Trioctyl benzene-1,2,4-tricarboxylate

1,2,4-ベンゼントリカルボン酸トリオクチル


[CAS No. 89-04-3]

Trioctyl trimellitate/1,2,4-Benzenetricarboxylic acid, trioctyl ester

トリオクチルトリメリタート

Molecular formula: C33H54O6　Molecular weight: 546.78

ABSTRACT

A single dose oral toxicity of trioctyl benzene-1,2,4-tricarboxylate revealed an LD50 value of more than 2000 mg/kg for both sexes.

Trioctyl benzene-1,2,4-tricarboxylate was evaluated for repeated dose oral toxicity and reproductive/developmental toxicity in Sprague-Dawley rats according to the OECD test guideline 422 at doses of 0, 30, 125 and 500 mg/kg. Males were administered the compound for 42 days from 2 weeks before mating to the necropsy, and females were dosed from 2 weeks before mating through gestation until day 4 of lactation.

No deaths were observed except one female in the 500 mg/kg group which died on day 23 of gestation. Temporally increase in salivation after dosing was observed in animals of the 500 mg/kg group. Although decrease in body weight gain from day 7 to 14 of gestation was observed in females of the 500 mg/kg group, there were no adverse effects on body weight change in males and food consumption in either sex. In females, decrease in erythrocyte count and increase in liver weights were observed in the 125 and 500 mg/kg groups, and decreased protein, increased glucose were observed in the 500 mg/kg group. In males, decreased protein and increased ALP were observed in the 500 mg/kg group. Histopathological examination revealed hypertrophy of hepatocytes in the centrilobular zone in males of the 500 mg/kg group. The pathological findings for other internal organs revealed no adverse changes in any treated animal.

There were no adverse effects on the estrous cycle, copulation, fertility, delivery or lactation. In addition, no alteration related to the treatment was observed with regard to the gestation index, gestation length, numbers of corpora lutea, implantation sites or implantation index. There were no changes in sex ratio, body weight, viability or morphology of pups.

In conclusion, the NOELs for repeated dose toxicity of trioctyl benzene-1,2,4-tricarboxylate are considered to be 125 mg/kg/day for males and 30 mg/kg/day for females. The NOEL for reproductive and developmental toxicity is considered to be 500 mg/kg/day for parent animals and offspring.

Trioctyl benzene-1,2,4-tricarboxylate was not mutagenic in Salmonella typhimurium TA100, TA1535, TA98, TA1537 and Escherichia coli WP2 uvrA, with or without an exogenous metabolic activation system.

Trioctyl benzene-1,2,4-tricarboxylate did not induce structural chromosomal aberrations or polyploidy in CHL/IU cells, with or without an exogenous metabolic activation system.

SUMMARIZED DATA FROM THE STUDIES

1. Single Dose Oral Toxicity 1)

Purity:99 wt%
Test species/strain:Rat/Crj:CD(SD)IGS
Test method:OECD Test Guideline 401
　Route:Oral (gavage)
　Dosage:0 (vehicle), 2000 mg/kg
　Number of animals/group:Males, 5; females, 5
　Vehicle:Corn oil
GLP:Yes

　Test results:

No deaths occurred of either male or female animals. No adverse effects were detected in terms of general condition, body weight changes or autopsy findings.

From the above results, the LD50 value is concluded to be more than 2000 mg/kg for both sexes.

2. Repeated Dose and Reproductive/Developmental Toxicity 1)

Purity:99 wt%
Test species/strain:Rat/Crj:CD(SD)IGS
Test method:OECD Test Guideline 422
　Route:Oral (gavage)
　Dosage:0 (vehicle), 30, 125, 500 mg/kg/day
　Number of animals/groupMales, 13; females, 13
　Vehicle:Corn oil
　Administration period:Males, 42 days
Females, from 14 days before mating to day 4 of lactation
　Terminal killing:Male, day 43 of administration
Female, day 5 of lactation
GLP:Yes

　Test results:

No deaths were observed except for one female in the 500 mg/kg group which died on day 23 of gestation. Temporally increase in salivation after oral dosing was observed in animals of the 500 mg/kg group. Although decrease in body weight gain from day 7 to 14 of gestation was observed in females of the 500 mg/kg group, there were no adverse effects on body weights in males and food consumption in either sex. In females, decrease in erythrocyte count and increase in liver weights were observed in the 125 and 500 mg/kg groups, and decreased protein, and increased glucose were noted in the 500 mg/kg group. In males, decreased protein and increased ALP were observed in the 500 mg/kg group. Histopathological examination revealed hypertrophy of hepatocytes in the centrilobular zone in males of the 500 mg/kg group. The pathological findings for other internal organs revealed no adverse changes in any treated animal. There were no adverse effects on estrous cycle, copulation, fertility, delivery or lactation. In addition, no changes related to the treatment were observed in terms of the gestation index, gestation length, numbers of corpora lutea, implantation sites or implantation index. There were no changes in sex ratio, body weight, viability or morphology of pups. The NOELs for repeat dose toxicity are considered to be 125 mg/kg/day for males and 30 mg/kg/day for females. The NOEL for reproductive and developmental toxicity is considered to be 500 mg/kg/day for parent animals and offspring.

3. Genetic Toxicity

3-1. Bacterial test 2)

Purity:99 wt%
Test species/strain:Salmonella typhimurium TA100, TA1535, TA98, TA1537, Escherichia coli WP2 uvrA
Test method:Guidelines for Screening Mutagenicity Testing of Chemicals (Chemical Substances Control Law of Japan) and OECD Test Guideline 471
　Procedures:Pre-incubation method
　Solvent:Acetone
　Positive controls:-S9 mix; 2-(2-Furyl)-3-(5-nitro-2-furyl)acrylamide (TA100, TA98), Sodium azide (TA1535), 9-Aminoacridine hydrochloride (TA1537) and N-Ethyl-N'-nitro-N-nitrosoguanidine (WP2 uvrA)
+S9 mix; 2-Aminoanthracene (five strains)
　Dosage:-S9 mix; 0, 313, 625, 1250, 2500, 5000 μg/plate (five strains)
+S9 mix; 0, 313, 625, 1250, 2500, 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 gene mutations in the Salmonella typhimurium and Escherichia coli strains. Toxicity was not observed up to 5000 μg/plate in the five strains, with or without metabolic activation.

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 wt%
Type of cell used:Chinese hamster CHL/IU cells
Test method:Guidelines for Screening Mutagenicity Testing of Chemicals (Chemical Substances Control Law of Japan) and OECD Test Guideline 473
　Solvent:Acetone
　Positive controls:-S9 mix; Mitomycin C
+S9 mix; Benzo[a]pyrene
　Dosage:-S9 mix (6 hr short-term treatment); 0, 1250, 2500, 5000 μg/mL
+S9 mix (6 hr short-term treatment); 0, 1250, 2500, 5000 μg/mL
-S9 mix (24 hr continuous treatment); 0, 1250, 2500, 5000 μg/mL
　S9:Rat liver, induced with phenobarbital and 5,6-benzoflavone
　Plates/test:2
GLP:Yes

　Test results:

This chemical did not induce structural chromosomal aberrations or polyploidy under the conditions of this experiment.

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

1)The tests were performed by the Hatano Research Institute, Food and Drug Safety Center, 729-5 Ochiai, Hadano-shi, Kanagawa, 257-8523, Japan. Tel +81-463-82-4751 Fax +81-463-82-9627
2)The tests were performed by the Kashima Laboratory, Mitsubishi Chemical Safety Institute Ltd., 14 Sunayama, Hasaki-machi, Kashima-gun, Ibaraki, 314-0255, Japan. Tel +81-479-46-2871 Fax +81-479-46-2874