mammary gland adenocarcinoma's were considered since 1) these have a high relevance for human carcinogenicity and 2) these were statistically significantly increased at both 37.5 and 75.0 mg/kg bw/d.

The dose of 37.5 mg/kg/d was corrected for 5 days dosing/wk instead of 7 days (factor 5/7), for 103 weeks dosing instead of 104 (factor 103/104) and for the purity of the glycidol used (94% instead of 100%: factor 94/100).

The percentage of this type of cancer at 37.5 mg/kg/d was 11 rats out of 48 rats or 23%, while the percentage at 0 mg/kg/d was 1 rat out of 50 rats or 2%. The net percentage increase was thus 21%.

This leads to a T25 for glycidol of 37.5*5/7*103/104*94/100*25/21= 29.7 mg/kg/d

This number was corrected to a T25 for GMA for molecular weight differences:

29.7 * 142.17/74.08 = 57 mg/kg/d