Diphenyl cresyl phosphate

リン酸ジフェニルクレジル

CAS No. 26444-49-5

Phosphoric acid diphenyl cresyl ester

リン酸ジフェニルクレジルエステル

Molecular formula: C19H17O4P Molecular weight: 340.33

ABSTRACT

With regard to repeat dose toxicity, increased salivation, suppression in body weight gain and increases in water intake and food consumption were noted. Hematological examination of males revealed anemia and an increase of leukocytes. Blood chemical examination showed a decrease of cholinesterase activities in the brain, serum and erythrocytes, increases in GPT, γ-GTP, total cholesterol and calcium, and decreases in GOT, albumin, the A/G ratio and triglycerides in the 300 mg/kg group of males. On urinalysis, decreases in pH and specific gravity, and an increase in urine volume were found. Histopathological examination showed various changes in the adrenals, liver, kidneys, stomach, testes, thymus and ovaries. The NOEL for the repeat dose toxicity is considered to be 12 mg/kg/day for both sexes. In terms of reproductive toxicity, the fertility index and the implantation index decreased in the 300 mg/kg group. These were probably caused by dysspermatogenesis. Observation of neonates revealed no test substance toxicity. NOELs for reproductive and developmental performances are considered to be 60 mg/kg/day for parental males, and 300 mg/kg/day for parental females and offspring.

Diphenyl cresyl phosphate was not mutagenic in Salmonella typhimurium TA100, TA98, TA1535, TA1537 and Escherichia coli WP2 uvrA. In the presence of an exogenous metabolic activation system, this chemical substance induced structural chromosomal aberrations reproducibly. Polyploid cells were not induced under the experimental conditions.

SUMMARIZED DATA OF THE STUDIES

1. Repeat dose and Reproductive/Developmental Toxicity 1)

Purity	:	41.9%
Test species/strain	:	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	:	Olive oil
Administration period	:	Male, 45 days Female, from 14 days before mating to day 3 of lactation
Terminal kill	:	Male, day 46 Female, day 4 of lactation
GLP	:	Yes

　Test results:

<Repeat dose toxicity>

In the 300 mg/kg group, increased salivation, suppression in body weight gain and an increase in water intake in both sexes, and an increase in food consumption in male rats were noted. At necropsy, enlargement of the adrenals and liver were observed in both sexes. Histopathological examination showed cortical vacuolation of the adrenals, enlargement of the liver and a fatty change of the proximal tubular epithelium in kidneys in both sexes. In addition, a reduction of fatty change of the hepatocytes, an increase in hyaline droplets and basophilia change in the proximal tubular epithelium in the kidneys, erosion or focal necrosis of the mucosa in the stomach, and atrophy of seminiferous tubules in the testes were observed in males. Increased glycogen of hepatocytes, atrophy of the thymus and interstitial cell hypertrophy and hyperplasia in the ovaries were also observed in female rats. Hematological examination of males showed anemia, and an increase of leukocytes in the 300 mg/kg group. Blood chemical examination revealed a decrease of cholinesterase activities in the brain, serum, and erythrocytes, increases in GPT, γ-GTP, total cholesterol and calcium, and decreases in GOT, albumin, the A/G ratio and triglycerides in males of the 300 mg/kg group. On urinalysis, decreases in pH and specific gravity, and an increase of urine volume were found in males of the 300 mg/kg group.

In the 60 mg/kg group, the similar histopathological changes in the adrenals were noted in both sexes. In addition, increases in food consumption and total cholesterol, a decrease in cholinesterase activity, and enlargement of the liver were found in male rats, and suppression in body weight gain as well as histopathological changes in the liver, kidneys and the thymus were noted in females.

The NOEL for the repeat dose toxicity is considered to be 12 mg/kg/day for both sexes.

<Reproductive and developmental toxicity>
Fertility and implantation indices decreased in the 300 mg/kg group. These were probably caused by dysspermatogenesis. In addition, the gestation index had a tendency to be low.However, there were no effects on other reproductive parameters such as copulation index, gestation length, number of corpora lutea, delivery index and parturition or maternal behavior. Observation of neonates revealed no significant differences in the numbers of offspring or live offspring, the sex ratio, live birth index, viability index or body weights. Furthermore, no anomalies related to the test substance were detected in any of the offspring in terms of clinical signs, and external, visceral or skeletal features.

NOELs for reproductive and developmental toxicity are considered to be 60 mg/kg/day for parental males, and 300 mg/kg/day for parental females and offspring.

2. Genetic Toxicity

2-1 Bacterial test 2)

Purity	:	unknown
Test species/strains	:	S.typhimurium TA100, TA1535, TA98, TA1537 E. coli WP2 uvrA
Test method	:	Guidelines for Screening Mutagenicity Testing of Chemicals (Japan)
Procedures	:	Plate incorporation method
Solvent	:	DMSO
Positive controls	:	-S9, AF-2 (TA100, WP2, TA98), sodium azide (TA1535) and 9-aminoacridine (TA1537) +S9, 2-aminoanthracene (all strains)
Dosage	:	0, 312.5, 625, 1250, 2500, 5000μg/plate
S-9	:	Rat liver, induced with phenobarbital and 5,6-benzoflavone
Plate/test	:	3
Number of replicates	:	2
GLP	:	Yes

　Test results:

Minimum concentration of test substance at which toxicity was observed:

No toxicity was observed up to a concentration of 5000 μg/plate with or without metabolic activation.

Genetic effects:
S. typhimurium TA100, TA1535, TA 98, TA1537

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

E. coli WP2 uvrA

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

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

Purity	:	41.9%
Type of cell used	:	Chinese hamster CHL/IU cells
Test method	:	Guidelines for Screening Mutagenicity Testing of Chemicals (Japan)
Solvent	:	DMSO
Positive controls	:	-S9, Mitomycin C +S9, Cyclophosphamide
Dosage	:	-S9(continuous treatment): 0, 0.004, 0.008, 0.016 mg/ml -S9(short-term treatment): 0, 0.011, 0.022, 0.043 mg/ml +S9(short-term treatment): 0, 0.011, 0.022, 0.043 mg/ml
S-9	:	Rat liver, induced with phenobarbital and5,6-benzoflavone
Plates/test	:	2
GLP	:	Yes

　Test results:

Short-term treatment with the highest concentration (0.043 mg/ml) of the test substance, incorporated with 9 mix, resulted in 8.6% of the cells demonstrating structural aberrations (including gaps). However, there were insufficient metaphase cells for analysis because of cytotoxicity. Therefore, a confirmation test was performed and the reproducibility was confirmed.

Lowest concentration producing cytogenetic effects in vitro:

without metabolic activation (continuous treatment ): > 0.016 mg/ml

without metabolic activation (short-term treatment): > 0.043 mg/ml

with metabolic activation (short-term treatment): 0.043 mg/ml (clastogenicity)

Genotoxic effects:

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

1)	The test was 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

Diphenyl cresyl phosphate

リン酸ジフェニルクレジル

[CAS No. 26444-49-5]

Phosphoric acid diphenyl cresyl ester

ジフェニルクレジルフォスフェート／リン酸ジフェニルクレジルエステル

Molecular formula: C19H17O4P Molecular weight: 340.33

ABSTRACT

SUMMARIZED DATA FROM THE STUDIES

1. Non-bacterial in vivo test (Micronucleus test)1)

Purity	:	uncertified
Test species/strains	:	Mice/Crj:BDF1, male and female
Test method	:	Guidelines for Screening Mutagenicity Testing of Chemicals (Japan) and OECD (474)
Procedure	:	Bone marrow/acridine orange staining
Solvent	:	Olive oil
Positive controls	:	Cyclophosphamide 50 mg/kg
Doses	:	0, 312.5, 625 and 1250 mg/kg
Mice/group	:	5 males and 5 females
GLP	:	Yes

　 Test results:

The frequency of micronucleated polychromatic erythrocytes was not significantly increased in male or female mice up to the dose of 1250 mg/kg 24 h after the application by oral gavage. Inhibition of bone marrow cell proliferation was not observed under the test conditions used.

Lowest dose producing toxicity:

Maximum tolerated dose: greater than 1250 mg/kg in males and females

Genotoxic effects:

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

1)	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