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    SUCROSE ACETATE ISOBUTYRATE

    First draft prepared by
    Ms E. Vavasour
    Toxicological Evaluation Division
    Bureau of Chemical Safety, Food Directorate
    Health and Welfare Canada
    Ottawa, Ontario, Canada

    1.  EXPLANATION

         Sucrose acetate isobutyrate, which is a mixture of esters of
    sucrose esterified with acetic and isobutyric acids, was evaluated
    at the nineteenth, twenty-first and twenty-sixth meetings of the
    Committee (Annex 1, references 38, 44 and 59).  At its twenty-first
    meeting, the Committee concluded that a complete toxicological
    profile was required for the evaluation of this compound, including
    carcinogenicity/toxicity studies in two animal species, a 2-year
    study in dogs with adequate numbers and dose groups to demonstrate a
    no-effect level and to assess the adverse effects of the substance
    on liver function, and a multigeneration reproduction/teratogenicity
    study.  This information was not yet available when the compound was
    again reviewed at the twenty-sixth meeting of the Committee, so no
    ADI was allocated, although a toxicological monograph summarizing
    the available toxicological data was prepared (Annex 1, reference
    60).  With the exception of the 2-year study in dogs, the requested
    data were available for consideration at the present meeting.  The
    new data that have been made available as well as relevant studies
    from the previous monograph are summarized in this monograph.

    2.  BIOLOGICAL DATA

    2.1  Biochemical aspects

    2.1.1  Absorption, distribution, and excretion

    2.1.1.1  Rats

         Male albino Holtzman rats, about 250 g, were intubated with
    14C-SAIB of specific activity 0.411 Ci/mg (all 14C-SAIB used this
    and the following studies was labelled on the sucrose portion of the
    molecule) in corn oil at dose levels equivalent to 27 or 100 mg/kg
    bw.  The proportion of the administered dose absorbed from the GI
    tract was greater at the low dose (74-82%) than at the high dose
    (45-50%).  Elimination of 88 to 90% of the administered dose
    occurred in 48 hours.  The relative proportion of radioactivity
    eliminated by the various routes varied with the dose.  At the high
    dose level, 54-56% of the absorbed activity was eliminated as CO2
    and 26-28% in the urine.  At the lower dose, 63-67% of the absorbed
    activity was eliminated in CO2 and 23-25% in the urine.  Four days
    after the administration of the test compound, less than 1% of the
    administered radioactivity was retained in the gastrointestinal
    tract (from cardiac valve to rectum), blood, liver and kidney. 
    Chromatography of extracts of the 24-hour faeces of rats showed the
    presence of SAIB and other metabolites.  Most of the radioactivity
    in urine was in the form of sucrose, although other unidentified
    substances were also present (Fassett and Reynolds 1962; Reynolds
    1972a; Reynolds  et al. 1974).

         Using the same protocol as in the previous study, male albino
    Holtzman rats weighing approximately 250 g received 100 mg/kg bw of
    14C-SAIB (specific activity, 0.38 Ci/mg) in corn oil by gavage. 
    At termination of the study, 3 or 3.5 hours after dosing, 78-84% of
    the radioactivity was recovered from the gastrointestinal contents. 
    An additional 7-9% of the radioactivity was recovered from the
    stomach, intestinal and caecal tissues.  Less than 4% of the
    radioactivity was excreted in the breath, urine and faeces within
    3-3.5 hours after dosing, indicating that little absorption had
    taken place.  Extracts of the gastrointestinal contents and organs
    were found to contain sucrose and partially acylated sucrose esters
    in addition to unchanged SAIB (Reynolds 1963).

         Two rats were given a single oral dose of 14C-SAIB (0.36
    Ci/mg) in aqueous emulsion at levels equivalent to 5.8 and 11.2
    mg/kg bw.  Within 3 days, 59 and 52% of the 14C-labelled SAIB were
    recovered in breath as respired CO2, 11 and 13% recovered in the
    urine, and 23 and 27% recovered in the faeces.  The rats retained 6
    and 6.6% of the 14C in the carcass;  the distribution of
    radioactivity among the organs was comparable.  Total absorption of
    administered SAIB was 71 and 77% of the administered dose when
    recovery of label from urine, expired air and whole carcass was

    combined.  The major 14C compounds in the faeces were SAIB or
    highly acylated sucrose molecules.  Chromatographic separation of
    urine showed 1 or 2 major peaks, which were not identified.  In
    comparison, rats given a single oral dose of 14C-labelled sucrose
    in aqueous solution at a level of 400 mg/kg bw showed rapid
    absorption and metabolism of the sucrose to 14CO2, the maximum
    rate of elimination being observed 2 hours post-dosing.  Only small
    amounts of 14C were eliminated in the urine and faeces.  At
    sacrifice (3 days post dosing), the carcass retained 9.6-12.9% of
    the 14C label.  Distribution of radioactivity in the carcass was
    similar for rats treated with SAIB or with sucrose.  No accumulation
    of radioactivity in a particular organ was observed (Reynolds 1972b; 
    Reynolds  et al. 1974).

         Female rats received 14C-SAIB (specific activity 1.0 Ci/mg)
    by oral intubation at a dose level of 50 mg/kg bw.  More than 90% of
    the radioactivity remained in the gastrointestinal tract at 6 hours,
    of which approximately 60% was situated in the lumen of the small
    intestine.  Less than 30% of this amount was present as SAIB.  Only
    4.9% of the dose was excreted in the urine, and 2.4% was expired as
    CO2 at 6 hours after dosing.  Twenty-four hours after
    administration of the test compound, 90% of the 14C had been
    excreted and less than 8% remained in the gastrointestinal tract. 
    Metabolism to CO2 accounted for 45% of the excreted radioactivity. 
    Faecal material contained 33% of 14C, of which 26% was in the form
    of unchanged SAIB.  14C metabolites present in urine were similar
    to those obtained from urine of rats given an equivalent dose of
    14C sucrose (Phillips  et al. 1976).

         In a series of experiments with sucrose octaisobutyrate (SOIB),
    a constituent ester of SAIB, male rats received approx.200 mg/kg bw
    14C-SOIB (specific activity 0.2 Ci/ml) by corn oil gavage. 
    Radioactivity was not detectable in urine, faeces or breath until 6
    hours following dosing, but by 5 days >95% of the dose had been
    excreted by these routes.  The major route of excretion was the
    faeces (78-93% of the dose);  consequently, only a small amount of
    administered SOIB was absorbed. 14CO2 in the breath was the major
    route of excretion for absorbed SOIB.  Radioactivity in bile samples
    collected from an indwelling catheter for 12 hours after dosing was
    negligible or only slightly above background and after 48 hours,
    only 0.2% of the administered dose had been collected from bile. 
    Similarly, radioactivity in terminal blood samples collected at 2,
    4, 8, 12, and 24 hours was only detectable in 24-hour samples and
    included a negligible percentage of the administered radioactivity
    (Noker 1982;  Noker  et al. 1986).

    2.1.1.2  Dogs

         Two dogs received single doses of 3.0 or 4.8 mg/kg bw 14C-SAIB
    (specific activity 0.36 Ci/mg) in aqueous emulsion by stomach tube. 
    A large proportion of the administered dose (compared with rats at
    the same dose) was eliminated in the faeces (52.5 and 45.5%,
    respectively), within 4 days of dosing.  Although collection of
    14CO2 excreted in breath was incomplete, it still represented the
    major portion of excreted radioactivity (26-28%).  Smaller amounts
    were eliminated in the urine (6 and 7% after 7 and 8 days
    respectively).  Chromatography of faecal extracts indicated the
    presence of SAIB and highly acylated sucrose esters.  Radioactivity
    in urine samples corresponded almost entirely to sucrose esters
    while no significant amount of sucrose was detected (Reynolds and
    Travis 1972; Reynolds  et al. 1974).

         14C-SOIB (specific activity 0.02 Ci/mg) was administered to
    male Beagle dogs by corn oil gavage at a dose of approx. 200 mg/kg
    bw.  Almost no radioactivity was detected as 14CO2 during the
    first 24 hours after dosing.  Throughout the 5-day study, the amount
    of radioactivity excreted as 14CO2 accounted for 1% or less of the
    dose.  The major route of elimination was the faeces, accounting for
    77 to 94% of the dose.  In one of the dogs, essentially the entire
    dose was recovered within 5 days, indicating that SOIB was not
    incorporated to any great extent in the tissues.  In another study
    using dogs with indwelling catheters, between 2 and 10% of the dose
    was retrieved in bile collections made over 48 hours or more after a
    delay of 4-6 hours following dosing.  Chromatographic analysis of
    the bile samples revealed at least 9 radiolabelled components. 
    Although the identity of none of them could be established, SOIB was
    not present in the samples and all the components were more polar
    than the parent compound.  The variability in total biliary
    excretion between individual animals and in the same animals in
    repeat-dose studies was attributed to differences in degree of
    absorption of the compound.  The results of a separate 12-hour bile
    collection study were considered to be possibly inaccurate since the
    anaesthesia (halothane-nitrous oxide) used during the collection
    period may have resulted in reduced gastric motility (Noker 1984a; 
    Noker  et al. 1986).

    2.1.1.3  Monkeys

         Male  Cynomolgus monkeys weighing approximately 2.5 kg
    received a single dose of approx.200 mg/kg bw 14C-SOIB (specific
    activity 0.08 Ci/mg) by oral gavage in corn oil.  The major route
    of elimination was the faeces, where the amount recovered from
    individual monkeys ranged from 61 to 85% of that administered. 
    Radioactivity was detected in the breath of one monkey at 12 hours
    and in the other two monkeys only after 24 hours.  During the 5-day
    observation period, the total amount of SOIB excreted as 14CO2
    accounted for less than 2% of the administered dose.  For each

    monkey, 1% or less of the dose was found in the urine.  Excretion of
    radioactivity in the bile was monitored in three monkeys for at
    least 52 hours.  For all 3 monkeys, very low levels of radioactivity
    were excreted into the bile, corresponding to only 0.1-0.2% of the
    administered dose.  No significant level of radioactivity was
    detected in the blood or plasma in the 48 hours following dosing
    (Noker 1984b;  Noker  et al. 1986).

    2.1.1.4  Humans

         14C-SAIB (specific activity 0.39 Ci/mg) was incorporated into
    a simulated non-carbonated soft drink and administered to 3 male
    subjects.  The 3 subjects were each given 2 or 3 single doses at
    widely spaced intervals.  The first dose was administered at a level
    of approx. 1 mg/kg bw to each subject, none of whom had been
    previously exposed to SAIB.  Two of these subjects were given a
    second dose at the same level 7-27 weeks after the first dose and
    following ingestion of unlabelled SAIB at a level of 1 mg/kg bw/dy
    for 7 days.  The third subject received a single dose at a level of
    0.18 mg/kg 25 weeks after the first dose.  One subject was given a
    third dose at a level of 1 mg/kg bw 10 weeks after the second dose
    and immediately after ingestion of a high-fat meal.  All subjects
    were monitored for elimination of radioactivity in expired air and
    urine for 30 days or more post-dosing.  Elimination of radioactivity
    from the lungs occurred rapidly.  [Only a small amount of the total
    was eliminated in the 6-8-hour period post-dosing, but excreted
    radioactivity reached maximum levels 9-15 hours post-dosing.]  The
    subjects excreted 14 to 21% of the dose in the urine, the maximum
    rate of urinary excretion occurring within 3 hours and decreasing by
    48 hours.  About 10% or less of the dose was unabsorbed and appeared
    in the faeces of all subjects.  Prior dosing with SAIB or 14C-SAIB
    had no effect on the pattern of elimination.  Chromatographic
    studies of urine showed several radioactive peaks, which have not
    been clearly identified;  however, the amount present as free
    sucrose was estimated to be 20% of the radioactivity and SAIB or
    highly acylated esters of sucrose were not detected. 
    Chromatographic studies of extracts of faeces showed the presence of
    radioactive materials which did not correspond with those in the
    urine and which were probably highly acylated esters of sucrose and
    SAIB.  No effect on blood haematology or selected blood chemical
    values was detected.  In another study, two subjects ingested
    14C-sucrose at a level of 400 mg/kg bw, corresponding to the
    concentration of sucrose in the simulated soft drink administered in
    the previous study.  Forty-two to 59% of the 14C-sucrose was
    metabolized to 14CO2 within 48 hours, the maximum rate of
    elimination occurring 3 hours post-dosing.  Both subjects eliminated
    small amounts of 14C in the urine (1.9 and 1.7% of the dose in 48
    hours).  Most of the radioactivity appeared to have been
    incorporated into urea and free sucrose was not detected in urine
    samples (Reynolds  et al. 1972;  Reynolds  et al. 1974).

         Two male subjects were given SAIB (100 mg or 1 g) as a single
    dose.  The urinary excretion of sucrose and sucrose esters was less
    than the limit of detection of the assay procedure used (1 ppm
    sucrose) in any 24-hour period up to 5 days post-dosing.  In another
    study, 2 male subjects were given 1 g of SAIB/day for 7 days.  No
    urinary excretion of sucrose was detected.  No unchanged SAIB or
    metabolites were detected in faecal samples of one subject given
    100 mg of SAIB daily for 7 days.  Two subjects were each given
    sucrose intravenously (100, 250 and 800 mg in a 10% solution w/v on
    different days) and the urine collected 3, 12 and 24 hours. 
    Approximately 50% of the administered sucrose was recovered in the
    urine by 3 hours at all 3 dose levels, and there was almost
    quantitative recovery of the lower dose by 12 hours (Phillips
     et al. 1976).

    2.1.1.5  Combined species

         The disposition of SAIB following a single oral dose was
    compared in the rat (5.8, 11.2, 27 and 100 mg/kg bw), dog (3.0 and
    4.8 mg/kg bw) and human (0.18 and 1.0 mg/kg bw).  The authors
    concluded that the excretion patterns for humans and rats showed
    more similarities than did the excretion patterns for humans and
    dogs.  Humans and rats (at the three lower doses) absorbed a larger
    proportion of the administered SAIB from the intestine and converted
    a higher proportion to CO2.  The results of chromatography of
    urine extracts indicated that the types of partial sucrose esters
    differed in dogs compared with rats and humans.  More highly
    acylated sucrose molecules were present in the urine of dogs and
    more polar esters in the urine of humans and rats (Reynolds  et al.
    1971;  Reynolds  et al. 1974).

         Comparison of the disposition of SOIB in rats, dogs and monkeys
    receiving the same single, oral dose (200 mg/kg bw), showed that the
    three species excreted similar amounts of the administered compound
    in the faeces and that this was the major route for excretion of
    SOIB.  However, the three species differed in the disposition of
    absorbed SOIB.  Measurement of biliary excretion indicated that the
    dog excreted substantial amounts of SOIB by this route (3-10% of the
    administered dose) compared with rats and monkeys (<0.2% of the
    administered dose).  In the rat, the preferred route of elimination
    of absorbed SOIB was through expired CO2, representing 3-15% of
    the dose; CO2 represented 0.1-1.7% of the dose in dogs and
    monkeys.  The authors conclude that the virtual absence of
    radioactivity in the blood, urine, expired CO2 and bile of the
    monkey suggests that this species did not readily absorb SOIB. 
    Chromatographic analysis of the faecal metabolites of SOIB indicated
    that this compound was hydrolyzed to a different extent in the gut
    of the rat, dog and monkey with the most extensive hydrolysis
    occurring in the rat, less extensive in the dog and little
    intestinal metabolism in the monkey (Noker  et al. 1986).

    2.1.2  Biotransformation

         The bile ducts of 3 rats and 1 dog were cannulated and the bile
    was collected following single  per os doses of 14C-SAIB.  The
    rats eliminated 4.5% of the administered dose in the bile within 15
    hours of dosing.  Chromatographic separation of the metabolites
    present in the bile showed that they had properties similar to
    sucrose or sucrose with few acyl groups attached.  In the case of
    the dog, which was subjected to 3 separate trials, about 6% of the
    dose was eliminated in the bile within 15 hours of dosing. 
    Separation of the metabolites showed the presence of SAIB or highly
    acylated sucrose (Reynolds  et al. 1975).

         Homogenates of the liver and small intestinal mucosa of rats
    prepared in Krebs-Ringer phosphate buffer (pH 7.4) were incubated
    with 14C-SAIB.  At 0, 1, 2, and 4 hours, samples were removed and
    assayed for metabolites.  The rate and extent of hydrolysis of SAIB
    by liver homogenates was less than that of the intestinal mucosa,
    and the rate and extent of hydrolysis decreased with increasing
    concentrations of SAIB.  In another experiment, 14C-labelled SAIB
    was incubated under anaerobic conditions with preparations derived
    from the contents of 3 regions of the rat gut, namely, stomach,
    small intestine and caecum.  Preparations from the proximal region
    of the small intestine showed the greatest hydrolytic activity.  The
    hydrolytic activity of the caecal contents was less than that of the
    small intestine, and the stomach contents showed no hydrolytic
    activity.  An  ex vivo study of the disappearance of radioactivity
    from loops of the small intestine of rats after introduction of
    14C-sucrose and 14C-SAIB showed that sucrose was rapidly cleared
    from the intestine, whereas the rate of removal of SAIB activity was
    very slow, less than 13% in 1 hour.  When 14C-SAIB was incubated
    with human faecal homogenates, 40% was hydrolyzed in a 16-hour
    period, with less than 2% completely hydrolyzed to sucrose. 
    Hydrolysis of SAIB by suspensions of bacteria isolated from human
    faeces was even less than that of the faecal suspensions (Phillips
     et al. 1976).

         Dogs and rats received a single dose of 14C-SAIB [not
    specified in previous monograph].  The rats eliminated 7-10% of the
    dose in the urine in 30-46 hours and the dogs, 2.8-5.2% of the dose
    in the urine in 29-30 hours.  Size exclusion chromatography of the
    dog and rat urine showed that 14C-labelled molecules larger than
    sucrose were not present to any significant extent.  The nature of
    the metabolites was not determined, although sucrose, glucose and
    fructose appeared to be absent.  A male subject was given a single
    dose of 14C-SAIB at a dose level of 1.18 mg/kg bw.  Samples of
    urine were collected before dosing and at 0 and 6.2 hours after
    dosing, and subjected to various chromatographic procedures. 
    Glucose, fructose and the esters of fructose and sucrose were not
    present in the urine.  Two unidentified peaks were considered to be
    the principal metabolites of SAIB (Reynolds and Zeigler 1977).

    2.2  Toxicological studies

    2.2.1  Acute toxicity studies

         The results of acute toxicity studies with sucrose acetate
    isobutyrate are summarized in Table 1.

    Table 1. Results of acute toxicity studies with sucrose acetate
             isobutyrate.

                                                                

    Animal     Route     LD50        Reference
                       (g/kg bw)

                                                                

    Rat        Oral       >5.0       Fassett and Reynolds 1962;
                                     Reynolds 1972a
                                                                

    2.2.2  Short-term toxicity studies

    2.2.2.1  Mice

         Five groups of B6C3F1/CrlBR mice (10/sex/goup) received
    approximately 0, 0.625, 1.25, 2.5 or 5.0 g SAIB/kg bw/day in the
    diet for 4 weeks.  Body weights, food consumption and physical
    examinations were recorded at initiation of treatment and weekly
    during the study.  Feeding of SAIB at these doses for 4 weeks had no
    effect on the biological performance of the treated animals.  No
    treatment-related observations were noted at the terminal necropsy
    (MacKenzie 1987).

    2.2.2.2  Rats

         A three-week feeding study was conducted in which groups of 30
    Sprague-Dawley rats (15/sex/group) were fed 0, 5 000 or 50 000 ppm
    SAIB in the diet.  Five rats/sex/group were sacrificed after 1, 2
    and 3 weeks of treatment.  Twice weekly determinations of body
    weight and food consumption indicated no adverse effect of treatment
    on these parameters.  Daily examination of the rats during the first
    week revealed a high incidence of respiratory disease which was not
    related to treatment;  no animals died.  Gross necropsy at sacrifice
    did not reveal any treatment-related changes.  Absolute and relative
    liver weights were comparable between control and treated groups
    (Procter and Chappel 1970a).

         In a series of studies, Sprague-Dawley rats were divided into
    14 treatment groups of 10 animals/sex/group and fed diets containing
    SAIB at dietary levels of 1.0, 2.0 and 4.0% (w/w) supplemented with


    5% corn oil (w/w).  The groups were fed the test diets for 28 or 56
    days continuously or for 28 days followed or preceded by 28 days on
    control diet.  Two groups were fed the control diet containing corn
    oil only for 28 or 56 days continuously.  At the termination of the
    study, animals were sacrificed and blood collected for determination
    of serum alkaline phosphatase (SAP), ornithine carbamyl transferase
    (OCT), blood urea nitrogen (BUN), triglyceride, cholesterol and
    glucose.  The animals were autopsied, examined grossly, and absolute
    and relative liver weights were determined.  Liver microsomal enzyme
    activity (p-nitroanisole demethylase), glucose-6-phosphatase and
    bilirubin--D-glucuronyl transferase were determined and the liver
    was histologically examined.  Weight gain and feed consumption of
    test and control groups were similar.  There were no significant
    changes in the serum chemistry of the test animals.  Gross pathology
    at autopsy was negative and liver weights (absolute and relative)
    were similar for test and control groups.   Microsomal enzyme
    activity was similar for test and control animals, with the
    exception that glucose-6-phosphatase activity was reduced in male
    rats on the 4% SAIB diet (Krasavage and Terhaar 1971b; Krasavage
     et al., 1973).

         Groups of 50 Holtzman albino rats, 25/sex/group, were
    maintained on diets containing 0, 1.0 or 5.0% SAIB (w/w) for a
    period of 95 days.  Haematological studies consisting of Hb, Hct and
    total and differential WBC counts were carried out at days 24, 52
    and 87 of the study.  Body weight and food intake were determined
    weekly.  The animals were necropsied on day 95 and liver and kidney
    weights recorded and a complete histological study made of 15
    tissues and organs, including the liver, stomach and small
    intestine.  There was a slight reduction in weight gain in the males
    fed 5% SAIB and a slight increase in the absolute and relative liver
    weight of females fed 5% SAIB.  No compound-related
    histopathological changes were observed (Fassett  et al., 1962).

         Four groups of 20 Sprague-Dawley rats (10 males, 10 females; 
    body weight 85-100 g), were maintained on diets for 13 weeks which
    contained 0, 0.30, 1.80 or 9.12% SAIB dissolved in vegetable oil, to
    a final concentration of 9.3% oil in the diet.  Body weights were
    determined weekly.  Prior to sacrifice at 13 weeks, blood samples
    were taken and Hb content and total and differential WBC count were
    determined.  At autopsy, absolute and relative organ weights were
    recorded for liver, kidneys, lungs, testes, spleen and heart and a
    microscopic examination was made of 10 tissues and organs including
    the liver.  At the highest dose level there was occasional
    diarrhoea.  However, there were no significant differences in weight
    gain between control and test animals.  Organ weight, blood
    chemistry and histopathology were similar in all groups and showed
    no compound-related effects (Hint, 1964).

         Groups of 80 rats (Sprague-Dawley), 40/sex/group, were
    maintained on diets containing 0, 2.5, 5.0 or 10% SAIB.  A positive
    control group for the study of liver enlargement and microsomal
    enzyme induction received phenobarbital daily by gavage at a dose
    equivalent to 100 mg/kg bw.  Half of each group received treatment
    for 6 weeks, and the other half for 12 weeks.  Following 6 and 12
    weeks on the test diet, one subgroup (10 rats/sex/group) was
    subjected to the Zoxazolamine muscle relaxant test and retested 4
    weeks after removal from treatment.  The other subgroup (10
    rats/sex/group) was subjected to extensive histological and
    biochemical tests at the end of 6 or 12 weeks, which included serum
    OCT and protein, glycogen, carboxylesterase, lipid and water of the
    liver.  In addition, urinary excretion of ascorbic acid was measured
    at weekly intervals during treatment.  At autopsy, absolute and
    relative organ weights of the adrenals, heart, kidney and liver were
    recorded for test and control animals for both subgroups.

         Dietary SAIB had no significant effect on the weight gain of
    test animals except at the low dose (2.5%) level, where there was
    slight decrease in weight gain of males after 6 weeks and in both
    sexes after 12 weeks.  In general, food consumption in the SAIB
    groups was not affected.  The SAIB-treated rats did not differ from
    negative controls in their response to the Zoxazolamine muscle
    relaxant challenge or in urinary excretion of ascorbic acid.  In
    contrast, in the phenobarbital-treated rats, the response to
    Zoxazolamine was markedly reduced and urinary excretion of ascorbic
    acid showed a prolonged and marked elevation.  On this basis, the
    authors concluded that induction of microsomal enzymes did not occur
    in SAIB-treated rats.  There were no significant compound-related
    effects in the organ weights, gross pathology or histopathology in
    the SAIB-treated animals.  The biochemical studies of SAIB-fed
    animals showed significantly increased glycogen and water content in
    the livers of the 10% males and females but no increase in hepatic
    carboxylesterase levels.  In contrast, the animals which had been
    administered phenobarbital had enlarged livers and demonstrated a
    significant reduction in glycogen and water content, an increase in
    lipid content, and a marked increase in carboxylesterase activity of
    the liver (Procter  et al., 1971a).

         Groups of 20 male and 20 female F-344 rats were fed diets which
    provided doses of 0, 0.5, 1 or 2 g SAIB/kg bw/day for 52 weeks. 
    Individual body weights and food consumption were recorded weekly. 
    Ophthalmoscopic examinations were performed on all animals at
    initiation, 6 months and 12 months; a battery of standard
    haematology, clinical chemistry and urinalysis parameters were
    measured at 6 and 12 months.  A bromosulfophthalein (BSP) clearance
    test was performed on all animals in the control and high-dose
    groups during weeks 23 and 48.  No information on the conduct of the
    BSP clearance test was supplied ( i.e. dose of BSP, clearance times
    used).  All surviving animals were sacrificed after 52 weeks of
    treatment and the organ weights for heart, kidneys, liver, gonads

    and brain recorded.  Histopathological examination was conducted on
    kidney, liver, lung and gross lesions from all animals in all dose
    groups and on 32 additional tissues, including the common bile duct
    and organs of the GI tract, from all control and high-dose animals. 
    Samples of the liver from 3 control and 3 high-dose animals were
    also examined by electron microscopy.

         Treatment with SAIB did not affect body weight gain, food
    consumption or the general health of the animals.  In addition,
    results from measurement of haematology, clinical chemistry and
    urinalysis parameters did not suggest adverse treatment-related
    effects.  Absolute, relative-to-brain or relative-to-body organ
    weights were not affected and no unusual histopathological
    observations were noted.  Ultrastructural examination of livers
    failed to reveal any change in liver cells or in bile canaliculi and
    sinusoidal linings as a result of treatment with SAIB.  A NOEL of
    2 g/kg bw/day was assigned for this study (MacKenzie 1990a).

    2.2.2.3  Dogs

         Three test groups of 8 pure-bred beagle dogs (4 males, 4
    females), were maintained on diets containing 0.2, 0.6 and 2.0% SAIB
    dissolved in cottonseed oil for a period of 90 days.  The control
    group consisted of 12 pure-bred beagles (6 males, 6 females).  The
    total fat content of the diets was adjusted to 12% by addition of
    cottonseed oil.  Physical examinations and clinical studies were
    made twice prior to commencement of the study and at week 12.  The
    clinical studies included measurement of haemoglobin concentration,
    haematocrit, total and differential WBC count, blood glucose, BUN,
    SAP and LDH, and standard urinary parameters.  Neurological reflexes
    were tested and body weight and food intake recorded weekly.  At the
    termination of the study (end of twelfth week), all dogs were
    sacrificed and autopsied.  Absolute and relative organ weights were
    determined for liver, kidneys, spleen, gonads, adrenals, pituitary
    and brain.  Twenty-three tissues, including the liver, gall bladder
    and small and large intestines from dogs in the control and 2%
    groups were examined microscopically.  The liver and kidneys of dogs
    in the 0.2 and 0.6% SAIB groups were also examined microscopically.

         There was no significant compound-related effect on food intake
    or weight gain.  Haematological and urine parameters of test animals
    and controls were comparable and within normal values.  Serum
    chemistry indicated a significant increase in SAP activity of both
    male and female dogs in the 2% group (approximately two times
    increase over pretreatment values).  At autopsy there was a marked,
    dose-related increase in relative liver weights in the 0.6% and 2%
    groups of both sexes when compared with controls; all other organ
    weights were normal.  No compound-related histopathology was
    observed (Morgareidge, 1965).

         In another study, groups of 12 beagle dogs (6/sex/group) were
    fed diets containing SAIB at 0, 0.5, 1.0, 2.0 and 4.0% for a period
    of 12 weeks.  Test animals in the 4.0% group were maintained for a
    further 3 weeks on an SAIB-free diet.  Body weight and food intake
    were determined during the course of the study.  Fasting blood
    samples and urine samples were obtained at weeks 4, 8 and 12 and
    standard haematological, biochemical and urinalysis tests were
    performed.  At these intervals, 30-minute bromosulfophthalein (BSP)
    and phenosulfophthalein (PSP) retentions were measured.  BSP and
    indocyanine green (ICG) plasma disappearance curves were determined
    at week 12 for male dogs in the 0 and 4.0% groups.  BSP clearance
    was measured in the 4.0% group during the 3-week withdrawal period. 
    At the end of the test period, the animals were sacrificed, and
    following completion of gross pathological examination, absolute and
    relative organ weights were determined for the brain, heart, liver,
    lung, kidneys, adrenals, gonads, prostate, uterus, pituitary, spleen
    and thyroid.  A microscopic examination was made of samples of 6
    tissues including the liver and small and large intestines. 
    Histochemical studies were carried out on liver sections of dogs
    from the 0.5, 1 and 2% groups, and included evaluation of succinate
    dehydrogenase, phosphorylase, glucose-6-phosphate dehydrogenase,
    glycogen, acid phosphatase, alkaline phosphatase, adenosine
    triphosphatase, and use of Masson's trichrome stain.  Additional
    samples of liver from test animals (not including the 4% groups)
    were analyzed for protein, glycogen, lipid and water, and
    carboxylesterase activity.  Serum OCT was measured in serum samples
    obtained terminally.  Electron microscopic studies were carried out
    on liver samples from animals in all groups except the 4.0% group.

         Daily clinical observation revealed no change in the treated
    dogs.  Growth and food intake appeared normal in all groups.  Urine
    and haematological analyses were similar in test and control groups
    and of the biochemical parameters, only SAP values demonstrated an
    increase in the treated animals which was directly related to dose
    level and duration of exposure.  Marked bromosulfophthalein (BSP)
    retention occurred among all test animals during the experimental
    period, but the magnitude of the response was not dose-related.  The
    marked increase in BSP retention in the 4% group was reversible
    following withdrawal of SAIB from the diet for 3 weeks.  Indocyanine
    green clearance rates were reduced in a manner paralleling the
    changes observed in the BSP tests.  Male dogs treated with SAIB
    showed a dose-related increase in absolute and relative liver weight
    which was reversible following 3 weeks on a SAIB-free diet.  No
    liver enlargement was observed in the female dogs.  Histochemical
    studies of liver sections did not reveal any changes in the
    hepatocytes;  however, there was a marked increase in enzyme
    activity (alkaline phosphatase, adenosine triphosphatase and
    glucose-6-phosphate dehydrogenase) of the bile canaliculi of treated
    animals when compared with controls.  There was a slight but
    statistically significant reduction of protein content and a slight
    increase in glycogen in the liver.  Liver lipid was slightly

    increased at the 2% level.  An increase in liver carboxylesterase
    was observed in the test groups, particularly in the males, but the
    effect was not dose-related.  Serum OCT values assayed in terminal
    blood samples were similar for test and control animals and within
    normal range.  Light microscopic examination of the liver from
    treated males showed hepatocellular hypertrophy, dilatation of the
    bile canaliculi, and an increase in the number of bile pigment
    granules.  Electron microscopic evaluation of the hepatocytes of
    treated dogs showed various changes, the most consistent being an
    increase in smooth endoplasmic reticulum (SER).  The effect was
    observed in both treated males and females, but the effect was most
    pronounced in the males.  The structural changes found in the bile
    canaliculi and the pericanalicular cytoplasmic areas included
    moderate dilatation of the canaliculi, pronounced microvillous
    pattern, prominent Golgi bodies and an increased number of
    microbodies in the intracellular pigment granules.  Since effects of
    the test material on the liver were observed at all dose levels, a
    NOEL was not observed for this study (Procter  et al., 1970).

         In a parallel study, a group of 8 beagle dogs (4/sex/group) was
    fed SAIB at a dietary level of 2.0% for 12 weeks and then maintained
    for 6 weeks on an SAIB-free diet prior to sacrifice.  SAIB caused a
    slight weight depression that was reversible upon removal of SAIB
    from the diet.  The effect of SAIB on two indicators of liver
    function, SAP activity and plasma BSP clearance was completely
    reversed following the 6-week withdrawal period.  At autopsy, the
    liver enlargement reported in organ weight studies, the high
    activity of alkaline phosphatase, adenosine triphosphatase and
    glucose-6-phosphate dehydrogenase in bile canaliculi reported in the
    histochemical studies, and the effect of SAIB administration on
    liver carboxylesterase activity were fully reversible following this
    withdrawal period.  Electron microscopic examination of the liver
    indicated that the cellular morphology was completely normal
    following removal of the SAIB from the diet (Procter  et al.,
    1971b;  Procter  et al., 1973).

         Six male beagle dogs, approximately 6 years old, were fed a
    control diet containing 5% (w/w) corn oil for 3 weeks and then an
    experimental diet containing 5% SAIB for 28 days.  The dogs were
    returned to control diet for the next 57 days.  Haematocrit,
    haemoglobin, total and differential WBC counts, ASAT, blood glucose,
    BUN, serum protein, SAP, OCT, and triglyceride and cholesterol
    determinations were made twice prior to and at weekly intervals
    during the feeding study.  Four of the dogs then received one day's
    allotment of the SAIB diet, and ICG plasma clearance rates and SAP
    were determined after 24 and 48 hours.  The study was terminated 3
    days later.  At the termination of the study, all dogs were
    sacrificed, absolute and relative liver and kidney weights
    determined, and 23 tissues and organs, including liver, gall bladder
    and organs of the GI tract, examined microscopically.  Dogs on diets
    containing 5% SAIB showed a moderate increase in SAP and a

    prolongation of ICG plasma clearance by the liver.  Within 5 weeks
    of withdrawal of SAIB from the diet, SAP activity was near normal. 
    The ICG clearance rate appeared within normal range 2 weeks after
    withdrawal of SAIB from the diet.  After receiving control diet for
    8 weeks, the 4 dogs returned to SAIB-containing diets for 24 hours
    showed a significant slowing of ICG clearance rate, but SAP did not
    appear to be increased.  All other parameters measured in test and
    control animals were similar (Krasavage and Terhaar, 1971a; 
    Krasavage  et al. 1973).

         In another study, groups of 5 male beagle dogs (11-13 months of
    age) were fed diets containing 5.0% SAIB plus 5% corn oil, or corn
    oil alone for 91 days.  Physical appearance, behaviour, food
    consumption and body weight were determined daily throughout the
    study.  Indocyanine green plasma clearance rates were determined at
    3-week intervals.  Serum bilirubin was measured at week 7 of the
    study and haematological and blood chemistry (haematocrit,
    haemoglobin, BUN, serum protein, SAP and OCT, triglyceride and
    cholesterol) studies were carried out at the termination of the
    study.  All dogs were autopsied at the termination of the study,
    liver and kidney weights recorded, and all tissues (not specified)
    examined microscopically.  Livers were analyzed for glycogen,
    protein and phospholipid content, and samples were assayed for
    microsomal enzyme activity (p-nitroanisole demethylase), and for
    glucose-6-phosphatase and bilirubin--D-glycuranyl transferase
    activities.  Liver, kidney, bone, bile and scrapings of the
    intestinal mucosa were analyzed for alkaline phosphatase activity. 
    Dogs fed SAIB showed a slight increase in SAP, as well as a
    prolonged indocyanine green clearance time, increased relative and
    absolute liver weight.  Liver glycogen and phospholipid content were
    increased while liver protein was decreased.  Disk electrophoresis
    and isoenzyme inactivation studies of tissue alkaline phosphatase
    indicated that the elevation of SAP was related to the liver
    isoenzyme.  The liver content of alkaline phosphatase in SAIB-fed
    animals was twice that of controls.  All other parameters studied
    were similar in test and control animals (Krasavage and Terhaar,
    1971c;  Krasavage  et al., 1973).

    2.2.2.4  Monkeys

         Two male and two female  Cynomolgus monkeys received SAIB by
    intubation in an orange juice vehicle over a period of 14 days. 
    Dosing started at 1.25 g/kg bw/dy and increased by a factor of 2
    with a 72-h rest period between doses, up to a dose of 20 g/kg bw/d. 
    The animals were observed daily for signs of adverse effects.  Body
    weight and food consumption were recorded daily.  Seventy-two hours
    after the last dose, the animals were sacrificed and complete gross
    postmortem examinations were conducted.  No deaths occurred during
    the study.  Moderate amounts of yellow, watery emesis and/or
    yellow/tan watery stools were observed in some males and some
    females 1 to 5 hours after dosing.  Twenty-four hours after dosing,

    all the animals passed moderate amounts of loose, tan stools.  Gross
    postmortem examinations did not reveal any changes which could be
    attributed to an effect of treatment (Tierney and Rinehart, 1979).

         Twelve  Cynomolgus monkeys were assigned to six goups
    (1/sex/group) in a range-finding study in which doses of 0, 0.5,
    1.0, 2.0, 5.0 and 10.0 g SAIB/kg bw/day were administered by gavage
    in orange juice concentrate for 15 consecutive days.  Physical
    observations, body weight and food consumption were recorded daily. 
    Thirty-minute BSP retention was determined pretest and prior to
    termination.  Following gross necropsy, adrenals, heart, kidneys,
    liver and all gross lesions were preserved for histopathological
    examination.  In addition, two sections of liver from control and
    high-dose monkeys were examined by electron microscopy.  Treatment
    with SAIB for 15 days had no effect on body weight or food
    consumption.  Gross postmortem examinations and light microscopic
    evaluations did not reveal evidence of changes attributable to
    treatment.  Electron microscopy of liver samples from the high-dose
    male and female revealed glycogen aggregation surrounded by smooth
    endoplasmic reticulum in hepatocytes which did not represent a
    significant alteration in ultrastructural organization (Tierney and
    Rinehart, 1980a).

         In another study, the evaluation of selected clinical chemical
    parameters was conducted in eight  Cynomolgus monkeys (1/sex/group)
    fed doses of 0, 2.0, 5.0 and 10.0 g SAIB/kg bw/day under the same
    conditions as in the previous study.  Blood samples were collected
    pretest and at termination of the study for measurement of ASAT,
    ALAT, SAP, BUN, total protein, albumin, globulin, creatinine, total
    bilirubin and bromosulfophthalein retention.  Although plasma levels
    of BSP were presented and the time for clearance indicated, no other
    details of the clearance test ( e.g. dose of BSP) were provided. 
    Gross necropsy was conducted at sacrifice.  Treatment with SAIB had
    no effect on body weight or food consumption.  There were no
    differences in the clinical chemistry parameters, including
    bromosulfophthalein retention, which could be attributed to
    treatment (Tierney and Rinehart, 1980b).

         In a 4-week oral toxicity study with  Cynomolgus monkeys,
    doses of 0, 500, 1 450 and 2 400 mg SAIB/kg bw/day were administered
    by corn oil gavage to 4 groups of 1 monkey/sex/group.  Clinical
    observations were made twice daily and included monitoring of
    inappetence.  Body weights were determined weekly and a complete
    physical examination was conducted prior to treatment and at the end
    of 4 weeks.  A standard set of haematology and clinical chemistry
    parameters (including gamma-glutamyl transpeptidase, SAP, OCT and
    30-minute BSP clearance) were measured from blood samples collected
    pretest and at four weeks.  Gross necropsy was conducted at
    sacrifice.  Inappetence was noted occasionally throughout the study
    for most monkeys, although it was observed on 13 separate days in
    the high-dose female.  Consequently, this animal experienced a 12%

    weight loss over the course of the study.  Body weight gains of the
    other animals were comparable.  No abnormalities related to
    treatment were detected from the physical examinations.  The results
    of haematological and clinical chemistry tests did not indicate an
    effect of treatment although lowered serum phosphorous levels were
    detected in the high-dose female.  For BSP clearance, only semi-
    quantitative results were presented,  i.e. >95% clearance for all
    groups.  This could indicate that the dose used was too low to
    detect any changes within a standard 30 min. period.  The
    concentration of BSP in blood was not presented.  Gross necropsy did
    not reveal any unusual findings (Blair, 1986).

         Groups of 4 male and 4 female  Cynomolgus monkeys received
    doses of 0, 500, 1 450 or 2 400 mg SAIB/kg bw/day by corn oil gavage
    for 52 weeks.  Clinical observations, including inappetance, were
    made twice daily and body weights determined weekly.  Complete
    physical examinations and separate ophthalmoscopic examinations were
    conducted on all monkeys pretest and during months 3, 6, 9, and 12. 
    Blood samples for determination of a standard set of haematological
    and clinical chemistry parameters (including SAP, gamma-glutamyl
    transpeptidase, OCT, BSP clearance and bile acid analysis) were also
    collected at the same intervals.  At termination, gross necropsy was
    performed, selected organs were weighed, and 40 tissues and organs
    including liver, GI tract and gross lesions were subjected to
    histopathological examination.

         During the study a few animals had signs of slight anal
    staining and slightly soft stool.  However, there were no signs of
    inappetance or changes relating to administration of the test
    material, and none of the animals demonstrated body weight loss over
    the course of the study.  The physical and ophthalmoscopic
    examinations did not reveal any treatment-related abnormalities.  In
    addition, analysis of the haematological and clinical chemistry
    parameters obtained during the study indicated that no effect of
    treatment on these parameters was evident.  Semi-quantitative
    measurements only of BSP clearance were given and blood levels of
    BSP were not presented.  There were no unusual histopathological
    observations indicating an effect of treatment, including the liver. 
    Since no effects of treatment were observed, the NOEL was the
    highest dose tested, 2400 mg/kg bw/day (Blair, 1990).

    2.2.3  Long-term toxicity/carcinogenicity studies

    2.2.3.1  Mice

         A carcinogenicity study was conducted with B6C3F1 mice in
    which 5 groups of 50 mice/sex/group received 0.0, 0.0, 1.25, 2.5 or
    5.0 g SAIB/kg bw/day in the diet for 104 weeks.  Physical
    examination, body weight and food consumption data were collected
    weekly.  A standard set of haematology parameters was determined for
    15 mice/sex from one control group and from the high dose group at

    26, 52, 78 and 104 weeks of the study.  Necropsy was performed on
    all animals dying on test or sacrificed.  The weights of liver with
    gall bladder, lungs and kidneys were recorded for all animals
    sacrificed at 104 weeks.  Histopathology was carried out on lungs,
    liver, kidneys and gross lesions from all animals and on 44
    additional organs and tissues, including the GI tract, from animals
    that died on test and the control and high-dose animals from the
    terminal sacrifice.

         Survival of the mice from all groups in this study ranged from
    66 to 80%.  No treatment-related effects on body weight gain were
    noted.  Food consumption was elevated in both male and female mice
    receiving SAIB in the diet.  The difference was frequently
    statistically significant in the high-dose males.  There were no
    treatment-related differences in the haematology parameters.  A
    dose-related decrease was apparent in the absolute weights of the
    kidneys of male mice which was statistically significant at the mid
    and high doses.  The relative kidney weights were also lower than
    controls but the magnitude of the decrease was not related to dose. 
    No unusual histopathological results for the kidney were observed. 
    The authors concluded that this represented a NOEL of 2.5 g SAIB/kg
    bw/day (mid dose) for the male mouse.  There was an increased
    incidence of hyperplasia of the perivascular and peribronchial
    lymphoid tissue of the lung in treated female mice which lacked
    dose-relationship;  the result was not considered by the authors to
    be toxicologically significant.  There were no treatment-related
    increases in the incidence of any tumour type.  Based on the reduced
    kidney weights in the two top doses, a NOEL of 1.25 g/kg bw/day was
    considered appropriate for this study.  The NOAEL was the highest
    dose tested, 5.0 g/kg bw/day (MacKenzie 1990c).

    2.2.3.2  Rats

         Groups of 20 (10 male, 10 female) Sprague-Dawley rats were
    maintained on diets containing 0, 0.38 or 9.38% (w/w) SAIB for 104
    weeks.  During this period the rats were bred on 3 successive
    occasions.  Body weight and food intake were measured weekly.  All
    animals dying during the test period and those sacrificed at 104
    weeks were autopsied.  Relative and absolute organ weights were
    determined for heart, kidneys, liver, lungs, ovaries, spleen and
    testes.  Histological examinations were made of 18 tissues,
    including the liver, stomach and ileum, from rats of the control and
    9.38% SAIB groups.

         Feeding SAIB did not increase the overall number of mortalities
    (15/20 in control, 13/20 in 0.38%  and 14/22 in 9.38% groups) even
    though 4 males in the 9.38% SAIB group died during the first 10
    weeks.  Autopsy revealed massive haemorrhages at multiple sites in
    each case.  Subsequent measurement of systolic blood pressure in
    surviving males failed to demonstrate any inter-group difference. 
    There were some differences in food intake and body weight between

    the various groups at various stages of the study.  At the end of
    the first year there were no significant differences in body weights
    of rats from the various groups.  During the second year, however,
    male survivors receiving treatment at either dose weighed less than
    the respective controls.  There appeared to be a dose-related
    increase in the absolute and relative kidneys weights of both the
    male and female rats.  Due to the disparities in body weight of
    treated and control males, and the small number surviving (2 or 3
    animals/group), no meaningful conclusions could be drawn from the
    organ weight data for male groups at the termination of the study. 
    Histological studies did not reveal any compound-related lesions
    (Harper  et al., 1966).

         A carcinogenicity study was conducted with F-344 rats in which
    5 groups of 50 rats/sex/group received 0.0, 0.0, 0.5, 1.0 or 2.0 g
    SAIB/kg bw/day in the diet for 104 weeks.  Physical examination,
    body weight and food consumption data were recorded weekly.  RBC and
    total and differential WBC counts were performed on all rats prior
    to study initiation and on all surviving rats at termination. 
    Clinical chemistry parameters were not measured.  Necropsy was
    performed on all animals dying on test or sacrificed.  Organ weights
    were determined for brain, heart, liver, kidneys and gonads for all
    animals sacrificed at 104 weeks.  Histopathology was carried out on
    lungs, liver, kidneys and gross lesions from all animals and on 44
    additional organs and tissues, including the organs of the GI tract,
    from animals that died on test and from the control and high-dose
    animals at termination.

         The health of the treated and control animals was comparable
    throughout the study and survival rates at 104 weeks were similar. 
    No effect on body weight was seen in the treated male groups; in
    females, a small but significant decrement was noted in the body
    weights of the high-dose group compared with control groups for the
    first 1 years.  Food consumption was not affected by treatment. 
    Treatment with SAIB had no effect on haematology, organ weights or
    macroscopic and microscopic examinations at termination of the
    study.  There were no treatment-related increases in the incidence
    of any tumour type.  The NOEL was 2 g/kg bw/day in this study
    (MacKenzie 1990b).

    2.2.4  Reproduction studies

    2.2.4.1  Rats

         Groups of 15 female and 5 male Holtzman rats, 60 days of age,
    were maintained on diets containing 0 or 5% SAIB.  These diets were
    fed to parents and their offspring throughout the study.  After 1
    month on the diet, the rats were regrouped, 1 male and 3
    females/cage.  Pregnant females were then housed separately.  The
    parameters recorded for assessing reproductive performance were
    length of gestation, number of young and live young, number of young

    weaned and average weight at weaning and post-weaning.  Fifty-one
    days after the last parturition, another mating was attempted. 
    Progeny of the first breeding (F1) were also bred.  At necropsy,
    liver and kidney weights were measured in both F0 and F1 parental
    animals, and 12 tissues, including liver and stomach, were examined
    microscopically.  Treatment with 5% SAIB did not affect the
    biological performance of the F0 generation.  The reproductive
    performance of the test parent generation resulting from the first
    breeding was equal to or superior to that of controls, based on the
    parameters measured.  At the second breeding, a somewhat lower
    percentage of pups from the treated groups was reared from birth to
    weaning compared to controls, and those surviving 2 weeks post-
    weaning weighed less than the controls.  The breeding of the F1
    generation appeared satisfactory.  Due to an outbreak of respiratory
    disease, many F1 parents and pups died during the test and none of
    the pups from the SAIB group survived post-weaning.  No differences
    in organ weights or histopathology were detected between treated and
    control groups (Fassett  et al., 1965).

         Groups of 20 Sprague-Dawley rats, 10/sex/group, age not
    indicated, were maintained on diets containing 0, 0.38 and 9.38% w/w
    SAIB for 5 weeks.  Pairs of rats from each dose group (10 pairs)
    were selected and caged together for 19 days, after which the male
    was removed.  Females were allowed to rear young to weaning at 21
    days.  Litters were weighed at days 1, 11 and 21 post-partum.  All
    pups were sacrificed at 21 days, sexed and examined for gross
    abnormalities.  The parent rats were bred 3 times during weeks 9-36
    of the study, each female receiving a different male at each mating. 
    Reproductive performance was based on number of pups born,
    conception rate, pups per litter, pups weaned, as well as the weight
    of pups on days 1, 11 and 21.  Reproductive performance as judged
    from the data presented was slightly better in the 0.38% group than
    in the control.  At the 9.38% level, fewer females became pregnant,
    fewer pups were born and fewer pups survived to weaning on the basis
    of the three breedings.  The observed effects could have been due to
    compromised nutritive value of the feed at this high level of
    inclusion.  Performance of the 0.38% group was comparable to
    controls (Harper  et al., 1966).

         A three-generation reproduction study was conducted with groups
    of 30 male and 30 female weanling rats which received 0, 0.5, 1.0 or
    2.0 g SAIB/kg bw/day in the diet for 10 weeks (males) or 2 weeks
    (females) prior to mating.  These F0 animals were mated for 21 days
    on a one-to-one basis to produce the F1 litters.  From these
    litters, groups of 30 rats/sex were selected randomly to continue
    with the same dosage of SAIB in the diet, and to be mated 10 weeks
    after weaning to produce the F2a and subsequently, the F2b litters. 
    The F2a litters were mated in a similar fashion to produce the F3
    litters and the F2b litters were used for teratologic evaluation
    (see Section 2.2.5.1).  The study was completed with the necropsy of
    the F2a females on Day 14 of the F3 gestation.  Rats received the

    test diet continuously throughout the premating, mating, gestation,
    lactation and weaning stages of the study.  Body weight and food
    consumption were measured weekly throughout the study with the
    exception of the mating periods and the 2-week rest period between
    the F2a and F2b litters.  The following reproductive parameters
    were assessed for the F1 and F2a litters: mating index, male and
    female fertility indices, gestation index, numbers of live- and
    stillborn pups, and pup weights, survival and sex ratio on days 0, 4
    and 28 of lactation.  Male and female fertility indices and numbers
    of corpora lutea and implantations were recorded for the F3
    litters.  All F0 and F1 adult male and female rats were necropsied
    with particular attention to reproductive organs and macroscopic
    lesions, the males after completion of parturition and the females
    after completion of weaning.  There were no consistent statistically
    significant differences in body weight gains, although body weights
    of the mid- and high-dose F0 females were lower than controls
    during the first part of the lactation period, and slightly lower
    food consumption was noted for the F2a males and females during the
    premating period.  No treatment-related effects were noted on
    fertility, gestation or survival indices for any of the generations
    (MacKenzie 1990d).  The NOEL was the highest dose tested, 2.0 g/kg
    bw/day.

    2.2.5  Special studies on teratogenicity

    2.2.5.1  Rats

         The F2b litters from the reproduction study described above
    were subjected to teratologic evaluation.  Groups of 30 male and 30
    female F-344 rats from the F1 generation were subjected to
     in utero and lifetime exposure to 0, 0.5, 1.0, and 2.0 g SAIB/kg
    bw/day in the diet.  The animals were bred on a one-to-one basis 2
    weeks after completion of weaning of the F2a litters.  Vaginal
    smears were taken daily and the presence of a copulatory plug or
    sperm in the vaginal smear was taken as positive evidence of mating
    and counted as Day 0 of gestation.  The F1 dams were sacrificed on
    Day 20 of gestation and examined for the number and distribution of
    fetuses, the number of fetuses undergoing resorption and the number
    of corpora lutea.  Live fetuses were removed from the uterus,
    weighed, sexed and examined for gross abnormalities.  Approximately
    one-half of the pups from each litter were examined for soft tissue
    abnormalities and the remainder were examined for skeletal
    abnormalities.  Weekly measurement of body weight and food
    consumption in the maternal animals did not reveal any effect of
    treatment on these parameters.  Treatment with SAIB also did not
    affect mating indices, male fertility indices, female fertility
    indices, the number of corpora lutea or implantations, implantation
    efficiency, uterine weights, the number of live fetuses, early
    resorptions, late resorptions, sex ratios or fetal weights. 
    External, skeletal and soft-tissue fetal examinations also did not
    reveal any treatment-related effects (MacKenzie 1990d).

    2.2.5.2  Rabbits

         Groups of 16 inseminated New Zealand white rabbits each
    received 0, 500, 850 or 1200 mg SAIB/kg bw/day orally by corn oil
    gavage in two doses on day 7 to 19 of gestation (the day of
    insemination was counted as day 0).  On day 29 of gestation, the
    dams were sacrificed and the pups delivered by Caesarean section. 
    The number and location of viable and nonviable fetuses, early and
    late resorptions and the number of total implantations and corpora
    lutea were recorded.  Each fetus was weighed and examined for
    external malformations, then dissected and examined for visceral
    malformations, and the carcass prepared for subsequent skeletal
    examination.  Laboured respiration was noted in several of the does
    from each of the treatment groups during the last few days of the
    treatment period but in none of the control animals.  The authors
    attributed this to tracheal irritation from the test material. 
    There were no treatment-related effects on body weight gain or food
    consumption measured on gestation days 0, 7, 13, 20 and 29, nor did
    macroscopic examination of the does following sacrifice reveal signs
    of maternotoxicity resulting from administration of the test
    material.  The reproductive parameters and the fetal examinations
    did not reveal any embryotoxic or teratogenic effects attributable
    to treatment (Schardein, 1988).

    2.2.6  Special studies on genotoxicity

         The results of genotoxicity studies with sucrose acetate
    isobutyrate are summarized in Table 2.

    2.2.7  Special studies on liver function

    2.2.7.1  Rats

         Groups of 5 male Wistar rats were maintained on diets
    containing 4% SAIB for 7 days.  Bromosulfophthalein clearance was
    measured at 0 (pretreatment) and 24 and 48 hours following
    withdrawal from the treated feed.  SAIB had no effect on
    bromosulfophthalein clearance (Procter and Chappel, 1971).

         Groups of male rats (Sprague-Dawley) (group size not specified)
    were fed diets containing 4% SAIB and corn oil, or 5% corn oil. 
    Indocyanine green (ICG) clearance was determined on at least 2 rats
    randomly selected from each group on days 1, 3, 5, 8, 10, 22, 26 and
    36 of the study.  The ICG plasma clearance rates in rats from the
    SAIB group was not significantly different from controls (Krasavage
    and Terhaar, 1972;  Krasavage  et al., 1973).


        Table 2.  Results of genotoxicity studies with sucrose acetate
              isobutyrate.

                                                                                                                                    

    Test System             Test Object                      Concentration of SAIB      Results        Reference

                                                                                                                                    

    Ames test1              S. typhimurium TA1535,           10-2 000 g/plate          Negative       Jagannath & Brusick 1978
                            TA1537, TA1538, TA98,
                            TA100, S. cerevisiae D4

    Ames test1              S. typhimurium TA98, TA100       100-10 000 g/plate        Negative       Bonin & Baker 1980

    Ames test1              S. typhimurium TA98, TA100,      333-10 000 g/plate        Negative       Lawlor & Valentine 1989
                            TA1535, TA1537, TA1538

    CHO/HGPRT forward       Chinese hamster ovary cells      10-1 000 g/ml             Negative       Young 1985
    mutation assay1

    Unscheduled DNA         Rat hepatocytes                  0.25-1 000 g/ml           Negative       Cifone 1985
    synthesis assay

    In vitro chromosomal    Chinese hamster ovary cells      200-2 000 g/ml            Negative       Ivett 1985
    aberration assay1

    Dominant lethal assay   Rats                             20, 200, 2 000 mg/kg bw    Negative2      Krasavage 1973
                                                                                                                                    

    1 Both with and without metabolic activation.
    2 Matings were conducted only every 2 weeks instead of every week.
    

    2.2.7.2  Dogs

         Two male and 2 female beagle dogs were fed a one day's dietary
    ration containing 0.1, 0.3 or 0.5% SAIB.  All 4 animals were tested
    for bromosulfophthalein clearance 24 hours after feeding of SAIB and
    again after 48 hours.  A rest period of 1 week was allowed between
    each dietary level.  No bromosulfophthalein retention occurred at
    the 0.1% dietary SAIB level; 0.3% and 0.5% SAIB resulted in distinct
    but reversible bromosulfophthalein retention (Procter and Chappel,
    1971).

         Two series of experiments were carried out with 14 young,
    adult, male beagle dogs.  In the first series, groups of 2 (control)
    or 3 (treated) dogs received a single dose of 2 g SAIB/kg bw or
    orange juice vehicle by gavage and 30-minute BSP clearance was
    measured 2, 4, 6, 10, 12, 18 or 24 hours later.  Compared with
    pre-treatment measurements, plasma BSP concentrations were increased
    at all post-treatment intervals, and were highest between 4 and 6
    hours.  Approximately 5 hours post-dosing was considered the maximal
    BSP retention time in the dog.  The second series of experiments was
    conducted to establish the range of doses of SAIB which produced
    increased BSP retention in the dog five hours after a single
    administration.  Fifteen-minute BSP retention values were increased
    7-10 fold with doses of 25 mg/kg bw to 2 g/kg bw.  No dose-response
    correlation was apparent.  At 5.0 mg/kg bw, only 1 of 3 dogs showed
    increased BSP retention and the authors considered this to be close
    to a no-effect dose.  Throughout the study, none of the dogs showed
    a marked change in body weight.  There were no significant changes
    in SAP values measured in blood samples at the same intervals as
    measurement of BSP clearance.  Changing the vehicle to corn oil in
    the last two studies of the second series of experiments eliminated
    the observations of vomiting and orange-coloured, loose stools which
    were common in the foregoing experiments (Dickie  et al. 1980a).

         Young, adult, male beagle dogs were tested for 15-minute BSP
    clearance and SAP levels 5 hours after a single oral administration
    of either sucrose hexaacetate diisobutyrate (SHADIB) or sucrose
    octaisobutyrate (SOIB) (constituent esters of SAIB) in a series of
    experiments.  The range of doses used was 100-1 000 mg/kg bw of
    SHADIB and 5-1 000 mg/kg bw SOIB.  In the first 3 experiments, 4
    treatment groups of 3 dogs and a vehcile control group of 2 dogs
    were used;  in the fourth experiment, 2 dose groups of 3 dogs and a
    vehicle control group of 1 dog were used.  Compared with
    pretreatment measurements, a single dose of SHADIB caused a
    significant increase (5-7 fold) in BSP retention at all doses
    tested.  SOIB administration also resulted in an increase of BSP
    retention of about 4-5 fold compared with pretreatment values at
    doses of 25 mg/kg bw and higher.  As in the previous experiment, no
    dose-response correlation was observed and mean BSP retention at
    5.0 mg/kg bw SOIB showed only a slight increase over control and
    pretreatment values.  Neither ester appeared to cause any gross

    clinical effects and neither affected SAP activity.  None of the
    dogs showed a marked change in body weight over the course of the
    study.  The observation of yellow-orange stools and vomiting was
    eliminated by changing the vehicle from orange juice to corn oil as
    in the previous experiment (Dickie  et al. 1980b).

    2.2.7.3  Monkeys

         Two groups of 3 male squirrel monkeys ( Saimiri sciureus)
    weighing approximately 1 kg, were fasted overnight and then received
    either SAIB (1 g in 2 ml cottonseed oil) or no treatment. 
    Twenty-four hours after treatment the monkeys were tested for
    bromosulfophthalein clearance.  Following a 7-day rest period, the
    treatment of the groups was reversed.  Clearance appeared normal in
    2/3 of the animals in each group (Procter and Chappel 1970b).

         The same experiment was repeated using doses of 2 g SAIB in
    4 ml cottonseed oil to deliver a dose of approximately 2 g/kg bw. 
    Unusually high plasma BSP levels were measured in 3 of the control
    animals, but these were considered by the authors to be technical
    errors since BSP clearance following treatment with SAIB was normal
    in all of the animals (Procter and Chappel, 1971).

         Thirty-minute BSP retention and SAP were measured in 10 male
     Cynomolgus monkeys 5 hours after a single oral dose of 5 g SAIB/kg
    bw, 5 g SOIB/kg bw or corn oil and compared with pretreatment values
    for these parameters.  Treatment had no effect on BSP retention time
    or SAP.  There were no unusual clinical observations or changes in
    body weight during the study.  It should be noted that the authors
    did not run a time series as in the corresponding dog experiment to
    determine the optimum interval for measurement of hepatic function
    following adminstration of the test material (Dickie  et al.
    1980c).

    2.3  Observations in humans

         Twenty subjects (10 males and 10 females) between 18 and 22
    years of age ingested a daily dose of SAIB at a level equivalent to
    10 mg/kg bw/dy for a period of 14 days.  The dose was taken as a
    bolus each morning.  The following blood parameters were measured
    prior to treatment and at days 7 and 18 of the study: ASAT, ALAT,
    SAP, serum bilirubin, total protein, albumin, uric acid, BUN,
    erythrocyte sedimentation rate, sodium, potassium, phosphorous,
    total CO2, cholesterol and glucose.  There were no significant
    differences in any parameters in any individual (Hensley 1975).

         In another 14-day study, 12 male and 12 female subjects were
    divided evenly by sex into 3 groups, receiving a carbonated drink
    only (controls), or a single daily dose of 7.0 or 20.0 mg SAIB/kg
    bw/day in a carbonated drink.  In addition, four men received 20 mg
    SAIB/kg bw/day for 1 or 3 days only in a pilot experiment to provide

    early evaluation of possible alterations in normal hepatic function. 
    The subjects were 21 to 42 years of age.  Blood was collected prior
    to testing and on days 7 and 14 for haematological (platelets, total
    and differential WBC count, ESR, Hct and Hb) and clinical chemistry
    (total protein, albumin, A/G ratio, calcium, cholesterol, glucose,
    BUN, uric acid total bilirubin, SAP, ASAT, ALAT, and LDH)
    parameters.  Standard urinalysis parameters were also recorded at
    these times.  A 45-minute BSP retention test (5 mg/kg bw BSP) was
    also conducted on all subjects prior to treatment and after
    completion of treatment.  Treatment with SAIB did not affect any of
    these parameters for any individual (Orr  et al. 1976).

         Twenty-seven adult subjects, 13 men and 14 women, between the
    ages of 18 to 55, received SAIB in an aqueous/orange juice emulsion
    daily for 14 days at a dose of 20 mg/kg bw.  In the 7 days prior to
    treatment, each subject acted as his/her own control by ingesting an
    orange juice beverage and placebo emulsion.  Blood samples were
    collected from each subject on days -6, 0, 7 and 14 of treatment for
    measurement of routine haematological and clinical chemistry
    parameters, including specific indicators of hepatobiliary function
    (SAP, ASAT, ALT, LDH, gamma-glutamyl transferase, total bilirubin,
    direct bilirubin, bile acids and serum proteins).  No treatment-
    related changes were detected in any of these parameters over the
    14-day dosing period (Chiang 1988).

    3.  COMMENTS

         Studies on the disposition of sucrose acetate isobutyrate in
    rats, dogs, and humans indicated that absorption from the
    gastrointestinal tract is delayed for several hours but that
    elimination is nearly complete by 4 to 5 days after ingestion. 
    Extensive metabolism of sucrose acetate isobutyrate occurred in the
    gastrointestinal tract, mainly in the small intestine, characterized
    by its de-esterification by non-specific esterases to partially
    acylated esters and sucrose.  Ingested sucrose acetate isobutyrate
    was partially absorbed from the gut and partially eliminated in the
    faeces.  In all three species, the absorbed dose was largely
    catabolized to CO2, and smaller amounts were excreted in the urine
    and bile.

         The extent of absorption from the gastrointestinal tract was
    greater in humans and rats than in dogs in the dosage range of
    1-10 mg/kg bw.  However, at doses approaching 100 mg/kg bw/day in
    the rat, absorption of sucrose acetate isobutyrate was less
    extensive, resembling more the situation in the dog.

         In studies with sucrose octaisobutyrate, the most lipophilic
    component of sucrose acetate isobutyrate, a dose of 200 mg/kg bw
    administered to rats, dogs, and monkeys was almost completely
    excreted in the faeces, although analysis of faecal metabolites
    indicated that the extent of hydrolysis in the gastrointestinal
    tract differed in the three species (rat > dog > monkey).  In
    addition, the small amount of absorbed sucrose octaisobutyrate was
    preferentially excreted in the bile of dogs and in the expired air
    of rats.  Chromatographic analysis of the urinary and biliary
    metabolites of sucrose acetate isobutyrate showed that dogs excreted
    more highly acylated sucrose molecules, whereas humans and rats
    excreted more polar sucrose esters.  Consequently, the dog differs
    from the rat and human in its disposition of sucrose acetate
    isobutyrate in that it absorbs less of the total dose of sucrose
    acetate isobutyrate in the 1 - 10 mg/kg bw range, but it is capable
    of absorbing more highly acylated sucrose esters and compared with
    the rat, excretes a larger proportion of the absorbed dose in the
    bile.  Data on the excretion of sucrose acetate isobutyrate in the
    bile of humans were not available for comparison.

         The results of short-term (up to 1 year) toxicity studies in
    mice, rats, and monkeys were also available.  The conclusions of an
    earlier 2-year study in rats were not considered to be reliable
    because of the small numbers of survivors at the end of the study. 
    SAIB administered at dose levels of up to 10% in the diet for 12
    weeks or 2 g/kg bw/day for 52 weeks had no toxicologically
    significant effect in the rat, nor was any effect evident in the
    liver as assessed by liver function tests, liver weights, and
    histopathology  In the  Cynomolgus monkey, oral doses of sucrose
    acetate isobutyrate of up to 2.4 g/kg bw/day had no apparent adverse

    effect.  In humans, up to 20 mg SAIB/kg bw/day for 14 days was also
    without effect.  In addition, special liver function tests conducted
    in rats, monkeys, and humans following oral administration of single
    or multiple exposures to sucrose acetate isobutyrate showed no
    effect on hepatobiliary excretion.

         The available studies clearly showed the liver to be the target
    organ in the dog.  Serum alkaline phosphatase levels were elevated
    and biliary excretory function was impaired.  Liver enlargement was
    noted in the males and histopathological changes were apparent in
    the liver of both sexes.  All of these changes were reversible
    within 3 weeks of removal of sucrose acetate isobutyrate from the
    diet.  In addition, histochemical studies revealed increased enzyme
    activity in the bile canaliculi, but not in the hepatocytes.  In
    special studies on liver function biliary excretion was reduced
    within 4-6 hours of oral administration of a single dose of sucrose
    acetate isobutyrate. The NOEL for this effect was 5 mg/kg bw/day. 
    The authors of the report concluded that this represented a
    functional rather than a toxic effect of sucrose acetate
    isobutyrate.  Although the effects on the liver of the dog were
    reversible, no study of longer than 12-13 weeks duration was
    available for evaluation.  It was not known whether continuous
    exposure to sucrose acetate isobutyrate for a longer period of time
    would have resulted in the development of pathological lesions.

         The carcinogenic potential of sucrose acetate isobutyrate has
    been investigated in mice and rats in long-term toxicity studies at
    doses of up to 2 and 5 g/kg bw/day, respectively, with negative
    results.  Sucrose acetate isobutyrate was not genotoxic in  in vitro
    point mutation, chromosomal aberration, or unscheduled DNA synthesis
    assays.  A multigeneration reproduction/teratologenicity study in
    rats and a teratology study in rabbits were also negative.

         The NOELs from the long-term studies in mice and rats and from
    a 1-year study in monkeys were similar (5, 2, and 2.4 g/kg bw/day,
    respectively).  However, the NOEL for the dog was much lower
    (5 mg/kg bw/day based on inhibition of biliary excretory function).

    4.  EVALUATION

         The Committee concluded that a 2-year study in dogs was no
    longer necessary since the effects of sucrose acetate isobutyrate
    and its constituent esters on the liver of the dog had been well
    characterized in liver function tests and 90-day toxicity studies,
    and a study of longer duration was unlikely to yield new information
    which would assist in setting an ADI.

         Three studies in humans, involving a total of 71 volunteers,
    were available for consideration by the Committee.  The results of
    these studies demonstrated that sucrose acetate isobutyrate had no
    effect on BSP clearance or indicator enzymes of cholestasis in
    humans when administered orally in a single daily dose (20 mg/kg bw)
    that dramatically reduced BSP clearance in the dog (25 mg/kg bw as a
    single dose).  Humans, therefore, did not respond to sucrose acetate
    isobutyrate in the same way as dogs.  The Committee agreed that the
    data suggested that the dog was an inappropriate species on which to
    base an ADI, but at the same time noted the absence of data on the
    mechanism by which cholestasis is induced in the dog.

         Taking this into account, the Committee decided to use the NOEL
    of 2 g/kg bw/day for rats, the lowest obtained in a long-term
    toxicity study, to allocate a temporary ADI of 0-10 mg/kg bw, using
    a safety factor of 200.  The submission of information that would
    clarify the disparate effects of sucrose acetate isobutyrate on
    hepatobiliary function in the dog compared with other species, in
    particular humans, is required for review by 1996.

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    PROCTER, B.G., DUSSAULT, P., BURFORD, R.G., RONA, G. & CHAPPEL, C.I.
    (1971a).  A subacute study of the effect of ingestion of sucrose
    acetate isobutyrate on the liver of the rat (a study of the subacute
    oral toxicity of sucrose acetate isobutyrate in the rat).  Unpub.
    Rept. No. 966, Bio-Research Laboratories Ltd., Quebec, Canada. 
    Submitted to WHO by the Canadian Soft Drink Association and Eastman
    Kodak Co., Rochester, NY, USA.

    PROCTER, B.G., DUSSAULT, P., RONA, G. & CHAPPEL, C.I. (1971b).  A
    study of the subacute oral toxicity of sucrose acetate isobutyrate
    (SAIB) in the beagle dog.  Unpub. Rept. No. 2, project No. 953,
    Bio-Research Laboratories, Ltd., Quebec, Canada.  Submitted to WHO
    by the Canadian Soft Drink Association and Eastman Kodak Co.,
    Rochester, NY, USA.

    PROCTER, B.G. DUSSAULT, P. & CHAPPEL, C.I. (1973).  Biochemical
    effects of sucrose acetate isobutyrate (SAIB) on the liver,  Proc.
     Soc. Expt. Biol. Med., 142, 595-599.

    REYNOLDS, R.C. (1963).  The  in vivo absorption of sucrose acetate
    isobutyrate from the intestine of the rat.  Unpub. Rept. No.
    BCH-63-5, Laboratory of Industrial Medicine, Eastman Kodak Company,
    Rochester, N.Y.  14652-3615.  Submitted to WHO by Eastman Kodak Co.,
    Rochester, NY, USA.

    REYNOLDS, R.C. (1972a).  Physiological fate of sucrose-14C(U)
    acetate isobutyrate in rats: (1) After single oral doses in corn
    oil.  Raw data report, BDH-72-5, Eastman Kodak Company.  Submitted
    to WHO by Eastman Kodak Co., Rochester, NY, USA.

    REYNOLDS, R.C. (1972b).  Physiological fates of sucrose-14C(U)
    acetate isobutyrate and sucrose-14C(U) in rats: (2)  After single
    oral doses in an aqueous emulsion.  Raw data report, BCH-72-6,
    Eastman Kodak Company.  Submitted to WHO by Eastman Kodak Co.,
    Rochester, NY, USA.

    REYNOLDS, R.C. & TRAVIS, M.G. (1972).  Physiological fate of
    sucrose-14C(U) acetate isobutyrate in dogs.  Raw data report,
    BCH-72-4, Eastman Kodak Company.  Submitted to WHO by Eastman Kodak
    Co., Rochester, NY, USA.

    REYNOLDS, R.C. & ZIEGLER, D.A. (1977).  Metabolites of sucrose
    acetate isobutyrate in the urine of rats, dogs and a man.  Unpub.
    Rept. (BC-77-T2), Eastman Kodak Co.  Submitted to WHO by Eastman
    Kodak Co., Rochester, NY, USA.

    REYNOLDS, R.C., ASTILL, B.D. & FASSETT, D.W. (1971).  The
    disposition of SAIB in mammals (rat, dog and man).  Unpub. Rept. No.
    BCH-71-8.  Laboratory of Industrial Medicine, Eastman Kodak Company. 
    Submitted to WHO by Eastman Kodak Co, Rochester, N.Y. USA.

    REYNOLDS, R.C., TRAVIS, M.G. & ELY, T.S. (1972).  Physiological fate
    of sucrose-14C(U) acetate isobutyrate and sucrose-14C(U) in
    humans.  Unpub. Rept. (BCH-72-1), Laboratory of Industrial Medicine,
    Eastman Kodak Co.  Submitted to WHO by the Eastman Kodak Co,
    Rochester, NY, USA.

    REYNOLDS, R.C., ASTILL, B.D., TERHAAR, C.J. & FASSETT, D.W. (1974). 
    Fate and disposition of sucrose-U-14C acetate isobutyrate in
    humans, rats and dogs.   J. Agr. Food Chem., 22, 1084-1088.

    REYNOLDS, R.C., KRASAVAGE, W.J., TRAVIS, M.G. & TERHAAR, C.J.
    (1975).  Elimination of radioactivity in bile of rats and a dog fed
    sucrose-14C(U) acetate isobutyrate.  Unpub. Rept. No. BCH-75-6,
    Health and Safety Laboratory, Eastman Kodak Co., Rochester, N.Y. 
    Submitted to WHO by Eastman Kodak Co., Rochester, NY, USA.

    SCHARDEIN, J.L. (1988).  Teratology study in rabbits with sucrose
    acetate isobutyrate (SAIB).  International Research and Development
    Corporation.  Unpub. Rept..  Submitted to WHO by Eastman Kodak Co.,
    Rochester, NY, USA.

    TIERNEY, W.J. & RINEHART, W.E. (1979).  An acute oral tolerance
    study of sucrose acetate isobutyrate (SAIB) in monkeys.  Unpub.
    Rept. No. 78-2187, Bio/dynamics Inc.  Submitted to WHO by Eastman
    Kodak Co., Rochester, NY, USA.

    TIERNEY, W.J. & RINEHART, W.E. (1980a).  A range-finding study with
    sucrose acetate isobutyrate (SAIB) in monkeys.  Unpub. Rept. No.
    78-2188, Bio/dynamics Inc.  Submitted to WHO by Eastman Kodak Co.,
    Rochester, NY, USA.

    TIERNEY, W.J. & RINEHART, W.E. (1980b).  Evaluation of selected
    clinical chemistry parameters in monkeys following administration of
    sucrose acetate isobutyrate (SAIB) for 15 days.  Unpub. Rept. No.
    79-2431, Bio/dynamics Inc.  Submitted to WHO by Eastman Kodak Co.,
    Rochester, NY, USA.

    YOUNG, R.R. (1985).  Evaluation of sucrose acetate isobutyrate
    special lot No. 84-8 in the CHO/HGPRT forward mutation assay. 
    Unpub. Rept. No. 22207, Litton Bionetics Inc.  Submitted to WHO by
    Eastman Kodak Co., Rochester, NY, USA.


    See Also:
       Toxicological Abbreviations
       SUCROSE ACETATE ISOBUTYRATE (JECFA Evaluation)