Improsulfan Hydrochloride

IPD (3,3'-Iminobis-1-propanol dimethanesulfonate (ester) hydrochloride)

TR-018: Bioassay of 3,3'-Iminobis-1-propanol Dimethanesulfonate (Ester) Hydrochloride (IPD) for Possible Carcinogenicity (CASRN 3458-22-8) (1978 )

11/28/77

Equivocal Evidence

Equivocal Evidence

Equivocal Evidence

/LABORATORY ANIMALS: Acute Exposure/ Yoshi-864 extends markedly the survival times of mice bearing L1210 leukemia or Ehrlich ascites carcinoma. Busulfan, with methanesulfonate leaving groups identical with those of Yoshi-864, is without effect. Tumor cells from mice bearing the Ehrlich tumor and treated with Yoshi-864 have a persistent reduction in ability to synthesize DNA. Synthesis of DNA in cells from mice treated with busulfan is moderately suppresed at 48 hr after treatment, but returns virtually to the control value at 72 hr.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Six antitumor platinum compounds were used in combination with cyclophosphamide plus 1 of 7 other antitumor drugs for treatment of L1210 leukemia in B6D2F C57BL/6 X DMA/2) F mice. Data obtained from each three-agent regimen were compared with those obtained after administration of each compound alone and each appropriate two-agent combination. No cure (greater than 60-day survival) was obtained with any compound used alone. Combination of cyclophosphamide with a platinum compound (Pt+CY) yielded a collective cure rate of 193/420, and the addition of a third cure rate to 290/420 (P<0.001). Certain regimens produced 100% cure rates. The most effective drugs when used in combination with PT+CY were cytosine arabinoside, 5-fluorouracil, hydroxyurea, and Yoshi-864. Adriamycin, methotrexate, and vincristine were less effective at the doses used. Toxicity, as evidenced by maximum weight loss, was slightly greater with the three-agent combinations than with the Pt+CY regimens.

/SRP:/ Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poison A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/

A bioassay of IPD for possible carcinogenicity was conducted by administering the test chemical intraperitoneally to Sprague-Dawley rats and B6C3F1 mice. The IPD was injected three times per week to groups of 35 animals, using doses of 12, 24, or 48 mg/kg for the rats, and 20 or 40 mg/kg for the mice. Rats at 12 mg/kg were treated for 52 weeks. Because of the toxicity of the chemical, administration of IPD for the group receiving 24 mg/kg was discontinued at week 34. Rats receiving 48 mg/kg were treated until all had died at week 23 (males) and week 27 (females). Both groups of mice were treated for 52 weeks. All survivors were killed after post-administration periods that varied among groups. With rats, untreated and vehicle-control groups, each consisting of 10 males and 10 females, were started with the high- and mid-dose groups and additional untreated and vehicle-control groups of the same size were started with the low-dose groups. With mice, untreated and vehicle-control groups each consisted of 15 males and 15 females. The toxicity of IPD was associated with lower mean body weights and lower rates of survival of both the rats and mice. The shortened life spans, particularly in the rats, reduced the likelihood of the development of tumors. In rats, peritonitis and fibrous adhesions, possibly, from direct irritation by the test chemical were observed in most treated rats at necropsy. Sarcoma, fibroma, or fibrosarcomaof the peritoneum occurred in two low-dose male, one mid-dose male, and one mid-dose female rats, but not in any control animals. Because of this low incidence, and because irritation by the test chemical have been involved in the pathogenesis, these tumors may have been due to local effects of the chemical. In mice, lymphomas were observed at the following incidences (males: controls 0/14, low-dose 0/26, high-dose 3/21; females: controls 1/15, low-dose 2/29, high-dose, 6/27). The Tarone test for life-table analysis of the probability of survival without lymphoma indicated a significant positive dose-related increase of lymphomas with a probability level of 0.011 for male mice and 0.003 for female mice. Squamous-cell carcinoma was noted in the mice (low-dose males 6/26, high-dose females 2/27). Seven of these tumors were observed in subcutaneous tissue in the inguinal region near the sites of injection. Although not statistically significant, this tumor may be associated with administration of IPD. Tumors of the peritoneum in rats and tumors in the subcutaneous tissue in mice may have been due to local effects related to administration of the test chemical. The lymphomas in mice, although marginally significant, were too few in number to clearly be related to dosing. Conclusions from this study are limited by early deaths and toxicity, but the appearance of tumors in the peritoneum near the injection sites in both rats and mice indicate the carcinogenic potential of IPD.