セムスチン

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop.

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.

Special protective equipment for fire-fighters: Wear self contained breathing apparatus for fire fighting if necessary.

Store in cool place. Keep container tightly closed in a dry and well-ventilated place.

PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen & date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/

Personal precautions: Wear respiratory protection. Avoid dust formation. Avoid breathing dust. Ensure adequate ventilation. Evacuate personnel to safe areas.

Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains.

Methods for cleaning up: Pick up and arrange disposal without creating dust. Keep in suitable, closed containers for disposal.

PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured & the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed & labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/

SMALL SPILLS AND LEAKAGE: Should a spill occur while you are handling this chemical, FIRST REMOVE ALL SOURCES OF IGNITION, then you should dampen the solid spill material with 60-70% ethanol and transfer the dampened material to a suitable container. Use absorbent paper dampened with 60-70% ethanol to pick up any remaining material. Seal the absorbent paper, and any of your clothes, which may be contaminated, in a vapor-tight plastic bag for eventual disposal. Solvent wash all contaminated surfaces with 60-70% ethanol followed by washing with a soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned.

SRP: Criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

Dissolve or mix the material with a combustible solvent and burn in a chemical incinerator equipped with an afterburner and scrubber. Observe all federal, state, and local environmental regulations. Contact a licensed professional waste disposal service to dispose of this material.

PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds & specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods & recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous & organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/

For more Disposal Methods (Complete) data for Semustine (7 total), please visit the HSDB record page.

In case of skin contact: Wash off with soap and plenty of water. Take victim immediately to hospital. Consult a physician.

In case of eye contact Rinse thoroughly with plenty of water for at least 15 minutes and consult a physician.

Hygiene measures: Avoid contact with skin, eyes and clothing.

Handling: Avoid formation of dust and aerosols. Provide appropriate exhaust ventilation at places where dust is formed.

For more Preventive Measures (Complete) data for Semustine (14 total), please visit the HSDB record page.

RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with a combination filter cartridge, i.e. organic vapor/acid gas/HEPA (specific for organic vapors, HCl, acid gas, SO2 and a high efficiency particulate filter). (NTP, 1992)

Respiratory protection: Where risk assessment shows air-purifying respirators are appropriate use a full-face particle respirator type N99 (US) or type P2 (EN 143) respirator cartridges as a backup to engineering controls. If the respirator is the sole means of protection, use a full-face supplied air respirator. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).

Hand protection: The selected protective gloves have to satisfy the specifications of EU Directive 89/686/EEC and the standard EN 374 derived from it. Handle with gloves.

Eye protection: Safety glasses.

Skin and body protection: Choose body protection according to the amount and concentration of the dangerous substance at the work place.

PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece & close-fitting at ankles & wrists), gloves, hair covering & overshoes. ... In chemical laboratory, gloves & gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, & disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 330(SRC), determined from a structure estimation method(2), indicates that semustine is expected to have moderate mobility in soil(SRC). However, by analogy to N-nitroso-N-ethylurea which exhibited a hydrolysis half-life of 47 minutes at pH 9(3), adsorption may be precluded by hydrolysis(SRC). Volatilization of semustine from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 2.5X10-10 atm-cu m/mole(SRC), using a fragment constant estimation method(4). Semustine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 5.6X10-6 mm Hg(SRC), determined from a fragment constant method(5). Biodegradation data were not available(SRC, 2009).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 330(SRC), determined from a structure estimation method(2), indicates that semustine is expected to adsorb to suspended solids and sediment(SRC). However, by analogy to N-nitroso-N-ethylurea which exhibited a hydrolysis half-life of 47 minutes at pH 9(3), adsorption may be precluded by hydrolysis(SRC). Volatilization from water surfaces is not expected(4) based upon an estimated Henry's Law constant of 2.5X10-10 atm-cu m/mole(SRC), developed using a fragment constant estimation method(5). According to a classification scheme(6), an estimated BCF of 70(SRC), from its log Kow of 3.30(7) and a regression-derived equation(8), suggests the potential for bioconcentration in aquatic organisms is moderate(SRC). Semustine is an alkylating agent that may hydrolyze under environmental conditions(4). Biodegradation data were not available(SRC, 2009).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), semustine, which has an estimated vapor pressure of 5.6X10-6 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase semustine is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 16 hours(SRC), calculated from its rate constant of 2.4X10-11 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Particulate-phase semustine may be removed from the air by wet or dry deposition(SRC). Semustine contains chromophores that absorb at wavelengths >290 nm(4) and therefore may be susceptible to direct photolysis by sunlight(SRC).

PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/

Using a structure estimation method based on molecular connectivity indices(1), the Koc of semustine can be estimated to be 330(SRC). According to a classification scheme(2), this estimated Koc value suggests that semustine is expected to have moderate mobility in soil. However, by analogy to N-nitroso-N-ethylurea which exhibited a hydrolysis half-life of 47 minutes at pH 9(3), adsorption may be precluded by hydrolysis(SRC).

/SIGNS AND SYMPTOMS/ Human systemic effects by ingestion: nausea or vomiting, damage to kidney tubules and glomeruli, and hematuria (blood in the urine).

/SIGNS AND SYMPTOMS/ May be fatal if inhaled. Causes respiratory tract irritation. Toxic if absorbed through skin. Causes skin irritation. Causes eye irritation.

/CASE REPORTS/ The nephrotoxicity of semustine (methyl-CCNU) has been studied in 45 adult patients with surgically resected Stage I or II malignant melanoma who received this drug as adjuvant chemotherapy. Abnormalities of renal function (including three cases of renal failure) were noted in seven of 45 patients (16 percent); all these patients received more than 1,400 mg/sq m. This represents an incidence of 26 percent in patients receiving more than 1,400 mg/sq m of semustine. Two distinct patterns emerged. Abnormal serum creatinine levels developed in two patients while receiving semustine and later progressed to renal failure. Five patients had normal serum creatinine levels throughout their treatment courses but had abnormal creatinine values one month to two years following the completion of drug therapy. Renal failure developed in one of these patients, but the remaining four have had stable renal function for one to two years of additional follow-up. No clinical signs of renal insufficiency were detected in any patients receiving less than 1,400 mg/sq m of semustine. No changes unequivocally attributable to semustine were seen in eight patients at autopsy despite the fact that three had received greater than 1,900 mg/sq m of nitrosourea. This incidence of nephrotoxicity appears to be significantly lower than that previously reported in children.

/CASE REPORTS/ Pulmonary fibrosis is a serious side effect of nitrosourea therapy, occurring most frequently in patients treated with BCNU. Pulmonary fibrosis developed in a 63 year-old male patient while being treated with adjuvant methyl-CCNU for rectal carcinoma. This toxicity is rare with methyl-CCNU, having only been reported once previously. The case of methyl-CCNU-induced pulmonary fibrosis reported here occurred at a much lower total dose than the first reported case (604 mg/sq m vs. 2,733 mg/sq m). ...

For more Human Toxicity Excerpts (Complete) data for Semustine (7 total), please visit the HSDB record page.

1-(2-Chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (Methyl-CCNU) (Semustine)

Group 1: Carcinogenic to humans

Volume Sup 7: Overall Evaluations of Carcinogenicity: An Updating of IARC Monographs Volumes 1 to 42, 1987; 440 pages; ISBN 92-832-1411-0 (out of print)

2012

2008

An estimated BCF of 70 was calculated in fish for semustine(SRC), using a log Kow of 3.30(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is moderate(SRC).

The Henry's Law constant for semustine is estimated as 2.5X10-10 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that semustine is expected to be essentially nonvolatile from water surfaces(2). Semustine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 5.6X10-6 mm Hg(SRC), determined from a fragment constant method(3).

/LABORATORY ANIMALS: Acute Exposure/ Administration of a single sc dose of the nephrotoxic anticancer agent 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea (MeCCNU) to rats led to a time-dependent decrease in renal function (i.e., renal slice anion accumulation, renal concentrating ability, and urinary output) which was correlated with the accumulation of carbamylating and alkylating intermediates of 14C-labeled MeCCNU that bound irreversibly to kidney protein. MeCCNU also produced a dose-dependent decrease in glutathione (GSH) preferentially in liver, but not in kidney. Pretreatment with piperonyl butoxide (PIP) decreased the renal toxicity and covalent binding of MeCCNU, and ameliorated the MeCCNU-dependent decrease in liver and kidney GSH. Radioactivity detected in the urine from the PIP-pretreated group was markedly lower than that in the MeCCNU-only group. In contrast, PIP pretreatment increased the accumulation of parent MeCCNU into fatty tissue. Pretreatment with phenobarbital (PB) increased the renal toxicity of MeCCNU. Moreover, PB pretreatment resulted in the increased alkylation of both liver and kidney macromolecules and to an increase in the urinary clearance of ethylene-labeled MeCCNU. In all experiments, modifiers of hepatic biotransformation produced changes in the level of covalent binding by ethylene-labeled MeCCNU (alkylation) which correlated with the degree of toxicity of MeCCNU in the kidney. Additional evidence supporting a role for hepatic biotransformation in the toxicity of MeCCNU was provided by an in vivo/in vitro colony-forming assay which demonstrated the presence of a cytotoxic metabolite in the bile of a MeCCNU-administered rat. These studies suggest that hepatic metabolism contributes significantly to the alkylating activity of MeCCNU in the liver and the kidney, and indicate that a liver-derived metabolite may be responsible for the renal toxicity of MeCCNU.

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Methyl-CCNU was tested for carcinogenicity by repeated ip injection in rats and mice. The compound increased the incidence of total tumors in rats and slightly increased the incidence of leukemia and lymphosarcomas in female mice.

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ When administered by intravenous injection, methyl-CCNU induced lung tumors in rats.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Single IP injection of high dose (LD 10) of methyl-CCNU administered to sexually mature male mice resulted in severe inhibition of spermatogenesis and reduction in testicular wet weight, without significant changes in plasma testosterone levels, and with hyperplasia of the interstitum, including Leydig cells, in the testis. These effects were temporary, spermatogenesis and testiculer weight recovered 50 days after treatment. Mating of the treated males with normal females demonstrated absolute sterility at 20 days and full recovery at 50 days after treatment. Administration of a single lethal dose (38 mg/kg, LD70) of methyl-CCNU to immature (25 day-old) male mice also caused severe but temporary inhibition of spermatogenesis, and mating of mice which survived the treatment and reached sexual maturity, with normal females, resulted in 80 to 100% pregnancies at 40 and 70 days after treatment, respectively. Three repeated injections of 30 mg/kg (at 10 day intervals) of methyl-CCNU to 15 day-old male mice resulted in inhibition of spermatogenesis without alteration in plasma testosterone. Ninety days after this treatment, only 40% of matings with normal females resulted in pregnancies. Female mice treated once with 20 mg/kg of methyl-CCNU, 3 days before or 7 days after mating with normal males, showed complete failure to complete pregnancy-resorption of the embryos was demonstrated in those female mice treated 7 days after mating. After a second mating trial with these two treated groups, performed 40 to 55 and 42 days after the first trial, respectively, 80 and 86% of the females delivered offspring. However, average litter size was reduced to 4 in the second group, as compared to 8 in untreated mice. There were no apparent birth defects in the offspring of methyl-CCNU treated male or female mice.

1-(2-Chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (MethylCCNU) is known to be a human carcinogen based on sufficient evidence of carcinogenicity in humans.

In October, 2008, 21 scientists from nine countries met at the International Agency for Research on Cancer (IARC) and reaffirmed the Group 1 classification "carcinogenic to humans" of 20 pharmaceutical agents /including semustine/. The assessments will be published as Volume 100 of the IARC Monographs.

Classification of carcinogenicity: 1) evidence in humans: Sufficient; 2) evidence in animals: Limited. Overall summary evaluation of carcinogenic risk to humans is Group 1: The agent is carcinogenic to humans. /From table/

The rate constant for the vapor-phase reaction of semustine with photochemically-produced hydroxyl radicals has been estimated as 2.4X10-11 cu cm/molecule-sec at 25 °C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 16 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Semustine is an alkylating agent that may hydrolyze under environmental conditions(2). The analogous compound N-nitroso-N-ethylurea exhibited a half-life of 47 minutes at pH 9(3). Semustine contains chromophores that absorb at wavelengths >290 nm(2) and therefore may be susceptible to direct photolysis by sunlight(SRC).

NIOSH (NOES Survey 1981-1983) has statistically estimated that 229 workers (82 of these were female) were potentially exposed to semustine in the US(1). Occupational exposure to semustine dermal contact with this compound at workplaces where semustine is produced or used(SRC). The general population may only be exposed to semustine via its use as drug, an antineoplastic agent(SRC).