Methoxymethanol

メトキシメタノール

CAS No. 4461-52-3

(Hydroxymethyl) methyl ether

（ヒドロキシメチル）メチルエーテル

Molecular formula: C2H6O2 Molecular weight: 62.07

ABSTRACT

Methoxymethanol was studied for oral toxicity in rats in a single dose toxicity test at doses of 707, 1000, 1414, 2000, and 2828 mg/kg, and in an OECD combined repeat dose and reproductive/developmental toxicity screening test at doses of 12, 60, and 300 mg/kg/day. Genotoxicity of methoxymethanol was also studied by the reverse mutation assay in bacteria and the chromosomal aberration test in cultured Chinese hamster lung (CHL/IU) cells.

The single dose oral toxicity test revealed LD50 values of 1269 mg/kg for males and 1451 mg/kg for females.

With regard to repeat dose toxicity, increased salivation was evident in both sexes, one male died, and suppression of body weight gain and a decrease in food consumption in males occurred in the 300 mg/kg group. Histopathologically, erosion or ulcer of the stomach and thickening of the mucosa of the duodenum were observed in males and females of the 300 mg/kg group. In the 60 mg/kg group, similar histopathological changes of the stomach were noted in males. Hematological examination revealed decreases in red blood cell counts, hematocrit value and hemoglobin concentration, and increases in reticulocyte counts and platelet counts in the males of the 300 mg/kg group. NOELs for repeat dose toxicity are considered to be 12 mg/kg/day for males and 60 mg/kg/day for females. In terms of reproductive/developmental toxicity, the compound showed no effects on any relevant parameters except for an increase in the incidence of persistent foramen ovale in the 300 mg/kg group. NOELs for reproductive and developmental toxicity are considered to be 300 mg/kg/day for parental animals and 60 mg/kg/day for offspring.

Methoxymethanol was mutagenic in Salmonella typhimurium TA100 and TA98 with or without metabolic activation. Structural chromosomal aberrations were induced dose dependently in CHL/IU cells in the absence and presence of exogenous metabolic activation system. Polyploid cells were also marginally induced.

SUMMARIZED DATA FROM THE STUDIES

1. Single Dose Oral Toxicity 1)

Purity	:	46.73%
Test species/strain	:	Rat/Crj:CD (SD)
Test method	:	OECD Test Guideline 401
Doses	:	707, 1000, 1414, 2000, and 2828 mg/kg
Number of animals	:	Male, 5; female, 5/group
Vehicle	:	Pure water
GLP	:	Yes

　Test results:

Dead rats were found in the 1000 mg/kg or higher dose groups. Decreased locomotor activity, bradypea, ptosis, salivation, lying on side, dyspea, clonic convulsion, lacrimation, reddish nasal discharge and straub tail were observed. These signs disappeared by five days. Body weights of all surviving rats increased on the fourteenth day after administration. Autopsy revealed thickening of mucosa, erosion/ulcer, and adhesion with liver of the stomach in the 1414 mg/kg or higher dose groups.

LD50: Male, 1269 mg/kg ; female, 1451 mg/kg

2. Repeat Dose and Reproductive/Developmental Toxicity 1)

Purity	:	46.73%
Test species/strains	:	Rat/Crj:CD (SD)
Test method	:	OECD Combined Repeat Dose and Reproductive/Developmental Toxicity Screening Test
Route	:	Oral (gavage)
Dosage	:	0 (vehicle),12, 60, 300 mg/kg/day
Number of animals	:	Male, 10; female, 10/group
Vehicle	:	Pure water
Administration period	:	Male, 44 days Female, from 14 days before mating to day 3 of lactation
Terminal kill	:	Male, day 45 Female, day 4 of lactation
GLP	:	Yes

　Test results:

<Repeat dose toxicity>

In the 300 mg/kg group, salivation in both sexes, and a death of one male, and suppression of body weight gain and decreased food consumption in males were noted. Histopathological examination revealed erosion or ulcer of the stomach and thickening of the mucosa of the duodenum in both males and females receiving 300 mg/kg. In the 60 mg/kg group, similar histopathological changes of the stomach were noted in males. Hematological examination showed decreases in red blood cell counts, hematocrit values and hemoglobin concentration, and increases in reticulocyte counts and platelet counts in males. Blood chemical examination revealed decreases in total protein, albumin and calcium, and an increase in the A/G ratio was also noted in the males.

NOELs for repeat dose toxicity are considered to be12 mg/kg for males and 60 mg/kg for females.

<Reproductive and developmental toxicity>

The parental animals exhibited no effects on reproductive parameters including copulation index, fertility index, gestation length, number of corpora lutea or implantations, implantation index, gestation index, delivery index, parturition or maternal behavior. On visceral examination of neonates, the incidence of persistent foramen ovale was found to be slightly elevated in the 300 mg/kg group. However, no external or skeletal anomalies related to the test substance administration were detected in any of the offspring. Furthermore, there were no significant differences in the numbers of offspring or live offspring, sex ratio, live birth index, viability index or body weights.

NOELs for reproductive/developmental toxicity are considered to be 300 mg/kg/day for parent animals and 60 mg/kg/day for offspring.

3. Genetic Toxicity

3-1 Bacterial test 2)

Purity	:	46.73%
Test species/strains	:	S.typhimurium TA100, TA1535, TA98, TA1537, E. coli WP2 uvrA
Test method	:	Guideline for Screening Mutagenicity Testing of Chemicals (Japan)
Procedures	:	Plate incorporation method
Solvent	:	Acetone
Positive controls	:	-S9, AF-2 (TA100, WP2, TA98), sodium azide (TA1535) and 9-aminoacridine (TA1537) +S9, 2-aminoanthracene (all strains)
Dosage	:	0, 19.53, 39.06, 78.12, 156.2, 312.5, 625 μg/plate (TA100, TA98, TA1535, TA1537), 0, 39.06, 78.12, 156.2, 312.5, 625, 1250, 2500 μg/plate (WP2)
S-9	:	Rat liver, induced with phenobarbital and 5,6-benzoflavonee
Plates/test	:	3
Number of replicates	:	2
GLP	:	Yes

　Test results:

Minimum concentration of test substance at which toxicity was observed:

Toxicity was observed at a concentration of 312.5μg/plate with or without metabolic activation.

Genetic effects:

S. typhimurium TA100, TA 98

	+	?	-
with metabolic activation	[*]	[ ]	[ ]
without metabolic activation	[*]	[ ]	[ ]

S. typhimurium TA1535, TA1537

	+	?	-
with metabolic activation	[ ]	[ ]	[*]
without metabolic activation	[ ]	[ ]	[*]

E. coli WP2 uvrA

with metabolic activation	[ ]	[ ]	[*]
without metabolic activation	[ ]	[ ]	[*]

3-2 Non-bacterial in vitro test (chromosomal aberration test) 2)

Purity	:	46.73%
Type of cell used	:	Chinese hamster CHL/IU cells
Test method	:	Guidelines for Screening Mutagenicity Testing of Chemicals (Japan)
Solvent	:	Acetone
Positive controls	:	-S9, Mitomycin C +S9, Cyclophosphamide
Doses	:	-S9 (continuous treatment): 0, 0.005, 0.01, 0.02 mg/ml -S9 (short-term treatment): 0, 0.005, 0.01, 0.02 mg/ml +S9 (short-term treatment): 0, 0.008, 0.016, 0.032 mg/ml
S-9	:	Rat liver, induced with phenobarbital and 5,6-benzoflavone
Plates/test	:	2
GLP	:	Yes

　Test results:

In the 24h continuous treatment groups without S9 mix, the frequencies of cells with structural aberrations and polyploids increased significantly in a dose dependent manner. In the middle concentration group (0.01 mg/ml) of 24h continuous treatment without S9 mix, 5% of the cells were observed to have structural aberrations (including gaps). In the high concentration group (0.02 mg/ml) after continuous treatment without an S9 mix, polyploidy was observed in 5% of the cells. In the high concentration group (0.032 mg/ml) short-term treatment with S9 mix, 16.5% of the cells were observed to have structural aberrations (including gaps) and polyploidy were observed in 16.5% of the cells.

Lowest concentration producing cytogenetic effects in vitro:

without metabolic activation (continuous treatment )	:	0.01 mg/ml (clastogenicity) 0.02 mg/ml (polyploidy)
without metabolic activation (short-term treatment)	:	0.020mg/ml (clastogenicity)
with metabolic activation (short-term treatment)	:	0.032 mg/ml (clastogenicity 0.032 mg/ml (polyploidy)

Genotoxic effects:

	clastogenicity			polyploidy
	+	?	-	+	?	-
without metabolic activation:	[*]	[ ]	[ ]	[ ]	[*]	[ ]
with metabolic activation:	[*]	[ ]	[ ]	[ ]	[*]	[ ]

1)	The tests were performed by the Mitsubishi-Kasei Institute of Toxicological and Environmental Sciences (New name: Mitsubishi Chemical Safety Institute Ltd.), 14 Sunayama, Hasaki-machi, Kashima-gun, Ibaraki 314-02, Japan. Tel +81-479-46-2871 Fax +81-479-46-2874
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