Dimethyl 2,6-naphthalenedicarboxylate

2,6-ナフタレンジカルボン酸ジメチルエステル


[CAS No. 840-65-3]

Molecular formula: C14H12O4 Molecular weight: 244.25

ABSTRACT

Dimethyl 2,6-naphthalenedicarboxylate was studied for oral toxicity in rats in a single dose toxicity test at doses of 0, 500, 1000 and 2000 mg/kg. An LD50 value of more than 2000 mg/kg was found for both sexes.

Dimethyl 2,6-naphthalenedicarboxylate was studied for oral toxicity in rats in an OECD combined repeat dose and reproductive/developmental toxicity screening test at doses of 0, 30, 100, 300 and 1000 mg/kg/day. With regard to repeat dose toxicity, no effects of the test substance on males or females were noted. The NOEL for repeat dose toxicity is considered to be 1000 mg/kg/day for both sexes. With regard to reproductive/developmental toxicity, no effects of the test substance on copulation, fertility, delivery as lactation were noted. The NOELs for reproductive performance of males and females, and for pup development are considered to be 1000 mg/kg/day both.

Dimethyl 2,6-naphthalenedicarboxylate was not mutagenic in Salmonella typhimurium TA100, TA1535, TA98, TA1537 and Escherichia coli WP2 uvrA, with or without an exogeneous metabolic activation system.

Genotoxicity of dimethyl 2,6-naphthalenedicarboxylate was studied by chromosomal aberration test in cultured Chinese hamster lung (CHL/IU) cells. Structural chromosomal aberrations were not induced up to a maximum concentration of 2.4 mg/ml (10 mM) with continuous treatment, or by short-term treatment with and without an exogenous metabolic activation system. Polyploidy was induced by continuous treatment with 2.4 mg/ml for 48 h. However, we concluded that dimethyl 2,6-naphthalenedicarboxylate did not induced chromosomal aberrations or polyploidy since the frequency was low.

SUMMARIZED DATA FROM THE STUDIES

1. Single Dose Oral Toxicity１）

Purity:99.9%
Test species/strain:Rat/Crj:CD (SD)
Test method:OECD Test Guideline 401
　Route:Oral (gavage)
　Doses:0 (vehicle), 500, 1000, 2000 mg/kg/day
　Number of animals/goup:Males, 5; females, 5
　Vehicle:0.5% sodium carboxymethylcelullose solution
GLP:Yes

　Test results:

No deaths occurred in any group.
Based on the above results, the LD50 value for dimethyl 2,6-naphthalenedicarboxylate was concluded to be 2000 mg/kg or more for both sexes.

2. Repeat Dose and Reproductive/Developmental Toxicity１）

Purity:99.9%
Test species/strain:Rat/Crj:CD (SD)
Test method:OECD Combined Repeat Dose and Reproductive/Developmental Toxicity Screening Test
　Route:Oral (gavage)
　Doses:0 (vehicle), 30, 100, 300, 1000 mg/kg/day
　Number of animals/group:Males, 12; females, 12
　Vehicle:0.5% sodium carboxymethylcellulose solution
　Administration period:Males, 49 days
Females, from 14 days before mating to day 3 of lactation
　Terminal kill:Males, day 50
Females, day 4 of lactation
GLP:Yes
　Test results:
<Repeat Dose Toxicity>
For the males, there were no effects of the test substance on the general signs, body weight, food consumption, hematology, blood chemistry, necropsy findings, organ weights or histopathology. For the females, there were no effects of the test substance on the general signs, body weight, food consumption, necropsy findings, organ weights or histopathology. The NOEL for the repeated dose toxicity is considered to be 1000 mg/kg/day for both sexes.

<Reproductive/Developmental Toxicity>
There were no effects of the test substance on the estrus frequency, copulation index, number of conceiving days, fertility index, length of gestation, number of corpora lutea or the gestation index. There were no effects of the test substance on the number of live pups born, birth index, number of dead pups, number of pups born, delivery index, live birth index, sex ratio, viability index, external anomalies, body weight or necropsy findings. The NOELs for the reproductive/developmental toxicity are considered to be 1000 mg/kg/day for reproduction in both sexes as well as for development of pups.

3. Genetic Toxicity

3-1. Bacterial test２）

Purity:99.9 wt%
Test species/strains:Salmonella typhimurium, TA100, TA1535, TA98, TA1537, Escherichia coli WP2 uvrA
Test method:Guidelines for Screening Mutagenicity Testing of Chemicals (Japan) and OECD Guideline No. 471 and 472
　Procedures:Pre-incubation method
　Solvent:Water
　Positive controls:-S9 mix, 2-(2-Furyl)-3-(5-nitro-2-furyl) acrylamide (TA100, TA98, WP2), Sodium azide (TA1535) and 9-Aminoacridine (TA1537)
+S9 mix, 2-Aminoanthracene (five strains)
　Doses:-S9 mix; 0, 313, 625, 1250, 2500, 5000 μg/plate (five strains)
+S9 mix; 0, 313 - 5000 μg/plate (five strains)
　S9:Rat liver, induced with phenobarbital and 5,6-benzoflavone
　Plates/test:3
　Number of replicates:2
GLP:Yes

　Test results:

This chemical did not induce mutations in the S. typhimurium and E. coli strains. Toxicity was not observed at 5000 μg/plate in five strains with or without an S9 mix.

Genetic effects:
Salmonella typhimurium TA100, TA1535, TA98, TA1537
+?-
Without metabolic activation:[ ][ ][*]
With metabolic activation:[ ][ ][*]

Escherichia coli WP2 uvrA
+?-
Without metabolic activation:[ ][ ][*]
With metabolic activation:[ ][ ][*]

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

Purity:99.9 wt%
Type of cell used:Chinese hamster lung (CHL/IU) cells
Test method:Guidelines for Screening Mutagenicity Testing of Chemicals (Japan) and OECD Guideline No. 473
　Vehicle:0.5 % carboxymethylcellulose sodium
　Positive controls:-S9 mix, Mitomycin C
+S9 mix, Cyclophosphamide
　Doses:-S9 mix (continuous treatment):0, 0.60, 1.2, 2.4 mg/ml
-S9 mix (short-term treatment):0, 0.60, 1.2, 2.4 mg/ml
+S9 mix (short-term treatment):0, 0.60, 1.2, 2.4 mg/ml
　S-9:Rat liver, induced with phenobarbital and 5,6-benzoflavone
　Plates/test:2
GLP:Yes
　Test results:
Structural chromosomal aberrations were not induced in any treatment group. With continuous treatment for 48 h, polyploidy (1.25 %) was weakly induced at 2.4 mg/ml (high concentration). However, we concluded that dimethyl 2,6-naphthalenedicarboxylate did not induced chromosomal aberrations or polyploidy since the frequency was low.

Genotoxic effects:
clastogenicitypolyploidy
+?-+?-
Without metabolic activation:[ ][ ][*][ ][ ][*]
With metabolic activation:[ ][ ][*][ ][ ][*]

1)The test was performed by Nihon Bioresearch Inc. Hashima Laboratory, 6-104 Majima, Fukuju-cho, Hashima, Gifu, 501-62 Japan Tel +81-58-392-6222 Fax +81-58-391-3171
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