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    POLYETHYLEMINE AND ETHYLENIMINE

    EXPLANATION

         Polyethylenimine is an immobilizing agent used in the production
    of enzyme preparations for food processing. The substance is also used
    in food packaging materials. Polyethylenime is produced by the acid-
    catalyzed homopolymerization of ethylenimine. The polymerized material
    is cross-linked with ethylene dichloride to give the 40,000 to 60,000
    molecular-weight substance utilized in enzyme immobilization.

    POLYETHYLEMINE

    EXPLANATION

         This substance has not been previously evaluated by the Joint
    FAO/WHO Expert Committee on Food Additives.

    BIOLOGICAL DATA

    Biochemical aspects

         No information available.

    Toxicological studies

    Special studies on mutagenicity

         Two different forms of polyethylenimine were evaluated for
    mutagenic activity in the presence or absence of an Archlor-induced
    rat liver activation system. The indicator organisms used were
    Salmonella typhimurium strains TA1535, TA1537, TA1538, TA98, and
    TA100. A sample of polyethylenimine obtained prior to cross-linking
    with ethylene dichloride was mutagenic to strains TA1535 and TA100
    both in the presence and absence of the activation system. The sample
    contained measurable amounts of ethylenimine which likely caused the
    mutagenic activity (Mortelmans & Shepherd, 1980).

         An ethylene dichloride cross-linked sample, the form utilized in
    enzyme immobilization (Corcat P-600), did not contain measurable
    amounts of ethylenimine and was not mutagenic in any of the tester
    strains in the presence or absence of the activation system. At
    concentrations of up to 5000 micrograms/plate, 2 other forms of
    polyethylenimine, Corcat P-12 and Corcat P-18, were not mutagenic
    under the same test conditions (Mortelmans & Miron, 1981).

         Polyethylenimine (P-1000) having a molecular weight of 70,000 was
    tested for mutagenicity with or without metabolic activation (source
    of the activating system not specified) using Salmonella typhimurium
    strains TA1535, TA1537, TA1538, TA98, and TA100 and E. coli strain
    wp2 uvrA. No mutagenic activity was found when concentrations of up to
    5000 micrograms/plate were tested (Kajiwara et al., 1984).

    Acute toxicity
                                                                      

                                       LD50
       Species        Route            (mg/kg b.w.)   Reference
                                                                      

    Mouse             oral             2,800          BASF, 1959

    Mouse             oral             8,000          Kobe University,
                                                      1974

    Mouse             i.p.             40             BASF, 1959

    Rat               oral (gavage                    Rushbrook &
                      in corn oil)                    Jorgenson, 1981
       Male                            7550(a)
       Female                          7500(a)
       Both sexes     oral             2286(b)
       Male                            2286(c)
       Female                          1991(c)

    Rat               gavage (aqueous  2000           Norris, 1973
                      solution)

    Rat               oral             3,000          BASF, 1959

    Rat               i.p.             70 mg/kg       BASF, 1959

    Rabbit            oral             2,000 (no      BASF, 1959
                                       injury)

    Rabbit            i.v.             4 (lethal      BASF, 1959
                                       dose)

    Cat               i.v.             10 (lethal     BASF, 1959
                                       dose)
                                                                      

    (a)  Polyethylenimine type Corcat 600 (type used in enzyme
         immobilization)
    (b)  Polyethylenimine type Corcat P-12
    (c)  Polyethylenimine type Corcat P-18

         It was not possible to determine the lethal oral dose of
    polyethylenimine in dogs and cats because of vomiting. Cats vomited
    within 30 minutes of receiving 100-500 mg/kg, so only a small amount
    of the material remained in the stomach. Doses of 100 mg/kg caused
    vomiting in dogs. In cases where vomiting did not occur, no adverse
    effects were reported (BASF, 1959).

         In guinea-pigs, a single oral dose of 600 mg/kg was lethal to
    6/10 animals and a dose of 800 mg/kg was lethal to 2/10 animals (BASF,
    1959).

    Short-term studies

    Rats

         Groups of 40 male and 40 female white rats received 0, 0.25, 0.5,
    or 1.0 g/kg b.w. of polyethylenimine in the diet for 8.5 months. No
    compound-related effects were reported with respect to mortality, body
    weight, feed consumption, clinical signs, haematology, urinalysis, or
    absolute and relative organ weights. An elevation in blood alkaline
    phosphatase levels was observed in high-dose male rats as compared to
    the controls, but the values were within normal limits for the
    performing laboratory. No treatment-related changes were observed in
    gross and microscopic pathology studies carried out on 5 animals/sex/
    dose (McCollister & Copeland, 1968a).

    Dogs

         Groups of 4 male and 4 female beagle dogs were fed 0, 0.25, 0.5,
    or 1.0 g/kg b.w. polyethylenimine in the diet for 9 months. No
    compound-related differences were noted with respect to haematology,
    urinalysis, clinical chemistry, or bromsulfophthalein dye retention.
    Group mean body-weight gains were reduced as compared to controls in
    high-dose males and females. Relative liver and kidney weights were
    increased in high-dose females and relative kidney weights were
    slightly increased in high- and mid-dose males and mid-dose females.

         The pathology report indicated that severe degenerative changes
    occurred in the kidney proximal convoluted tubules in the high-dose
    animals. The same lesion, but not as severe, was reported to occur in
    all mid-dose and 5 of 8 low-dose animals. No lesions of the proximal
    convoluted tubules were reported in control animals. All of the low-
    dose females and one of the low-dose males were reported to have the
    lesion to a "very slight" degree. Brown pigmentation of Kupffer's
    cells in the liver was considered to be compound-related. In the high-
    dose animals, it was present in 3 of 4 males at a moderate to very
    slight degree and in 2 of 4 females at a marked to moderate extent. In
    the mid-dose groups, 1 of 4 animals of each sex had the lesion present

    at a grade of "very slight". The lesion was not present in controls of
    either sex or low-dose males, but was present at a "very slight" grade
    in 1 of 4 low-dose females. There did not appear to be any other
    compound-related microscopic lesions (McCollister & Copeland, 1968b).

    Rabbits

         Rabbits were reported to tolerate several once-per-week oral
    doses of 1.0 g/kg polyethylenimine for several weeks without
    impairment of liver function. No injury to the liver or kidney was
    noted in rabbits receiving 1.0 g/kg daily, but the report stated that
    the rabbits tolerated a maximum of 6 doses. Daily doses of 0.5 g/kg
    were reportedly tolerated without any injury; however, details of the
    study were not provided (BASF, 1959).

    Comments

         Although not up to modern standards of toxicity testing, the
    8.5-month rat study of free polyethylenimine did not reveal any
    adverse effects. In the 9-month dog study, compound-related changes in
    the kidney and liver were found. Since absorption and distribution
    studies are not available to show if appreciable uptake of this high-
    molecular-weight compound occurs, it is not clear what the mechanism
    of action is for the liver and kidney lesions. Polyethylenimine free
    of measurable levels of ethylenimine showed no mutagenic activity when
    tested with or without metabolic activation using Salmonella
    typhimurium strains.

    EVALUATION

    Estimate of acceptable daily intake for man

         Polyethylenimine is considered to be a suitable substance for use
    as an immobilizing agent in the production of immobilized enzymes (see
    ethylenimine).

    REFERENCES

    BASF (1959). Preliminary report on the toxicity of PEI. Unpublished
         report of Badische Analin & Soda Fabrik AG. Submitted to WHO by
         UOP, Inc.

    Kajiwara, Y., Oguru, S., & Takeyasu, K. (1984). Ames metabolic
         activation test to assess the potential mutagenic effect of
         polyethylenimine. Unpublished report of the Hita Research
         Laboratories, Chemicals Inspection & Testing Institute. Submitted
         to WHO by UOP, Inc.

    Kobe University (1974). Acute toxicity of P-1000. Unpublished report
         of Kobe University, Medical Faculty, Public Health Section.
         Submitted to WHO by UOP, Inc.

    McCollister, D.D. & Copeland, J.R. (1968a). Results of 8.5 month
         dietary feeding studies of polyethylenimine in rats. Unpublished
         report of the Dow Chemical Company. Submitted to WHO by Cordova
         Chemical Company.

    McCollister, D.D. & Copeland, J.R. (1968b). Results of 9 month dietary
         feeding studies of polyethylenimine in Beagle hounds. Unpublished
         report of the Dow Chemical Company. Submitted to WHO by Cordova
         Chemical Company.

    Mortelmans, K.E. & Miron, K.L. (1981). In vitro microbiological
         mutagenicity assays of Cordova Chemical Company's compounds
         Corcat P-12, Corcat P-18, and Corcat P-600. Unpublished report of
         SRI International. Submitted to WHO by Cordova Chemical Company.

    Mortelmans, K.E. & Shepherd, G.F. (1980). In vitro microbiological
         mutagenicity assays of Cordova Chemical Company's compound PEI
         prepolymer, Sample No. SWM D32-084-1. Unpublished report of SRI
         International. Submitted to WHO by Cordova Chemical Company.

    Norris, J.M. (1973). Acute toxicological properties of PEI-600.
         Unpublished report of the Dow Chemical Company. Submitted to WHO
         by UOP, Inc.

    Rushbrook, C.J. & Jorgenson, T.A. (1981). Acute toxicity studies of
         three Corcat compounds. Unpublished report of SRI International.
         Submitted to WHO by Cordova Chemical Company.
    

    ETHYLENIMINE

    EXPLANATION

         Ethylenimine has not been previously evaluated by the Joint
    FAO/WHO Expert Committee on Food Additives. Trace amounts of
    ethylenimine may potentially migrate into food from the presence of
    small amounts of unreacted monomer present as a contaminant in
    polyethylenimine.

    BIOLOGICAL DATA

    Biochemical aspects

    Distribution

         Five male rats (Dow-Wistar strain) were injected i.p. with 0.3 to
    0.4 mg/kg b.w. of 14C-labelled ethylenimine and sacrificed after 24
    or 96 hours. In both cases about 50% of the radioactivity was excreted
    in the urine and small amounts were present in faeces and exhaled
    air. A small amount of ethylenimine and a number of non-volatile
    metabolites were present in the urine and both ethylenimine and CO2
    were present in expired air. About 2.5% of the radioactivity was
    present in the liver after 24 hours and about 1% after 96 hours.
    Smaller amounts were present in many other tissues. The authors
    concluded that the compound was generally distributed throughout the
    rat before reaction with tissue components occurred (Wright & Rowe,
    1967).

    Excretion

         Monoethanolamine and ethylenimine were excreted in the urine of
    rats following introduction of ethylenimine into the stomach
    (presumably by gavage). The urinary excretion of these 2 compounds
    accounted for approximately 50% of the administered dose. The fraction
    of the administered dose that was excreted in the urine was dose-
    dependent. At a dose of 1/20 the LD50 (0.85 mg/kg according to the
    authors) about 60% of the administered dose was excreted as
    monoethanolamine and ethylenimine in the urine over a 6-day period;
    50% of the dose was excreted in the first 24 hours (Sanotsky et al.,
    1977).

    Toxicological studies

    Special studies on renal toxicity

    Rats

         Groups of 6 or 7 female Sprague-Dawley rats were given single
    subcutaneous injections of 0.25, 0.5, 1.0, 1.25, 2.0, 4.0, 6.25, or

    8.0 mg/kg of ethylenimine in water. Animals were sacrificed 4 days
    after treatment. Renal papillary necrosis was observed at doses of
    1.25 mg/kg ethylenimine and greater, whereas none occurred at
    1.0 mg/kg and below (Axelson, 1978).

    Rabbits

         Renal medullary necrosis occurred in male and female New Zealand
    strain rabbits injected i.v. with a single 0.005 ml/kg dose (about
    5 mg/kg) ethylenimine as a 1% v/v solution in water (Davies 1969;
    Davies, 1970).

    Dogs

         Groups of 4 male beagle dogs were given either a single i.v.
    injection of 3 µl/kg (about 3 mg/kg) ethylenimine or an initial
    injection of 0.6 µl/kg ethylenimine followed by a second injection of
    1 µl/kg 3 days later. In the animals receiving 2 injections of
    ethylenimine the tubules of the collecting ducts and loop of Henle
    were dilated and inflamation was found in the renal pelvis. A small
    number of dilated tubules were observed in the medulla, and dilation
    of the distal convoluted tubules and collecting ducts of the cortex
    were noted. Almost complete necrosis of the papilla was observed in
    2 dogs that became moribund after receiving the single high dose
    (3 µl/kg) of ethylenimine. Functional and clinical chemistry studies
    showed that treatment was related to impairment of renal function,
    proteinuria, and elevated excretion of urinary enzymes (Ellis et
    al., 1973).

    Special studies on carcinogenicity

    Mice

         A carcinogenesis study of ethylenimine was carried out using
    2 strains of mice, (C57BL/6 × C3H/Anf)F1 (strain x) and
    (C57BL/6 × C3H/AKR)F1 (strain y). Test animals were given the maximum
    tolerated dose (MTD), 4.64 mg/kg, daily by gavage in a 0.5% gelatin
    vehicle from day 7 through day 28 of age (the MTD for this study was
    the maximal dose giving no mortality when administered daily for
    19 consecutive days). Thereafter, the animals received the same
    calculated daily dose of ethylenimine mixed in the feed. Groups of
    18 animals/sex/strain were used. A number of other compounds were
    tested in this study. All the animals receiving a particular compound
    were placed in 1 of 4 rooms. Each room also contained an untreated
    control group of 18 animals/sex/strain. There was also 1 additional
    control group of 18 animals/sex/strain given a gelatin suspension
    during the time when the compounds were administered by stomach tube.
    Ethylenimine was actually employed as a positive control. There was at
    least 1 positive control group in each room. Ethylenimine-treated
    animals were on test for 77 or 78 weeks. The controls were on test for
    78 to 89 weeks.

         Data on mortality, body weight, food and water consumption,
    haematology, clinical chemistry, and non-carcinogenic pathological
    effects were not reported.

         A list of the major organs examined microscopically was not
    provided. The report stated that all major organs and grossly-visible
    lesions were examined microscopically. However, the cranium was not
    dissected. Thyroid glands were sectioned in only 1 of the 5 control
    groups and not in the ethylenimine-treated animals. The tabulation of
    tumours listed only the following categories: hepatomas, pulmonary
    tumours, lymphomas, and total mice with tumours. The investigators
    lumped all 5 negative control groups together for purposes of
    comparison with positive controls and experimental compounds.

         In the ethylenimine-treated animals there was a significant
    increase in the relative risk for development of hepatomas, pulmonary
    tumours, and total tumours. In strain x males given ethylenimine, the
    incidence of hepatomas, pulmonary tumours, and lymphomas was 15/17,
    15/17, and 0/17, respectively. Corresponding values for the control
    strain x males were 8/79, 5/79, and 5/79. For strain x females given
    ethylenimine, the incidence of the different tumours was 11/15, 15/15,
    and 0/15, respectively, while the corresponding values for controls
    were 3/92, 3/92, and 5/92. In strain y males given ethylenimine, the
    incidence of hepatomas, pulmonary tumours, and lymphomas was 9/16,
    12/16, and 0/16, respectively. Corresponding values for strain y male
    controls were 5/90, 10/90, and 1/90. In strain y females given
    ethylenimine, the respective tumour incidences were 2/11, 10/11, and
    2/11; the corresponding values for strain y female controls were 1/82,
    3/82, and 4/82. The actual dose of ethylenimine the animals received
    from the diet in this study is unclear. The concentration of
    ethylenimine in the feed was not measured and some material would
    certainly have been lost by volatilization and reaction with dietary
    constituents. An experiment, aimed at mimicking conditions of mixing
    in the diet and storage of ethylenimine during the conduct of the
    study, indicated loss of a considerable amount of the test substance
    (Bionetics Research Labs, Inc., 1968; Green & Lowry, 1983; Innest
    et al., 1969).

         The same group of workers gave single s.c. injections of
    4.64 mg/kg b.w. of ethylenimine to groups of 18 male and 18 female
    mice of strains (C57Bl/6 × C3H/Anf)F1 and (C57BL/6 × C3H/AKR)F1. The
    animals were then observed for 18 months. Tumours developed in 7 of
    the males of the (C57Bl/6 × C3H/Anf)F1 strain - 2 lymphomas, 2
    hepatomas, and 5 pulmonary tumours. In the (C57BL/6 × C3H/AKR)F1
    strain, 6 of 18 males each developed a lung tumour. For males of both
    strains the total number of tumours and the incidence of pulmonary
    adenomas was significantly greater than in the controls (P < .01). In
    the treated females, 1 animal of each strain developed a lung tumour.
    The controls consisted of 9 separate groups lumped together for
    purposes of comparison with a total of about 160 animals/sex/strain
    (Bionetics Research Labs., Inc., 1968).

         Fragmentary data are available from another study of ethylenimine
    administered s.c. at doses of 0.4, 1.3, or 4.0 mg/kg at weekly
    intervals for 48 weeks to 187 male and female C56BL × CBA mice. After
    2 years, dosed animals had an increased incidence of sarcomas at the
    injection site, tumours of the harderian gland and lung, and malignant
    hepatomas (Linnik, 1980).

    Rats

         A series of ethylenimine derivatives was administered by s.c.
    injection to groups of 6 male and 6 female albino rats. Ethylenimine
    was injected twice weekly in an arachis oil vehicle. The dosing
    regimen occurred over a 67-day period, with a total dose of 20 mg/kg
    being administered. Sarcomas were found at the injection site in 5 of
    6 males and 1 of the females. The tumours were discovered between 355
    and 511 days after the beginning of dosing. The study was terminated
    at 546 days after the beginning of dosing. No tumours were found at
    locations remote from the point of injection. In controls injected
    with arachis oil for the same duration as the ethylenimine group, 1 of
    10 males developed an injection-site sarcoma at 568 days while 2
    tumours developed at remote sites. None of 9 control females developed
    sarcomas at the injection site; however, a fibroma was found in 1
    animal at that site and tumours were found in 2 other animals at
    remote sites.

         In another experiment, groups of 6 males and 6 females were given
    ethylenimine dissolved in water twice weekly by s.c. injection. A
    total dose of 10 or 12 mg/kg was given to males and females,
    respectively, over a 59-day period (dosed 5 days/week). The animals
    were observed up to 540 days; 2 sarcomas were observed at the
    injection site in females and none in males, while a transitional cell
    carcinoma of the kidney was seen in 1 male. Concurrent control groups
    injected with a carbowax-300 vehicle had no injection-site sarcomas
    (Walpole et al., 1954).

    Special studies on mutagenicity

         Sex-linked recessive lethals and translocations were reported in
    a study in which day-old male Drosophila were treated with an i.p.
    injection of 0.4 µl of a 10-2 M solution of ethylenimine and
    subsequently mated. The authors stated that the compound was
    radiomimetic in producing chromosomal abnormalities - translocations
    were nearly as frequent as sex-linked lethals - but resembled some
    chemical mutagens, such as mustards, in producing delayed lethals and
    translocations which appeared in the F2 generation from F1 parents
    that appeared normal (Alexander & Glanges, 1965).

         Other studies have also found that ethylenimine induces recessive
    lethals and translocations in Drosophila (Lim & Snyder, 1968;
    Alexander, 1967).

         Ethylenimine was mutagenic in Salmonella typhimurium strains
    TA1535 and TA100 without metabolic activation (McCann et al., 1975).

         The compound was also reported to be mutagenic in spot tests on
    Neurospora crassa strain N-23 (reverted by base pair mutagens), but
    not by strain N-24 (reverted by frame shift mutagens) (Ong, 1978),

         Severe inhibition of replicon initiation and blocked-chain
    elongation occurred when 5 × 10-4 M ethylenimine was added to
    cultured HeLa 53 cells (Painter, 1978).

         Injection of 1 mg/kg ethylenimine (i.p.) into male mice resulted
    in about a 2/3 reduction in incorporation of 3H-thymidine into
    testicular DNA as compared to control animals (Seiler, 1977).

         Lymphocyte cultures from 10 workers exposed to workroom
    ambient-air concentrations of 0.5 ppm ethylenimine reportedly did not
    show an increase in chromosomal aberrations (Gaeth & Thiess, 1972).

         The effect of incubation with ethylenimine was studied in
    cultures of WI-38 cells and in leukocytes from an adult male
    volunteer. A concentration of 10-2 M ethylenimine was cytotoxic to
    the WI-38 cells. Concentrations of 10-3 and 10-4 M were associated
    with chromatid breaks, gaps, and exchanges. Radiolabel studies with
    leukocyte cultures incubated with 10-4 M ethylenimine also showed
    gaps, exchanges, and breaks, occurring primarily in the S-period of
    the cell cycle (Chang & Elequin, 1967).

    Acute toxicity
                                                                   
                                    LD50
    Species       Route          (mg/kg b.w.)       Reference
                                                                   

    Rat           oral           17                 Santoski et al.,
                                                    1977

    Rat           oral           15                 NIOSH, 1977

    Rat           i.p.           3.8                NIOSH, 1977
                                                                   

    Short-term studies

         No information available.

    Long-term studies

         No information available.

    Comments

         Ethylenimine appeared to be carcinogenic when administered orally
    to 2 strains of mice. Both sexes were affected, with the liver and
    lung being the major target organs. When administered s.c. to rats and
    mice, the compound appared to be associated with sarcomas at the
    injection site as well as at other locations. Ethylenimine was found
    to be mutagenic in Neurospora, Salmonella, and Drosophila, and
    chromosomal aberrations occurred in cultured mammalian cells exposed
    to the compound.

         Use of the oral feeding study in mice for risk analysis is
    complicated because of the one-dose design of the experiment,
    questions about the actual dose of ethylenimine received by the
    animals, the appearance of tumours at 2 sites, and the very high
    tumour incidence. While clearly indicating that ethylenimine is
    carcinogenic, the mouse study is not up to modern standards of
    toxicity testing. Carcinogenicity studies by the oral route are
    available only in the mouse. Reproduction and teratology studies are
    not available.

    EVALUATION

    Level causing no toxicological effect

         Ethylenimine has been determined to be carcinogenic in mice. A
    "no-effect" level in experimental animals has not been established.

    Estimate of acceptable daily intake for man

         Acceptable on condition that human exposure to ethylenimine
    as a result of its migrations into food from immobilized enzyme
    preparations is reduced to the lowest level technically possible
    (see polyethylenimine).

    REFERENCES

    Alexander, M.L. (1968). Mosaic mutations induced in Drosophila by
         ethylenimine. Genetics, 56, 273-281.

    Alexander, M.L. & Glanges, E. (1965). Genetic damage induced by
         ethylenimine. Proc. Nat'l Acad. Sci., 53, 282-288.

    Axelson, R.A. (1978). Experimental renal papillary necrosis in the
         rat: the selective vulnerability of medullary structures to
         injury. Virchows Arch. A. Path. Anat. and Histol., 381,
         79-84.

    Research Labs., Inc. (1968). Evaluation of carcinogenic, teratogenic,
         and mutagenic activities of selected pesticides and industrial
         chemicals. Volume I, Carcinogenic Study. Prepared for National
         Cancer Institute. Available from National Technical Information
         Service, U.S. Department of Commerce.

    Chang, T. & Elequin, F.T. (1967). Induction of chromosome aberrations
         in cultured human cells by ethylenimine and its relation to cell
         cycle. Mut. Res., 4, 83-89.

    Davies, D.J. (1969). The structural changes in the kidney and urinary
         tract caused by ethylenimine (vinylamine). J. Path., 97,
         695-703.

    Davies, D.J. (1970). The early changes produced in the rabbit renal
         medulla by ethylenimine: electron-microscope and circulatory
         studies. J. Path., 101, 329-332.

    Ellis, B.G., Price, R.G., & Topham, J.C. (1973). The effect of
         papillary damage by ethylenimine on kidney function and some
         urinary enzymes in the dog. Chem-Biol. Interact., 7, 131-141.

    Gaeth, V.J. & Thiess, A.M. (1972). Chromosome studies on chemical
         workers, Zentralbl. Arbeitsmed. Arbeitsschutz, 22, 357-362.

    Green, D.R. & Lowry, J.R. (1983). Stability of ethylenimine in mouse
         chow and 0.5% gel solution. Unpublished report of Cordova
         Chemical Company. Submitted to the World Health Organization by
         Cordova Chemical Company.

    Innes, J.R.M., Ulland, B.M., Valerio, M.G., Petrucelli, L., Fishbein,
         L., Hart, E.R., Pallota, A.J., Bates, R.R., Falk, H.L., Gart,
         J.J., Klein, M., Mitchell, I., & Peters, J. (1969). Bioassay of
         pesticides and industrial chemicals for tumorigenicity in mice: A
         preliminary note. J. Nat. Cancer Inst., 42, 1101-1114.

    Lim, J.K. & Snyder, L.A. (1968). The mutagenic effects of two mono
         functional alkylating chemicals on mature spermatozoa of
         Drosophila. Mutation Res., 6, 129-137.

    Linnik, A.B. (1980). Study of the carcinogenic effect of ethylenimine
         on F1(C57BL × CBA) mice. Eksp. Onkol., 2, 67-68.

    McCann, J., Choi, E., Yamasaki, E., & Ames, B.N. (1975). Detection of
         carcinogens as mutagens in the Salmonella/microsome test: Assay
         of 300 chemicals. Proc. Nat'l Acad. Sci., 72, 5135-5139.

    NIOSH (1977). Registry of toxic effects of chemical substances.
         National Institute of Occupational Safety and Health, Washington,
         DC, USA.

    Ong, T. (1978). Use of the spot, plate and suspension test systems for
         the detection of the mutagenicity of environmental agents and
         chemical carcinogens in Neurospora crassa. Mutation Res.,
         53, 297-308.

    Painter, R.B. (1978). Inhibition of DNA replicon initiation by 4
         nitroquinoline 1-oxide, adriamycin and ethylenimine. Cancer
         Res., 38, 4445-4449.

    Sanotosky, I.V., Muravieva, S.I., Zaeva, G.N., & Semiletkina, N.N.
         (1977). Urinary excretion of ethylenimine and its metabolite,
         monoethanolamine, under experimental conditions. Gig. Tr. Prof.
         Zabol., p. 10-14.

    Seiler, J.P. (1977). Inhibition of testicular DNA synthesis by
         chemical mutagens and carcinogens. Preliminary results in the
         validation of a novel short-term test. Mutation Res., 46,
         305-310.

    Walpole, A.L., Roberts, D.C., Rose, F.L., Hendry, J.A., & Homer, R.F.
         (1954). Brit. J. Pharmacol., 9, 306-323.

    Wright, G.J. & Rowe, V.K. (1967). Ethylenimine: Studies of the
         distribution and metabolism in the rat using carbon-14.
         Toxicol. Applied Pharmacol., 11, 575-584.
    


    See Also:
       Toxicological Abbreviations