Ferrous sulfate heptahydrate

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[CAS No. 7782-63-0]

Iron() sulfate heptahydrate

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Molecular formula: FeH14O11S¡¡Molecular weight: 278.01

ABSTRACT

Ferrous sulfate heptahydrate was studied for oral toxicity in rats of both sexes in a single dose toxicity test at doses of 0, 250, 500, 1000, and 2000 mg/kg. LD50 values were estimated to be more than 2000 mg/kg for both sexes.

Ferrous sulfate heptahydrate was studied for oral toxicity in rats in an OECD combined repeated dose and reproductive/developmental toxicity screening test at doses of 0, 30, 100, 300, and 1000 mg/kg/day.

Deaths were noted of 1 animal of each sex given 1000 mg/kg. Body weight was low in the males at 1000 mg/kg and tended to be low in the females at 1000 mg/kg in the final stages of pregnancy. Food consumption was transiently low in both sexes at 1000 mg/kg. On urinalysis, a high value for volume and a low value for specific gravity were noted in the males at 1000 mg/kg. In the hematological examination, low values for the red blood cell count and APTT and high values for MCV, MCH, and the reticulocyte count were noted in the males at 1000 mg/kg. In the blood chemical analysis, a high value for inorganic phosphate was noted in the females at 300 mg/kg, low values for total protein, albumin, and Ca and high values for ALT, ¦Ã-GTP, and A/G in the males at 1000 mg/kg, and high values for ¦Ã-GTP and inorganic phosphate in the females at 1000 mg/kg. On organ weight measurement, high values for the absolute and relative adrenal weights and the relative liver weights were noted in the males at 1000 mg/kg, and high values for the absolute and relative liver weights were obtained for the females at 1000 mg/kg. On histopathological examination, extramedullary hematopoiesis of the spleen was noted in the males at 300 mg/kg, atrophy of the thymus, inflammatory cell filtration in the glandular submucosa, deposit of yellowish brown pigment in the periportal hepatocytes, deposits of yellowish brown pigment in periportal Kupffer cells, extramedullary hematopoiesis of the spleen, deposits of yellowish brown pigment in the red pulp of the spleen, and basophilic changes in the tubular epithelium of the kidney were noted mainly in the males at 1000 mg/kg. Deposits of yellowish brown pigment in the red pulp of the spleen and of yellowish brown pigment in the periportal hepatocytes were noted in the females at 1000 mg/kg. The NOEL for repeated dose toxicity is considered to be 100 mg/kg/day for both sexes.

Regarding the reproductive and developmental toxicity, no changes attributable to the test substance were noted in parental animals or pups. The NOEL for reproductive performance is considered to be at 1000 mg/kg/day for parental animals and pups.

Ferrous sulfate heptahydrate was not mutagenic in Salmonella typhimurium TA100, TA1535, TA98, TA1537 and Escherichia coli WP2 uvrA/pKM101, with or without an exogenous metabolic activation system.

Ferrous sulfate heptahydrate induced structural chromosomal aberrations in CHL/IU cells after short term treatment with and without an exogenous metabolic activation system. Polyploidy was not induced in any treatment group.

SUMMARIZED DATA FROM THE STUDIES

1. Single Dose Oral Toxicity 1)

Purity:91.6 %
Test species/strain:Rat/Crj:CD(SD)IGS
Test method:OECD Test Guideline 401
¡¡Route:Oral (gavage)
¡¡Dosage:0 (vehicle), 250, 500, 1000, 2000 mg/kg
¡¡Number of animals/group:Males, 5; females, 5
¡¡Vehicle:Water for injection
GLP:Yes

¡¡Test results:

No deaths were observed in either sex. At 2000 mg/kg salivation, decrease of locomotor activity, and lowering of body weight were noted in males, and decrease of locomotor activity and lowering of body weight in females. LD50 values were estimated to be more than 2000 mg/kg for both sexes.

2. Repeated Dose and Reproductive/Developmental Toxicity 1)

Purity:91.1 and 90.6 %
Test species/strain:Rat/Crj:CD(SD)IGS
Test method:OECD Test Guideline 422
¡¡Route:Oral (gavage)
¡¡Dosage:0 (vehicle), 30, 100, 300, 1000 mg/kg
¡¡Number of animals/groupMales, 12; females, 12
¡¡Vehicle:Water for injection
¡¡Administration period:Males, 49 days
Females, from 14 days before mating to day 5 of lactation
¡¡Terminal killing:Males, day 50
Females, day 6 of lactation
GLP:Yes

¡¡Test results:

<Repeated dose toxicity>

Deaths were noted of 1 animal of each sex at 1000 mg/kg. Body weights were low in the males at 1000 mg/kg and tended to be low in the females at 1000 mg/kg in the final stages of pregnancy. Food consumption was transiently lowered in both sexes at 1000 mg/kg. On urinalysis, a high value for volume and a low value for specific gravity were noted in the males at 1000 mg/kg. In the hematological examination, low values for the red blood cell count and APTT and high values for MCV, MCH, and the reticulocyte count were noted in the males at 1000 mg/kg. In the blood chemical analysis, a high value for inorganic phosphate was noted in the females at 300 mg/kg, low values for total protein, albumin, and Ca and high values for ALT, ¦Ã-GTP, and A/G in the males at 1000 mg/kg, and high values for ¦Ã-GTP and inorganic phosphate in the females at 1000 mg/kg. On necropsy, dark red spots in the glandular mucosa and ulcers were noted in the males at 1000 mg/kg. High values for the absolute and relative adrenal weights and the relative liver weights were noted in the males at 1000 mg/kg, and high values for the absolute and relative liver weights were obtained for the females at 1000 mg/kg. On histopathological examination, extramedullary hematopoiesis of the spleen was noted in males at 300 mg/kg. Atrophy of the thymus, ulcers and erosion in the glandular stomach, inflammatory cell filtration in the glandular submucosa, hemorrhage in the stomach, vacuolization in the forestomach epithelium, deposit of yellowish brown pigment in the periportal hepatocytes, deposits of yellowish brown pigment in periportal Kupffer cells, extramedullary hematopoiesis of the spleen, deposits of yellowish brown pigment in the red pulp of the spleen, basophilic changes in the tubular epithelium of the kidney, and increased hematopoiesis of the femoral bone marrow were noted in the males at 1000 mg/kg. Deposits of yellowish brown pigment in the periportal hepatocytes and of yellowish brown pigment in the red pulp of the spleen were noted in the females at 1000 mg/kg.

The NOEL for repeated dose toxicity is considered to be at 100 mg/kg/day for both sexes.

<Reproductive and developmental toxicity>

Regarding the reproductive and developmental toxicity, no changes attributable to the test substance were noted in terms of the number of estrous cases, copulation index, number of days before copulation, fertility index, gestation length, gestation index, delivery conditions, nursing conditions, number of corpora lutea, number of implantation sites, or implantation rate.

The NOEL for reproductive performance of parental animals is considered to be 1000 mg/kg/day for both sexes.

Regarding the pups, no changes attributable to the test substance were noted in terms of the number, number of stillbirths, number of live pups on Day 0 of lactation, sex ratio, delivery index, birth index, live birth index, general signs, number of live pups on Day 4 of lactation, viability index on Day 4 of lactation, external observation, body weight change, or necropsy findings.

The NOEL for pups is considered to be 1000 mg/kg/day.

3. Genetic Toxicity

3-1. Bacterial test 2)

Purity:91.6 %
Test species/strain:Salmonella typhimurium TA100, TA1535, TA98, TA1537, Escherichia coli WP2 uvrA/pKM101
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), Sodium azide (TA1535), 9-Aminoacridine hydrochloride (TA1537) and N-Ethyl-N'-nitro-N-nitrosoguanidine (WP2 uvrA/pKM101)
+S9 mix; 2-Aminoanthracene (five strains)
¡¡Dosage:-S9 mix; 0, 156, 313, 625, 1250, 2500, 5000 ¦Ìg/plate (five strains)
+S9 mix; 0, 156, 313, 625, 1250, 2500, 5000 ¦Ìg/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 observed at 2500 ¦Ìg/plate or more (five strains) with and without metabolic activation.

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

Escherichia coli WP2 uvrA/pKM101
+?-
Without metabolic activation:[ ][ ][*]
With metabolic activation:[ ][ ][*]

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

Purity:91.6 %
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
¡¡Vehicle:Isotonic sodium chloride solution
¡¡Positive controls:-S9 mix, Mitomycin C
+S9 mix, Benzo[a]pyrene
¡¡Dosage:-S9 mix (6 hr short-term treatment); 0, 250, 500, 1000, 1500, 2000 ¦Ìg/mL (main test)
-S9 mix (6 hr short-term treatment); 0, 1200, 1300, 1400, 1500, 1600 ¦Ìg/mL (confirmation test)
+S9 mix (6 hr short-term treatment); 0, 125, 250, 500, 1000, 1500 ¦Ìg/mL (main test)
+S9 mix (6 hr short-term treatment); 0, 600, 700, 800, 900, 1000 ¦Ìg/mL (confirmation test)
¡¡S9:Rat liver, induced with phenobarbital and 5,6-benzoflavone
¡¡Plates/test:2
GLP:Yes

¡¡Test results:

Structural chromosomal aberrations were induced after 6 hr short term treatment with S9 mix (9.0 and 72.5 % at 500 and 1000 ¦Ìg/mL [main test], 23.0, 44.0, 75.0, 77.0 and 85.5 % at 600, 700, 800, 900 and 1000 ¦Ìg/mL [confirmation test]) and without S9 mix (19.0 % at 1500 ¦Ìg/mL [main test], 13.5, 17.0, 18.5, 39.0 and 52.0 % at 1200, 1300, 1400, 1500 and 1600 ¦Ìg/mL [confirmation test]). Polyploidy was not induced in any treatment groups.

Lowest concentration producing cytogenetic effects in vitro:
Without metabolic activation (short-term treatment):1.2 mg/mL (clastogenicity)
With metabolic activation (short-term treatment):0.6 mg/mL (clastogenicity)

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

1)The tests were performed by Nihon Bioresearch Inc., 6-104, Majima, Fukuju-cho, Hashima, Gifu, 501-6251, Japan. Tel +81-58-392-6222 Fax +81-58-392-1284
2)The tests were performed by the 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