Diheptyl phthalate

フタル酸ジヘプチルエステル


[CAS No. 3648-21-3]

ジヘプチルフタレート

Molecular formula: C22H34O4 Molecular weight: 362.51

ABSTRACT

Diheptyl phthalate was studied for oral toxicity in rats both in a single dose toxicity test at doses of 0, 500, 1000 and 2000 mg/kg, and in a 28-day repeat dose toxicity test at doses of 0, 62.5, 250 and 1000 mg/kg/day.

The single dose toxicity test revealed LD50 values of above 2000 mg/kg for both sexes.

In the repeat dose toxicity test, body weight gains and their rates during the administration period were decreased in males given 1000 mg/kg. As for renal changes, the incidence of a urine protein-positive reaction and the relative kidney weights were increased in females given 1000 mg/kg and serum urea nitrogen was increased in males given 1000 mg/kg. Relative to hepatic changes, prothrombin and activated partial thromboplastin times were prolonged in males given 250 mg/kg and above, and the serum b-globulin fraction was decreased and relative liver weights were increased in males given 1000 mg/kg. Histopathologically, centrilobular hypertrophy, centrilobular fatty change and focal necrosis of hepatocytes were observed in males given 1000 mg/kg. In females, activated partial thromboplastin times were prolonged, the serum albumin fraction was increased, the β-globulin fraction was decreased and absolute and relative liver weights were increased in the 1000 mg/kg group. In the male reproductive organs, a bsolute testis and epididymis weights were decreased, and these organs were macroscopically noted to be small. Histopathologically, loss of spermatogenic cells in the testes, decrease in sperm in the ducts and appearance of detached spermatogenic cells in the epididymides were observed in the 1000 mg/kg group.

With regard to the changes in testes and epididymides, no recovery was noted during the 14 days after withdrawal, while many of the other changes disappeared. The repeat dose toxicity revealed NOELs of 62.5 mg/kg/day for males, and 250 mg/kg/day for females.

Diheptyl phthalate was not mutagenic to Salmonella typhimurium, TA100, TA1535, TA98, TA1537 and Escherichia coli WP2 uvrA. Neither structural nor numerical chromosomal aberrations were induced in CHL/IU cells up to the limit concentration of 5 mg/ml, in the absence or presence of an exogenous metabolic activation system.

SUMMARIZED DATA FROM THE STUDIES

1. Single Dose Oral Toxicity 1)

Purity:99.56%
Test species/strain:Rat/Crj:CD (SD)
Test method:OECD Test Guideline 401
 Doses:500, 1000, 2000 mg/kg
 Number of animals/group:Males, 5; females, 5
GLP:Yes

 Test results:

No deaths occurred in any of the treated groups including males and females. No effects were detected in terms of general appearance, body weight changes, autopsy or histopathology findings.
LD50: Male, > 2000 mg/kg; female, > 2000 mg/kg

2. Repeat Dose Toxicity 1)

Purity:99.56%
Test species/strain:Rat/Crj:CD (SD)
Test method:Guidelines for 28-Day Repeat Dose Toxicity Testing for Chemicals (Japan)
 Route:Oral (gavage)
 Doses:0 (vehicle), 62.5, 250, 1000 mg/kg/day
 Number of animals

  Administration period:Males and females, 14, 7, 7 and 14/group for the 0, 62.5, 250 and 1000 mg/kg doses, respectively
  Recovery period:Males and females, 7 each for the 0 and 1000 mg/kg groups
 Vehicle:Olive oil
 Administration period:Males and females, 28 days
 Terminal kill:Day 29 or 43
GLP:Yes

 Test results:

Body weight gains and their rates were decreased in males given 1000 mg/kg during the administration period. The incidence of a urine protein-positive reaction was increased in females given 1000 mg/kg. Hematological examination revealed prolonged prothrombin and activated partial thromboplastin times in males given 250 mg/kg and above, and prolonged activated partial thromboplastin times in females given 1000 mg/kg. Blood chemical examination revealed decreases in the β-globulin fraction in males and females given 1000 mg/kg, an increase in blood urea nitrogen in males given 1000 mg/kg, and an increase in the albumin fraction in females given 1000 mg/kg. Relative liver weights were increased in males given 1000 mg/kg, and absolute testis and epididymis weights were decreased in two males given 1000 mg/kg. Absolute and relative liver weights and relative renal weights were increased in females given 1000 mg/kg. Macroscopic examination at autopsy revealed testes and epididymides to be small in size in males given 1000 mg/kg. Histopathologically, males given 1000 mg/kg showed centrilobular hypertrophy, centrilobular fatty change and focal necrosis of hepatocytes, loss of spermatogenic cells in the testes, decrease in sperm in the ducts and detachment of spermatogenic cells in the epididymides. With regard to the changes in testes and epididymides, no recovery was noted during 14 days after withdrawal, while many of the other changes disappeared. The repeat dose toxicity test revealed NOELs of 62.5 mg/kg/day for males and 250 mg/kg/day for females.

3. Genetic Toxicity

3-1. Bacterial test 2)

Purity:≧ 99.56 %
Test species/strain:Salmonella typhimurium, TA100, TA1535, TA98, TA1537 Escherichia coli WP2 uvrA
Test method:OECD guideline (No. 471, 472) and Guidelines for Screening Mutagenicity Testing of Chemicals (Japan)
 Procedures:Pre-incubation method
 Solvent:DMSO
 Positive controls:-S9 mix, AF-2 (TA100, TA98), sodium azide (TA1535), ENNG (WP2 uvrA) and 9-aminoacridine (TA1537)
+S9 mix, 2-aminoanthracene (all strains)
 Doses:313, 625, 1250, 2500, 5000 μg/plate
 S-9: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 S. typhimurium and E. coli strains. No toxicity was observed up to a concentration of 5000 μg/plate with or without metabolic activation.

Genotoxic effects:
S. typhimurium, TA100, TA1535, TA98, TA1537
+?-
Without metabolic activation:[ ][ ][*]
Wit metabolic activation:[ ][ ][*]

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

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

Purity:≧ 99.56 %
Type of cell used:Chinese hamster CHL/IU cells
Test method:OECD guideline (No. 473) and Guidelines for Screening Mutagenicity Testing of Chemicals (Japan)
 Solvent:Acetone
 Positive controls:-S9 mix, Mitomycin C
+S9 mix, Benzo[a]pyrene
 Doses:-S9 mix (24 h treatment): 0, 25, 50, 100 μg/ml
-S9 mix (48 h treatment): 0, 15, 30, 60 μg/ml
-S9 mix (6 h pulse treatment): 0, 1250, 2500, 5000 μg/ml
+S9 mix (6 h pulse treatment): 0, 1250, 2500, 5000 μg/ml
 S-9:Rat liver, induced with phenobarbital and 5,6-benzoflavone
 Plates/test:2
GLP:Yes

 Test results:
Neither structural nor numerical chromosomal aberrations were induced under the experimental conditions used.

Genotoxic effects:

clastogenicitypolyploidy

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

1)The tests were performed by the Safety Research Institute for Chemical Compounds Co., Ltd., 363-24, Shin-ei, Toyohira-ku, Sapporo, Hokkaido, 004, Japan. Tel +81-11-885-5031 Fax +81-11-885-5313
2)The tests were performed by the 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