2,3-Epoxypropyl methacrylate

メタクリル酸 2,3-エポキシプロピルエステル

[CAS No. 106-91-2]

Glycidyl methacrylate

メタクリル酸グリシジルエステル

Molecular formula: C7H10O3　　Molecular weight: 142.17

ABSTRACT

2,3-Epoxylpropyl Methacrylate was studied for oral toxicity in rats in an OECD combined repeat dose and reproductive/developmental toxicity screening test at doses of 0, 10, 30 and 100 mg/kg/day.

In the repeat dose study, salivation was observed in 5 male rats receiving 30 mg/kg and in all males (12 rats) receiving 100 mg/kg. Increased absolute and relative kidney weights were observed in both sexes receiving 100 mg/kg. Histopathologically, squamous hyperplasia of the forestomach was evident in males receiving 30 and 100 mg/kg,and edema of the forestomach submucosa was observed in males receiving 30 mg/kg. NOELs for repeat dose toxicity are considered to be 10 mg/kg/day for males and 30 mg/kg/day for females.

In terms of reproductive/developmental toxicity, the fertility index decreased significantly in the 100 mg/kg group. No effects were observed on the development of the next generation. NOELs for reproductive performance of both sexes, and pup development are considered to be 30 mg/kg/day and 100 mg/kg/day, respectively.

Genotoxicity of 2,3-epoxypropyl methacrylate was studied by chromosomal aberration test in cultured Chinese hamster lung (CHL/IU) cells. Structural chromosomal aberrations were induced under the following conditions: 24 h continuous treatment at 0.013 and 0.025 mg/ml (mid and high concentrations); 48 h continuous treatment at 0.025 mg/ml; short-term treatment with an exogenous metabolic activation system at 0.18 mg/ml (high concentration); short-term treatment without a metabolic activation system at 0.044 mg/ml (high concentration). Polyploidy was induced at 0.025 mg/ml with 48 h continuous treatment and at 0.044 mg/ml with short-term treatment without a metabolic activation system.

A significant and dose-dependent increase of micronucleated polychromatic erythrocytes (MNPCE) was observed in both male and female mice after 48 hours treatment. The proportion of polychromatic erythrocytes in the total erythrocytes was significantly lower at the highest dose in male and female mice.

SUMMARIZED DATA FROM THE STUDIES

1. Repeat Dose and Reproductive/Developmental Toxicity１）

Purity	:	99.93%
Test species/strains	:	Rat/Crj:CD (SD)
Test method	:	OECD Combined Repeat Dose and Reproductive/Developmental Toxicity Screening Test
Route	:	Oral (gavage)
Doses	:	0 (Vehicle), 10, 30, 100mg/kg/day
Number of animals	:	Males, 12; females, 12/group
Vehicle	:	Corn oil
Administration period	:	Males, 45 days Females, from 14 days before mating to day 3 of lacation
Terminal kill	:	Males, day 45 Females, day 4 of lacation
GLP	:	Yes

　Test results:

<Repeat dose toxicity>

Salivation was observed in 5 male rats receiving 30 mg/kg and in all males (12 rats) receiving 100 mg/kg. There were no obvious influences of the test substance on the body weight gain or food consumption in either sex, or in the hematological and blood chemistry examinations of male rats. Increased absolute and relative kidney weights were observed in both sexes receiving 100 mg/kg. Pathological examination revealed no specific macroscopical findings attributable to the administration of the test substance. As histological findings, squamous hyperplasia of the forestomach was observed in males receiving 30 and 100 mg/kg, and edema of the forestomach submucosa was noted in males receiving 30 mg/kg. Many animals were infertile apparent in the 100 mg/kg group. However, morphological abnormalities were not apparent in the testes, ovaries, epididymis, seminal vesicles, prostate, uterus or pittuitary gland. Moreover, counts of Stage VIII seminiferous tubules in the testes of the 100 mg/kg group did not reveal any effects attributable to the administration of the test substance.

NOELs for repeat dose toxicity are considerd to be 10 mg/kg/day for males and 30 mg/kg/day for females.

<Reproductive and developmental toxicity>

The fertility index decreased significantly in the 100 mg/kg group, presumably due to the low sperm motility revealed by secondary investigations. There were no effects of the test substance on the estrous cycle, copulation index, gestation length, or parturition. Slight decreases in the numbers of corpora lutea, implants, pups born and live pups as well as the implantation and delivery indices were observed in the 100 mg/kg group. However, clear effects attributable to the administration of the test substance could not be concluded because of the few cases. There were no significant differerences in the gestation index, live birth index or viability index on day 4. No abnormalities attributable to the administration of the test substance were noted in the body weights of live pups or on necropsy of pups fo any treated group.

NOELs for reproductive performance of males and females, and pup development are considered to be 30 mg/kg/day and 100 mg/kg/day respectively.

2. Genetic Toxicity

2-1. Non-bacterial in vitro test (chromosomal aberration test)２）

Purity	:	99.93 %
Type of cell used	:	Chinese hamster lung (CHL/IU) cells
Test method	:	Guidelines for Screening Mutagenicity Testing of Chemicals (Japan)
Solvent	:	Dimethylsulfoxide
Positive controls	:	-S9 mix, Mitomycin C +S9 mix, Cyclophosphamide
Doses	:	-S9 mix (continuous treatment):0, 0.0063, 0.013, 0.025 mg/ml -S9 mix (short-term treatment):0, 0.011, 0.022, 0.044 mg/ml +S9 mix (short-term treatment):0, 0.044, 0.088, 0.18 mg/ml
S-9	:	Rat liver, induced with phenobarbital and 5,6-benzoflavone
Plates/test	:	2
GLP	:	Yes

　Test results:

Cytogenetic effects were seen as follows.

Structural chromosomal aberrations (including gap) were induced under the following conditions: 24 h continuous treatment (0.013 and 0.025 mg/ml: mid and high concentrations, 3.5 and 89.5%); 48 h continuous treatment (0.025 mg/ml, 48.5 %); short-term treatment with an exogenous metabolic activation system (0.18 mg/ml: high concentration, 9.5%); short-term treatment without the metabolic activation system (0.044 mg/ml: high concentration, 28.5%). Polyploidy was induced under the following conditions: 24 h continuous treatment (0.013 mg/ml, 1.38%); 48 h continuous treatment (0.025 mg/ml, 9.40%); short-term treatment with an exogenous metabolic activation system (0.088 mg/ml: mid concentration, 0.88%); short-term treatment without the metabolic activation system (0.044 mg/ml, 0.88%). However, a trend test showed no dose-dependency for the induction of polyploidy with the 24 h continuous treatment and the short-term treatment with the metabolic activation system.

Lowest concentration producing cytogenetic effects in vitro:

Without metabolic activation (continuous treatment )
	: 0.013 mg/ml (clastogenicity) : 0.025 mg/ml (clastogenicity and polyploidy)
Without metabolic activation (short-term treatment)
	: 0.044 mg/ml (clastogenicity and polyploidy)
With metabolic activation (short-term treatment)
	: 0.18 mg/ml (clastogenicity) : 0.088 mg/ml (polyploidy)

Genotoxic effects:

	clastogenicity			polyploidy
	+	?	-	+	?	-
Without metabolic activation:	[*]	[ ]	[ ]	[*]	[ ]	[ ]
With metabolic activation:	[*]	[ ]	[ ]	[ ]	[*]	[ ]

2-2. Non-bacterial in vivo test (Micronucleus test)２）

Purity	:	99.93%
Test species/strains	:	Mice/Crj:BDF1, male and female
Test methods	:	Guideline for Screening Mutagenicity Testing of Chemicals (Japan) and OECD Guideline No. 474
Procedure	:	Bone marrow/acridine orange staining
Solvent	:	Olive oil
Positive control	:	Cyclophosphamide 50 mg/kg
Doses	:	0, 188, 375 and 750 mg/kg in males 0, 250, 500 and 1000 mg/kg in females
Mice/group	:	5 male and female/group
GLP	:	Yes

　Test results:

The frequency of micronucleated polychromatic erythrocytes was significantly increased in males and females with dose-dependency at 48h after oral gavage administration. Inhibition of bone marrow cell proliferation was observed at the high dose in both sexes under the test conditions.

Lowest dose producing toxicity: 400 mg/kg in males and females

Maximum tolerated dose

:

750 mg/kg in males 1000 mg/kg in females

Genotoxic effect:

	+	?	-
Micronucleus test:	[*]	[ ]	[ ]

1)	The tests were performed by the Biosafety Research Center, Foods, Drugs and Pesticides (An-pyo Center), Japan, 582-2 Shioshinden Arahama, Fukude-cho, Iwata-gun, Shizuoka, 437-12, Japan. Tel +81-538-58-1266 Fax +81-538-58-1393
2)	The tests were performed by the Hatano Research Institute, Food and Drug Safety Center, 729-5 Ochiai, Hadano-shi, Kanagawa, 257, Japan. Tel +81-463-82-4751 Fax +81-463-82-9627