Developmental toxicity evaluation of 3‐chloro‐4‐(dichloromethyl)‐5‐hydroxy‐2(5H)‐furanone (MX) in Wistar rats

Abstract

3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) is a genotoxic chlorination by-product in drinking water. There is some evidence that it has developmental toxic effects in vitro but its potential to cause developmental effects in vivo is not known. The developmental effects were evaluated in Wistar rats. Rats (22-26 dams per dose group) were administered MX by gavage at the dose levels of 3, 30, or 60 mg/kg in water on gestation days 6-19. Control animals received plain water. Clinical signs, body weight, and food and water consumption were recorded for the dams. On gestation day 20, a cesarean section was performed and the ovaries anduterine contents of the dams were examined and the liver, kidneys, spleen, and thyroid glands weighed. The fetuses of all dose groups were weighed, sexed, and observed for external and skeletal malformations and the fetuses of the two highest dose groups were evaluated for visceral malformations. The highest dose, 60 mg/kg of MX, was slightly toxic to the dams. It decreased the corrected body weight gain of dams by 32% and the water consumption by 16-17%. Kidney and liver weights were slightly increased. MX did not affect the number of implantations nor did it cause any resorptions. The body weights of fetuses were not significantly affected. MX did not cause external malformations or skeletal anomalies. Two fetuses at 60 mg/kg and one fetus at 30 mg/kg had major visceral malformations (persistent truncus arteriosus, diaphragmatic hernia, dilated aorta with a stenosis of pulmonary arteries) and two minor artery abnormalities were observed in those animals. The frequency of unilateral displaced testis was slightly higher (9.2%) in the 60-mg/kg dose group than in controls (1.6%). Since the abnormalities did not form a consistent pattern and occurred most at maternally toxic dose, we conclude that MX can be regarded as non-teratogenic.

MX, a by‐product of water chlorination, lacks in vivo genotoxicity in gpt delta mice but inhibits gap junctional intercellular communication in rat WB cells

“…The results of the present study support the conclusion that such defensive systems could be sufficient to detoxify MX ingested in drinking water at concentrations well above environmental levels [Melnick et al, 1997]. A recent study [Huuskonen et al, 2003] showing no teratogenicity in rats receiving up to 60 ppm MX also supports this hypothesis.…”

Numeric Estimates of Teratogenic Severity from Embryo–Fetal Developmental Toxicity Studies

“…The study by Huuskonen et al. () produced a score of 38 in the control group, and the work by Liberati et al. () revealed numerous malformations and variations at higher incidences than those reported for the SD rat.…”

“…Regarding the teratogenic severity scores of control groups of WH rats compared to SD rats, there are some suggestions of a notable difference between the two strains. The study by Huuskonen et al (2003) produced a score of 38 in the control group, and the work by Liberati et al (2002) revealed numerous malformations and variations at higher incidences than those reported for the SD rat. Based on this author's experience, increased scores for WH rats are primarily due to higher C values for variations (approximately threefold above SD), while postimplantation loss and the incidence of fetuses with malformations are comparable between the two rat strains.…”

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“…Registered by WHO, MX is one of the strongest bacterial mutagens ever tested, as highlighted by the Ames Salmonella typhimurium TA100 assay [8]. The observed mutagenic activity is significantly correlated only to the electrophilicity response of the ring forms [11]. However, analytical difficulties in measuring the low doses of MX encountered in drinking-water lead to uncertainty over whether this species would be genotoxic in vivo [12].…”