Chromic acid disodium salt dihydrate

二クロム酸ナトリウム二水和物


[CAS No. 7789-12-0]

Sodium dichromate dihydrate/Dichromic acid disodium salt dihydrate

重クロム酸ナトリウム二水和物/重クロム酸二ナトリウム二水和物

Molecular formula: Cr2H4Na2O9　Molecular weight: 297.99

ABSTRACT

A single dose oral toxicity test of chromic acid disodium salt dihydrate revealed LD50 values of 252.4 mg/kg for males and 181.0 mg/kg for females.

Chromic acid disodium salt dihydrate was studied for oral toxicity in rats in an OECD combined repeated dose and reproductive/developmental toxicity screening test at doses of 0, 1, 6, and 30 mg/kg.

No deaths occurred in any of the treated groups. Salivation after dosing was observed in both sexes of the 30 mg/kg group. Decrease in body weight gain and food consumption on Day 4 of lactation was observed in females of the 30 mg/kg group. In addition, total litter loss was observed in one female of the 30 mg/kg group. Hematological examination revealed decrease in MCH and MCHC in both sexes of the 30 mg/kg group, with increase in reticulocytes in males, and decrease in hemoglobin in females. Histopathologically, the effects of test substance were erosion and ulceration in the stomach, and changes of renal tubular epithelium in females of the 30 mg/kg group. Blood chemistry examination revealed decrease in total protein in males of the 6 and 30 mg/kg groups, and increase in Cl in males of the 30 mg/kg group. The NOEL for repeated dose toxicity is considered to be 1 mg/kg/day for both sexes.

With regard to reproductive and developmental toxicity, the compound caused extension of gestation length in females of the 30 mg/kg group. It had no effects on other parameters. The NOELs for reproductive and developmental toxicity are considered to be 30 mg/kg/day for males, 6 mg/kg/day for females, and 30 mg/kg/day for offspring.

Genotoxicity of chromic acid disodium salt dihydrate was studied by a reverse mutation test in bacteria. This substance was mutagenic in Salmonella typhimurium TA100, TA98, TA1537 and Escherichia coli WP2 uvrA, with or without an exogenous metabolic activation system.

Genotoxicity of chromic acid disodium salt dihydrate was studied by chromosomal aberration test in cultured Chinese hamster lung (CHL/IU) cells.

Chromic acid disodium salt dihydrate induced structural chromosomal aberrations dose-dependently under the short-term treatment conditions with and without metabolic activation, at doses of 0.0056-0.023 mg/mL and 0.00056-0.0023 mg/mL, respectively.

SUMMARIZED DATA FROM THE STUDIES

1. Single Dose Oral Toxicity 1)

Purity:100.07 %
Test species/strain:Rat/Crj:CD(SD)IGS
Test method:OECD Test Guideline 401
　Route:Oral (gavage)
　Dosage:0 (vehicle), 100, 130, 180, 240, 330 mg/kg
　Number of animals/group:Males, 5; females, 5
　Vehicle:Water for injection
GLP:Yes

　Test results:

Deaths occurred in males given 240 and 330 mg/kg and in females given 130 mg/kg or more. Treatment-related clinical signs were noted as follows: hypoactivity, bradypnea, loose stool, periproctal soiling, abdominal distention, lacrimation, cyanosis and adoption of a prone position. Decreases in body weight and/or depression of body weight gain were observed in all treatment groups. Necropsy of the dead animals revealed dark red colorations of the mucosa of the glandular stomach, which was histopathologically confirmed to be ulceration. Other than the above, dark red coloration and inflation of the lungs were apparent macroscopically, and these were accompanied by retention of frothy fluid in the trachea. Histopathological examination revealed congestion and/or edema of the lungs. Necropsy of the surviving males revealed thickening of the limiting ridge between the forestomach and the glandular stomach and histopathological ulceration of the forestomach and the glandular stomach, and hyperplasia of the squamous cells of the limiting ridge were observed. No abnormal gross findings were observed in any of the surviving females.

LD50: Males, 252.4 mg/kg; females, 181.0 mg/kg

2. Repeated Dose and Reproductive/Developmental Toxicity 2)

Purity:100.07 %
Test species/strain:Rats/Crj:CD(SD)IGS
Test method:OECD Test Guideline 422
　Route:Oral (gavage)
　Dosage:0 (vehicle), 1, 6, 30 mg/kg
　Number of animals/groupMales, 12; females, 12
　Vehicle:Water for injection
　Administration period:Males, 37 days
Females, from 14 days before mating to day 4 of lactation
　Terminal killing:Males, day 38
Females, day 5 of lactation
GLP:Yes

　Test results:

<Repeated dose toxicity>

No deaths occurred in any of the treated groups. Salivation after dosing was observed in of both sexes animals of the 30 mg/kg group. Decrease in body weight gain and food consumption on Day 4 of lactation was observed in females of the 30 mg/kg group. In addition, total litter loss was observed in one female of the 30 mg/kg group. Hematological examination revealed decrease in MCH and MCHC in both sexes, increase in reticulocytes in males, and decrease in hemoglobin in females of the 30 mg/kg group. Histopathologically, erosion and ulceration in the stomach, was evident in both sexes of the 6 and 30 mg/kg groups, and changes of the renal tubular epithelium in females of the 30 mg/kg group. Examination of blood chemistry revealed decrease in total protein in males of the 6 and 30 mg/kg groups, and increase in Cl in males of the 30 mg/kg group.

The NOEL for repeated dose toxicity is considered to be 1 mg/kg/day for both sexes.

<Reproductive and developmental toxicity>

In the 30 mg/kg group, extension of gestation length was observed in female parental animals. The compound had no effects on other reproductive parameters such as the mating index, the fertility index, number of corpora lutea or implantations, the implantation index, the delivery index, the gestation index, parturition or maternal behavior. On examination of neonates, there were no significant differences in number of offspring or live offspring, the sex ratio, the live birth index, the viability index or body weight. No abnormal findings ascribable to the compound were found regarding external features, clinical signs or necropsy of the offspring.

The NOELs for reproductive and developmental toxicity are considered to be 30 mg/kg/day for males, 6 mg/kg/day for females, and 30 mg/kg/day for offspring.

3. Genetic Toxicity

3-1. Bacterial test 3)

Purity:100.07 %
Test species/strains: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
　Vehicle:Water for injection
　Positive controls:-S9 mix; 2-(2-Furyl)-3-(5-nitro-2-furyl)acrylamide (TA100, TA98, WP2 uvrA), Sodium azide (TA1535) and 9-Aminoacridine (TA1537)
+S9 mix; 2-Aminoanthracene (five strains)
　Dosage:-S9 mix; 0, 1.95, 3.91, 7.81, 15.6, 31.3, 62.5 μg/plate (TA100)
-S9 mix; 0, 0.977, 1.95, 3.91, 7.81, 15.6, 31.3, 62.5 μg/plate (TA1535, TA98, TA1537)
-S9 mix; 0, 7.81, 15.6, 31.3, 62.5, 125, 250 μg/plate (WP2 uvrA)
+S9 mix; 0, 3.91, 7.81, 15.6, 31.3, 62.5, 125 μg/plate (TA100, TA1535, TA98, TA1537)
+S9 mix; 0, 15.6, 31.3, 62.5, 125, 250, 500 μg/plate (WP2 uvrA)
　S9:Rat liver, induced with phenobarbital and 5,6-benzoflavone
　Plates/test:3 (1 for cytotoxicity test)
　Number of replicates:2 (plus 1 cytotoxicity test)
GLP:Yes

　Test results:

This chemical induced gene mutations in S. typhimurium TA100, TA98 and E. coli WP2 uvrA strains with and without S9 mix and S. typhimurium TA1537 without S9 mix. Growth inhibition was observed at 31.3 μg/plate (TA1535, TA98 and TA1537), 50.0 μg/plate (TA100) and 150 μg/plate (WP2 uvrA) without S9 mix and 125 μg/plate (TA100, TA1535, TA98 and TA1537) and 500 μg/plate (WP2 uvrA) with S9 mix.

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

Salmonella typhimurium TA1535
+?-
Without metabolic activation:[ ][ ][*]
With metabolic activation:[ ][ ][*]

Salmonella typhimurium 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)3)

Purity:100.07 %
Type of cell used:Chinese hamster lung (CHL/IU) cells
Test method:Guidelines for Screening Mutagenicity Testing of Chemicals (Chemical Substances Control Law of Japan) and OECD Test Guideline 473
　Vehicle:Water for injection
　Positive controls:-S9 mix; Mitomycin C
+S9 mix; Cyclophosphamide
　Dosage:-S9 mix (short-term treatment); 0, 0.00056, 0.0011, 0.0023 mg/mL
+S9 mix (short-term treatment); 0, 0.0056, 0.011, 0.023 mg/mL
　S9:Rat liver, induced with phenobarbital and 5,6-benzoflavone
　Plates/test:2
GLP:Yes

　Test results:

Cells with structural chromosomal aberrations were significantly increased with dose-dependence after short-term treatment with and without metabolic activation (the maximum frequencies: 40.5 % without metabolic activation and 50.5 % with metabolic activation).

Lowest concentration producing cytogenetic effects in vitro:
Without metabolic activation (short-term treatment):0.00056 mg/mL (clastogenicity)
With metabolic activation (short-term treatment):0.011 mg/mL (clastogenicity)

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

1)The test was performed by the Safety Assessment Laboratory, Panapharm Laboratories Co., LTD., 1285 Kurisaki-machi, Uto-shi, Kumamoto, 869-0425, Japan. Tel +81-964-23-5111 Fax +81-964-23-2282
2)The test was 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
3)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