GLUFOSINATE AMMONIUM
First draft prepared by Dr. Otto Meyer,
National Food Agency,
Soborg, Denmark
Ammonium 4-[hydroxy(methyl)phosphinoyl]-DL-homoalaninate.
EXPLANATION
Glufosinate ammonium is the active ingredient in a new
non-selective herbicide. The herbicidal action of this substance, a
phosphinic acid analogue of glutamic acid, is related to the
inhibition of glutamine synthetase, an enzyme utilized in ammonia
detoxification and amino acid metabolism in plants. Glufosinate
ammonium has not previously been evaluated by JMPR.
BIOLOGICAL DATA
Biochemical aspects
Absorption, distribution and excretion
Glufosinate ammonium, 14C (3,4-14C, 2-2.12 mCi/g) was
administered orally in a single dose of 30 mg/kg bw to 5 male and 5
female SPF Wistar rats, 10-12 weeks of age (1 male and 1 female served
as controls). Excretion was 84% in faeces and 7% and 12% in urine for
males and females, respectively, after 0-168 hours. More than 92% in
both sexes was excreted within 24 hours. The biological half-lives
for the biphasic excretion were 5-7 hours for phase 1 in urine and
faeces and 1.5 days for phase 2. After 7 days only the kidneys,
testes, and liver in males and the kidneys and liver in females
contained regularly detectable concentrations, none exceeding 0.4 ppm.
Concentrations found in other tissues (spleen, bone, brain) were 0.2
ppm and below. The total balance of tissue residues and excreted
radioactivity was 95% for males and 96% for females (Kellner & Eckert,
1985).
A single dose at about 2 mg/kg bw, 14C-labelled at the
2-position (19.4 mCi/g) was administered intravenously and orally to
groups of 10 male and 10 female SPF Wistar rats, weighing about 200 g.
The blood levels after oral administration were low and only
measurable in males up to 3 hours (C max. 0.008 µg/ml) and in females
up to 8 hours (C max 0.029 µg/ml) after application. After iv
application the concentrations in blood could be followed for up to 2
days after application, the t´ being about 20 min, 3-4 hours and
97-126 hours. After oral administration 89% and 81% of the substance
was excreted in faeces in males and females, respectively, while the
corresponding figures for renal excretion were 7% and 14%,
respectively. More than 97% (males) or 92% (females) of the faecally
excreted radioactivity was eliminated after one or two days for males
and females. The t´ for the biphasic renal elimination was: males 5
hours and females 7 hours, respectively, and males 58 hours and
females 52 hours. After intravenous administration the figures for
renal and faecal excretion were: males 85% and females 93%, and males
18% and females 8%, respectively. The t´ for the bi-phasic renal
elimination was 8 hours first place for both sexes and males 64 hours
and females 52 hours second place. No detectable radioactivity was
found in expired air over 24 hours at a limit of detection of 0.1%.
Of the organs/tissues examined 7 days after oral application, only the
kidneys, testes and liver of males and liver and kidneys of females
contained detectable concentrations, none exceeding 0.2 ppm. These
values are equivalent to about 0.2% or 0.1% of the dose. The rate of
absorption was estimated to be females 13% and males 8% (Kellner &
Eckert, 1983).
Glufosinate ammonium was administered orally in doses of 2 mg/kg
bw/day to 5 male and 5 female SPF Wistar rats (1 rat/sex served as
controls), 10-12 weeks of age for 14 days. On the 15th day the animals
received a single dose of glufosinate ammonium (3,4-14C, 21.87
mCi/g). A total of 91% and 89% was excreted in faeces in males and
females, respectively, and 9% in the urine of both sexes. More than
90% (males) and 94% (females) of the excreted radioactivity was
eliminated after 1 day. The biological half-lives for the biphasic
excretion were 5-6 hours and 1.3-2 days. After 7 days only the
kidneys, testes, and liver in males and the kidneys, liver, and spleen
(0.008 ppm) in females contained regularly detectable concentrations,
all under 0.1 ppm. The total of radioactivity found in excreta and
tissues was males 101.4% and females 97.83% (Kellner & Eckert 1985).
Groups of 28 male SPF Wistar rats weighing 167-198 g received one
single dermal application of 0.1, 1.0 and 10 mg radiolabelled
glufosinate ammonium (3, 4-14C, 47.7 mCi/g)/kg bw for a maximum of 10
hours. Four males served as controls. Absorption of radioactivity
from the skin was highest at the lowest dose level (51%, 43 and 26%
after 168 hours for low-, mid- and high-dose, respectively). The
excretion pattern showed that both urinary and faecal (biliary)
excretion represent important routes for the elimination of test
substance and/or metabolites. Total recoveries of radioactivities
ranged, on average, for all animals between 80% and 91%. Highest
residual radioactivity in organs/tissues and blood were found 4-10
hours after starting of exposure (Ellgehausen, 1986).
Two male and 2 female beagle dogs, 4-6 months of age were
administered a single dose of 8 mg radiolabelled glufosinate ammonium
(3,4-14C, 54.08 mCi/g)/kg bw. Within 24 hours, males 95% and females
94% of the dose was excreted. The urinary excretion constituted 9-10%.
Blood and plasma levels reached the maximum (range 0.1-0.5 µg/g) after
2 hours for males and 4 hours for females, and the half-life
thereafter was 2 to 4 hours. Residual radioactivity in the different
brain regions in males and females ranged from 0.02-0.07 µg/g after
6-24 hours. The values for heart, liver, and kidney ranged between
0.02-0.06, 1.3 and 1.2-2.4 µg/g, respectively. The only metabolite
found was 3-methylphosphinico-propionic acid. This metabolite
constituted 11-16% of the residue in urine, while the parent compound
was found to range between 84-89%. The extractable residue in faeces
(68-93% of the radioactivity found in faeces) was exclusively the
parent compound. Analysis of the extractable residue in liver and
kidney after 6-24 hours (90-99%) showed only parent compound.
Analysis of selected plasma samples collected 2 and 6 hours after
administration showed that 75-84% of the radioactivity present was
extractable and only 16-25% was precipitated with plasma proteins.
Only parent compound was detected (Ellgehausen, 1986).
Groups of 6 male and 6 female Beagle dogs about 5-8 months of age
were administered glufosinate ammonium (purity 95.3%) perorally in
capsules in doses 0, 1 and 8 mg/kg bw/day for 18 days. Four and one
animals/sex/group then received radiolabelled substance in the same
daily doses for 10 days or one day, respectively (3,4-14C, 54.08
mCi/g). One animal/sex/group was sacrificed without being dosed with
the radiolabelled substance, the one animal/sex/dose receiving one
dose was sacrificed 6 hours after dosing and the 4 animals/sex/dose
24, 48 and 96 hours after the last dose, respectively. Excretion of
the substance was almost complete for males and females of both dose
levels ranging from males 97% to females 98% of the administered dose.
Urinary excretion constituted 14-17% of radioactivity. Blood and
plasma levels showed that a steady state condition between absorption
and excretion was reached after 2-5 days. Levels of radioactivity at
high dose level in different parts of the brain showed relatively low
levels, less than 0.6 µg/g in all cases. Significantly lower
concentrations were found in cortex, spinal cord, and heart. After 96
hours the figures approximated the limits of quantification.
The maximum levels in liver and kidney of 3.7 and 6.5 µg/g,
respectively, were reached 48 and 24 hours after the last treatment in
top-dosed animals. The elimination of radioactivity in liver, kidneys
and heart was shown to be rapid. Analysis of urinary radioactivity
and of radioactivity found in faeces, kidney and liver showed that
besides the parent molecule only 3-methylphosphinico-propionic acid
was present. The parent compound accounted for males 100% and females
89% of radioactivity in urine. In liver and especially kidneys the
metabolite generally exceeded the amount of parent compound
(Ellgehausen, 1986).
Two lactating Swiss mini-goats, weighing 21.5 and 20 kg received
five oral doses of a radiolabelled equimolar mixture of glufosinate
ammonium (3,4-14C, 23.9 mCi/g) and the major metabolite in animal,
plant and soil, 3-methylphosphinico-propionic acid (3-14C, 24.8
mCi/g), at a dose level of about 3.5 mg/kg bw. A third goat served as
control. The total amount of radioactivity recovered 96 and 8 after
last administration varied substantially between the two animals - 75%
and 98% of which 37% and 48% was found in urine, 35% and 47% in
faeces, 0.02% and 0.03% in milk and 2.5% and 0.1% in tissues/organs
for the two goats. Experimenters noted that the amount of
radioactivity remaining in the gut of the 8 hour animal was not
determined. The level in the blood reached a plateau 8 hours after
administration of the last dose (0.2 µg/g), and after 96 hours the
level was close to limit of quantification (0.01 µg/g). In milk the
maximum concentration of 0.1 µg/ml was found 8 and 24 hours after the
last administration. Ninety-six hours after last administration the
level was decreased to 0.03 µg/g. Residual radioactivity in organs
and tissues ranged from 24 µg/g (kidneys) to 0.06 µg/g (brain) in the
animal killed 8 hours after last dose. In the 96-hour animal, the
residual radioactivity was 0.4 µg/g (kidneys) and 0.07 µg/g (brain).
On average the radioactivity residue levels 96 hours after the last
administration were 14 times lower than after 8 hours Four days
later, the residual radioactivity accounted for 0.4 mcg/g (kidneys)
and 0.07 mcg/g (brain). On average the radioactivity residue levels 96
hours after the last administration were 14 times lower than after 8
hours (Ellgehausen, 1984b).
Equimolar mixtures of radiolabelled glufosinate ammonium
(3,4-14C, 23.9 mCi/g) and its major metabolite,
3-methylphosphinico-propionic acid (3-14C, 24.8 mCi/g), were
administered to 10 Leghorn hybrid laying hens perorally in daily doses
of 3.5 mg/kg bw for five days (additional 2 hens served as controls).
The substance and its major metabolite do not seem to accumulate or be
retained by laying hens (Ellgehausen, 1984a).
One single dose of 20 mg/kg bw radiolabelled
3-methylphosphinico-propionic acid (3-14C, 6.810 mCi/g) was
administered perorally or iv to groups of 5 female SPF Wistar rats
weighing 175-200 g. Four days after administration the perorally
dosed rats excreted 92% in urine and 3.7% in faeces while iv dosed
rats excreted 93% in urine and 0.6% in faeces. For both applications
the half-lives were 6-7 hours. The findings demonstrate a nearly
complete absorption of this metabolite (Kellner & Eckert, 1984).
Biotransformation
Glufosinate ammonium, (3,4-14C, 4.91 mCi/g) was administered to
20 female SPF Wistar rats weighing an average of 200 g in a single
oral dose of 10.8 mg/kg bw. A total of 10.6% of the radioactivity was
excreted in the urine and 82% in faeces within 48 h after dosing and
in the period 49-120 h after administration of the compound 1.3% and
1.2% of the radioactivity was eliminated via urine and faeces,
respectively. In urine 8.5% of the applied dose was identified as the
parent compound, 0.5% as 3-methylphosphinico-propionic acid and 1% as
3-methylphosphinico-3-oxo-propionic acid. In faeces 74% of the applied
dose was active ingredient, 2.6% was 3-methylphosphinico-propionic
acid and 5.8% an unidentified metabolite (Dorn et al., 1983).
Glufosinate ammonium, (3.4-14C, 49.4 mCi/g) was administered to
10 male and 10 female SPF Wistar rats, 10 weeks of age (2 rats/sex
served as controls) in a single oral dose of 2.5 and 2.9 mg/kg bw,
respectively. More than 80% of the applied radioactive dose was
eliminated via faeces and 6% via urine during the first 24 h after
administration and the total recovery after 96 h was 99.7% and 98.1%
for males and females respectively. The highest radioactivity in
organs and tissues after 4 days was found in liver, 0.06% or 0.003
mg/kg and 0.06% or 0.04 mg/kg, and in kidneys, 0.09% or 0.22 mg/kg
and 0.02 or 0.01 mg/kg for males and females respectively. Blood,
brain, spleen and fat contained significantly lower residues. The
excreted radioactivity in faeces (extractable part = 86 % of the total
excreted activity during 48 h) and in urine (during 24 hours)
represents only the parent compound (Wink et al., 1986).
The metabolism of glufosinate ammonium (3,4-14C, 21.86 mCi/g)
was investigated in 20 male and 20 female Wistar SPF rats, 10 weeks of
age receiving a single oral dose of 29.4 mg/kg bw. Ninety-six h after
administration the recovery of radioactivity was 96% and 88% in
females and males, respectively. Females and males excreted 14 and
17% in urine and 83 and 71% in faeces, respectively. The main amount
(> 86%) of radioactivity excreted via urine was found in urine
samples taken 0-24 hours after administration. The radioactivity
found in liver was 0.07% (0.45 mg/kg) and 0.09% (0.48 mg/kg) and in
kidney 0.01% (0.4 mg/kg) and 0.02% (0.75 mg/kg) for females and males,
respectively. The radioactivity in other organs was > 10 times lower.
More than 95% of the radioactivity in faeces and urine consisted of
the unchanged compound. The only metabolite in urine and faeces, Hoe
061517 (Figure 1), was found to constitute than 3% of the
adminis-tered dose (Wink et al., 1986). Ten male and 10 female
(2/sex served as controls) SPF Wistar rats, 6 and 9 weeks of age
respectively, received doses of 2 mg glufosinate ammonium/kg bw daily
for 14 days, and one dose at day 15 of 2 mg/kg bw of radiolabelled
test substance (3, 4-14C, 43.6 mCi/g). No relevant sex dependent
differences were observed, neither in excretion route nor in excretion
rate. More than 80% of the applied dose was excreted via faeces and
approximately 5% via urine during the first 48 h after administration.
More than 80% of the radioactivity in faeces and urine was the
unchanged parent compound. Two main metabolites, 3-methylphosphinico-
propionic acid (< 8% of applied dose) and 3-methylphosphinico-
3-oxo-propionic acid (<4% of applied dose) were found in urine and
faeces. Two minor metabolites were not characterized (Wink et al.,
1986b).
Nine male and 9 female SPF Wistar rats, 10-12 weeks of age
received one oral dose of 800 mg radiolabelled glufosinate ammonium
(3,4-14C, 54.1 mCi/g)/kg bw and sacrificed 6 and 24 h after
administration. Unchanged substance was present in all samples. Two
main metabolites were found in urine and extracts of liver and kidneys:
3-methylphosphinico-propionic acid and 3 methyl-phosphinico-
3-oxo-propionic acid. No sex-related difference was found in
excretion not metabolism (Schwalbe-Fehl et al., 1985).
Groups of 15 female SPF Wistar rats, 10-12 weeks of age were
dosed orally with 10 or 100 mg glufosinate ammonium (purity: 99.6%)/kg
bw/day for 10 days. For the administration on the days 1, 8, 9 and 10,
radiolabelled substance (3,4-14C, 47.7 mCi/g) was used. Different
groups of the animals were sacrificed after 24 and 48 hours. The
administrated radioactivity was rapidly excreted mainly via faeces
(73-103%), less than 5% was eliminated via urine. Repeated dosing did
not influence the route nor rate of excretion. The major part of
excreted radioactivity consisted of unchanged substance. Two
metabolites were detected in urine and faeces; 3-methylphosphonico-
propionic acid and 3-methyl-3-oxo-propionic acid in amounts of 5% and
1% of excreted radioactivity respectively. Liver, kidneys, spleen and
brain contained less than 0.1% of the total administrated
radioactivity at all sacrifice dates. Excretion and characterization
of these radioactive residues demonstrated the presence of unchanged
substance (68-81 %) and the metabolite 3-methylphosphinico-propionic
acid (20-32%) (Schwalbe-Fehl et al., 1986).
Analysis of radioactivity in liver and kidney of laying hens
after repeated oral administration of an equimolar mixture of
radiolabelled glufosinate ammonium and its major metabolite,
3-methylphosphinico-propionic acid was performed (see Ellgehausen
et al., 1984 in section "Absorption, distribution and excretion").
Eight hours after the final administration only the metabolite was
found. After 24 hours the radioactivity present was too low for
further analysis (Ellgehausen, 1986).
Effects on enzymes and other biochemical parameters
Glufosinate ammonium (purity 95.3%) was administered once orally
(in deionized water, 10 ml/kg bw) in doses of 0, 50 or 200 mg/kg bw to
groups of female SPF NMRI mice with an average weight of 17.7 g.
Zero, 200 and 800 mg/kg bw was administered to female SPF Wistar rats
weighing an average of 203.0 g. The animals were killed 4 hours after
dosing. No deaths or clinical signs of intoxication were observed.
One single treatment with doses up to the sublethal range did not
cause inhibition of glutamine synthetase activity in the brain or any
change in the NH4+, glutamine or glutamic levels in this organ (only
the latter two parameters were measured in rats). However, in the
kidneys of both species in both doses and in the liver of top-dosed
rats, there was a marked inhibition of glutamine synthetase activity,
accompanied by an increase of NH4+ level in liver in top-dosed mice.
No changes of glutamine and glutamic acid were observed in liver of
rats, the only species analyzed in this study (Ebert & Kramer, 1985).
Glufosinate ammonium (purity 96.9%) intravenously administrated
to rats (strain not specified) in a single dose of 10 or 100 mg/kg bw
caused a slight decrease in glutamine synthetase activity in the
brain. No changes were found in catecholamine concentrations in
frontal cortex, striatum or hippocampus (Gerhards & Köcher, 1986).
Glufosinate ammonium (purity 92.5%) was administered in the diet
to groups of 10 male and 10 female F344/Du CrJ rats (4 weeks of age at
arrival) for 13 weeks in concentrations of 0, 8, 64, 500 or 4000 ppm.
Half of the animals in the respective groups were killed at the end of
the dosing period, the other half after a 4 week recovery period. An
inhibition of glutamine synthetase activity in the liver was found at
the end of the dosing period in top-dosed males and in the females
dosed with 500 or 4000 ppm. No effect was found after the 4 week
recovery period. No treatment-related effect was found on serum
levels of ammonia (Ohashi et al., 1982).
Glufosinate ammonium (purity 96.9%) was administered once orally
by gavage in deionized water, 10 ml/kg bw to groups of 15 or 30 (in
the top-dose) female SPF Wistar rats, 8-9 weeks of age in doses 0,
200, 800 and 1600 mg/kg bw. One-third of the animals in the groups
was killed 24 hours, 3 or 7.5 days after dosing respectively. The
animals dosed with 200 and 800 ppm exhibited a very slight impairment
of behaviour (reduced motivation and performance), which diminished
increasingly towards the end of the examinations. One animal in the
800 mg group killed at day 1 had convulsions. The top-dosed animals
exhibited different degrees of signs of CNS excitability (tendency to
convulsions and spasms). Three animals died. These clinical signs
receded during the course of the study. A marked inhibition of
glutamine synthetase was observed in liver and kidneys in all treated
animals and in brain in high dose animals. An increase in glutamate
level was only observed in the liver and was significant in high dose
animals one day after dosing. A decrease was seen in the brain which
was statistically significant in animals dosed with either 800 or 1600
mg, 7.5 days after dosing. However, clear evidence for an increase in
the level of NH4+in these organs could not be established. A
borderline effect on behaviour was reported in the animals dosed at
200 mg/kg bw (Ebert et al., 1986c).
Glufosinate ammonium (purity 96.9%) was administered to groups of
40 male and 40 female SPF Wistar rats approximately 6 weeks of age in
the diet at doses of 0, 40, 200, 1000 and 5000 ppm. Analysis showed
that the actual concen-trations of active ingredient were 32-35,
173-184, 803-896, and 4285-4576 ppm for the 4 doses respectively, and
that the substance remained satisfactorily stable in the diet for 30
days. The actual calculated doses were 0, 3.7, 18.7, 93.5 and 443
mg/kg bw/day for males and 0, 3.7, 18.3, 89.4 and 424 mg/kg bw/day for
females.
Glufosinate ammonium (purity 96.9%) was administered to groups of
40 male and 40 female SPF Wistar rats approximately 6 weeks of age in
the diet at doses of 0, 40, 200, 1000 and 5000 ppm. The actual
calculated doses were 0, 3.7, 18.7, 93.5 and 443 mg/kg bw/day for
males and 0, 3.7, 18.3, 89.4 and 424 mg/kg bw/day for females. Ten
animals/sex/group were killed 0, 3, 7 and 28 days after last day of
dosing. Treatment-related behavioural changes (hypersensitivity,
excitation of the autonomous nervous system, subnormal temperature,
convulsions) were observed in high-dose animals. No effects on
behaviour nor on various parameters reflecting the function of the
central, peripheral and autonomous nervous system nor general
intoxication were observed at 1000 ppm. Bodyweight gain was only
affected in top-dosed males. An initial reduction in food intake and
an increase in water consumption was observed in high-dose animals.
The macrosocopic findings revealed no differences between the groups.
Kidney weights were increased in top-dosed females. Determination of
the catecholamine transmitters in the brain, revealed a slight,
statistically significant lowering in dopamine only in top-dosed
females. A dose-related inhibition of glutamine synthetase was found
in males and females dosed 200 to 5000 ppm in liver, in top-dosed
males in the brain and in males doses at 200 to 5000 ppm in the
kidneys. None of the changes in glutamine synthetase was present
after 28 days of recovery. Determination of NH+ in brain, liver and
kidneys did not reveal any treatment-related changes.
No effect of the substance was seen on aspartate, glutamate,
asparagine and glycine in either brain, liver or kidneys. However,
the examination of glutamine revealed a decrease in free amino acid
level, statistically significant in the liver in the 200, 1000 and
5000 ppm groups and in the brain and kidneys in the 5000 ppm group.
After a 3-day treatment-free period this effect on glutamine was not
present. No indication of changes could be found in alanine in the
liver or taurine in the brain. None of the parameters examined
(isocitrate-DH (NADP-dependent), succinate-dehydrogenase, maleate
enzyme (decarboxylating), fructose diphosphatase or glycogen) yielded
any indication of substance-related changes in energy and carbohydrate
metabolism. Glutamate pyruvate transaminase was lowered in males in
the three highest dosage groups at the end of the treatment, which may
have been due to an exceptionally high activity of the controls. No
treatment-related changes were observed on glutathione level nor
gamma-glutamyltranspeptidase. No substance-related changes were found
in glutamate oxaloacetate transaminase nor glutamate dehydrogenase.
Glutamate pyruvate transaminase was reduced in males dosed at 200 ppm
and greater. However, the figures exhibited no marked
dose-relationship and were within normal range. Alanine level in the
liver revealed no change. The NOAEL is 40 ppm equal to 3.7 mg/kg
bw/day (Ebert et al., 1986b).
In two studies, in which groups of 10 male and 10 female Wistar
rats, weighing 167-227 g were administered single lethal doses by oral
gavage, no therapeutic effect of ip treatment with atropine sulfate
and pyridine-2-aldoxim methiodide was observed. Phenobarbital-sodium
proved an efficient therapeutic agent (Ebert & Weigand, 1983; Ebert &
Leist, 1986).
Glufosinate ammonium (purity 95.3%) was administered orally (by
capsule) to groups of 6 male and 6 female Beagle dogs, 5-8 months of
age in doses 0, 1 and 8 mg/kg bw/day for 18 days followed by 10 days
similar dosing with labelled glufosinate ammonium (3,4-14C, 54.1
mCi/g). One animal/sex/group was sacrificed on days 18, 19 and 28 of
treatment and on days 1, 2 and 4 of the recovery period. Parameters
including blood chemistry, haematology, neurological parameters and
histopathology were examined. No animal died during the study.
Neurological examinations showed only slightly increased motor
activity in high-dose animals. Females exhibited a slightly lower
food intake, and body weight gain was supp-ressed in male and female
high-dose animals (in the first week and after the first week -
females only). A slight decrease in haematocrit, eryrthrocyte count
and haemoglobin was seen in treated females and less pronounced in
males after 28 days treatment and at the end of the recovery period
was considered to be a secondary effect and not treatment related. No
treatment-related changes were found in standard biochemical
parameters. A slight, dose-correlated but not significant decrease in
brain cholinesterase was seen in males only at 28 days of treatment.
However, no treatment-related changes were noted in cholinesterase
activity or in thyroid function, acid-base parameters, glutathione
levels in whole blood, glucose-6-phosphate dehydrogenase and
glutathione reductase levels in whole blood nor amino acids in the
plasma. Analysis of tissue extracts showed a decrease in aspartic
acid, glutamic acid, glutamine, glycine and taurine in brain stem,
aspartic acid, phosphoethanolamine, glutamine synthetase and an
increase in alpha-ketoglutarate in cerebellum, an increase in
phosphoethanolamine and a decrease in glutamine-synthetase in the
midbrain and a decrease in threonine and glutamine-synthetase in
spinal cord in the top-dosed males. In low-dosed males the only
changes were seen in phosphoethanolamine and threonine in cerebellum
and spinal cord, respectively. In high-dose females, the following
were observed to decrease; glutathione, arginine and
glutamine-synthetase in midbrain, aspartic acid, glutamine,
phosphoethanolamine and taurine in brain stem, arginine and
alpha-ketoglutarate in spinal cord, phosphoethanolamine, taurine, and
glutamine-synthetase. An increase was observed in alpha-ketoglutarate
in cerebellum and glutamine, phosphoethanolamine and taurine in
cortex. Changes were found in arginine in spinal cord and in
phosphoethanolamine and taurine in the cortex. In heart, a decrease
was observed with glutamine in both doses and in taurine in the
high-dose females. No changes were seen in urinanalysis and no
treatment-related effect was noted in the pathological examinations.
The substance caused marginal signs indicative of increased
stimulation of CNS in top-dosed animals. However, no changes of
excitatory and inhibitory amino acid neurotransmitters or
catecholamine neurotransmitters were noted. The NOEL for the
neurological system and physiological homeostasia is 1 mg/kg bw/day
while the top-dose can be considered threshold dose level for an
effect on physiological function (Sachsse, 1986).
In an in vitro study of phosphonic analogs of glutamic acid
2-amino-4-(methylphosphino)butyric acid was shown to be a strong
inhibitor of rat brain glutamate decarboxylase (Lacoste et al.,
1985).
In an in vitro study with phosphonic analogues of glutamic acid
it was shown that these compounds competitively inhibit rat liver
glutamine synthetase (Lejczak et al., 1981).
Glufosinate ammonium was investigated in a number of in vitro
receptor binding assays. No significant effect was found in either
transmitter receptors GABA, noradrenalin-alpha2, noradrenalin-beta,
dopamine and serotonin nor in other binding sites (calcium ion channel
and benzodiazepine) (Schacht, 1986).
In an in vitro study, glufosinate ammonium (purity: 99.5%) was
added to mitonchodria of livers of Wistar female rats weighing
140-180 g. When the substrate was preincubated with substance for 10
minutes at 25 °C or 120 minutes at 0 °C, no block of the oxidative
consumption was measured. Either the substance has no direct influence
on the metabolism of intact rat liver mitochondria or the substance was
not been taken up by these organelles (Metzger, 1986).
In vitro studies on effect of glufosinate ammonium or
DL-homoalanin-4-yl(methyl)-phosphinic acid on glutamate oxalacetate
transaminase, glutamate pyruvate transaminase and gamma-glutamyl
transpeptidase from the pig and glutamate dehydrogenase from the
bovine liver showed, with bovinal liver glutamate dehydrogenase only,
a 19 or 15% reduction in activity due to the test substances (Köcher
& Schulze, 1986).
Toxicological studies
Acute toxicity
Table 1. Acute toxicity of glufosinate-ammonium
LD50 or LC50 (mg/kg bw)
Species Males Females Reference
LD50 (po)
Mouse 431a Mayer & Weigand (1980a)
436b Inoue & Okamura (1982a)
416a Mayer & Weigand (1980b)
464b Inoue & Okamura (1982a)
Rat 2000c Mayer & Weigand (1980c)
1660d Ohtaka et al. (1981a)
1620c Mayer & Weigand (1980c)
1510d Ohtaka et al. (1981b)
Doge >200 Mayer & Kramer (1980)
>400
Table 1 (contd).
LD50 or LC50 (mg/kg bw)
Species Males Females Reference
LC50 (percutaneous)
Rat >4000c Mayer & Weigand (1982a)
4000c Mayer & Weigand (1982b)
Rabbitf 2000 Parcell & Kynoch (1986)
2000
LC50 (inhalation)
Aerosol: Ratc
>0.621 mg/l Hollander & Weigand (1982)
>0.621 mg/l Hollander & Weigand (1982)
Dust: 1.26 mg/l Hollander & Weigand (1982)
Ratc 2.60 mg/l Hollander & Weigand (1982)
LD50 (ip)
Mouseb 103 Inoue & Okamura (1982c)
82 Inoue & Okamura (1982c)
Rat 96d Ohtaka et al. (1981c)
204c Mayer & Weigand (1982c)
93.2c Mayer & Weigand (1982d)
83d Ohtaka et al. (1981d)
LD50 (sc)
Mouse 88b Inoue & Okamura (1982c)
104b Inoue & Okamura (1982c)
Rat 73d Ohtaka et al. (1981f)
61d Ohtaka et al. (1981g)
a = NMRI, SPF d = F344
b = ICR, SPF e = Beagle
c = Wistar, SPF f = NZW
Short-term studies
Mice
Glufosinate (purity: 95.3%) was administered to groups of 10 male
and 10 female SPF NMRI mice, 5 weeks of age, in their diet in
concentrations 0, 80, 320 and 1280 ppm for 13 weeks. The calculated
mean doses were 0, 17, 67 and 278 mg/kg bw/day and 0, 19, 87 and 288
mg/kg bw/day for males and females, respectively. Analysis for
homogeneity of substance in diets were approximately within +/- 15%
and mean concentrations were 0, 119, 82 and 92%, respectively. The
subst ance is stable in the diet at room temperature at levels of
50-5000 ppm. No sign of systemic toxicity was observed in any animal.
The mean body weights of treated animals were comparable to those of
the controls and no relevant, dose-related changes were seen in food
consumption or ophthalmoscopic inspection. Apart from an increase in
monocyte-count in high dose males, no significant compound-related
effect was found in any haematological measurements. Alkaline
phosphatase was elevated in high-dose females. A slight increase in
aspartate aminotransferase in high-dose males and an increase in
potassium in males in the 1280 and 320 ppm groups were seen. A
dose-dependent increase was noted in absolute organ weights, organ to
body weight ratios and organ to brain weight ratios in the liver and
kidneys which was only statistically significant in the liver to body
weight ratio in high dose males. No treatment-related pathological
findings were noted. The NOAEL is 80 ppm corresponding to 17 and 19
mg/kg bw/day for male and female mice, respectively (Suter & Sachsse,
1984b).
Rats
Groups of 10 male and 10 female F344 rats, 5 weeks of age, were
administered glufosinate ammonium (purity: 92.1%) in the diet at
dosage levels of 0, 8, 16, 32, 64, 320 and 3200 ppm for 2 weeks. The
mean doses were 0, 0.7, 1.4, 2.9, 5.8, 28.5 and 262 mg/kg bw/day for
males and 0, 0.8, 1.7, 3.3, 6.6, 33.7 and 296 mg/kg bw/day for females
based on food consumption and nominal concentrations. No effect was
observed in the clinical condition of the animals. Body weight gain
was suppressed and food consumption and efficiency and water
consumption were decreased during the first week in high dose animals.
No dose-correlated changes were noted in haematological investigation
or urinalysis. Apart from a decreased LDH activity in females in the
3200 ppm group, no compound-related effects were observed. The
absolute weights of heart, lung, liver and spleen in both sexes and
the ovaries in females dosed 3200 ppm were lower when compared to
those of the controls. For the heart and the ovaries in high dose
females, a concomitant effect was noted in relative organ weight. No
changes related to the administration of the compound were observed in
any other groups (Ohtaka & Nakayoshi, 1981).
Groups of 5 male and 5 female SPF Wistar rats, 5-6 weeks of age
were administered glufosinate ammonium (purity: 93.5%) in the diet at
dosages 0, 50, 500, 2500 and 5000 ppm for 28 days. Analysis showed
the actual concentrations to be 0, 101.1%, 95.3%, 92.7% and 105.9%
respectively, and the homogeneity to be within +/- 15%. The compound
remained stable at all levels over a 21-day period at room
temperature. No signs or symptoms of systemic toxicity were observed.
Slightly reduced food consumption and a corresponding decrease in food
conversion in the start of the study were seen in animals in the 2
highest dosage groups. No treatment-related effects were noted in
haematology, clinical biochemistry or urinalysis. Statistically
significant increases in relative kidney weights were seen in males in
2500 ppm group and in all dosed females, although the increases did
not appear to be dose-related. Apart from reddening of the gastric
mucosa in 4 out of 5 males in the 5000 ppm group, no treatment-related
macroscopic or microscopic findings were noted. The NOAEL is 500 ppm,
equivalent to 53 mg/kg bw/day for males and 58 mg/kg bw/day for
females (Suter & Sachsse, 1984).
In a 13-week toxicity study, glufosinate ammonium (purity: 92.1%)
was administered in the diet to groups of 30 male and 30 female F344
rats, 5 weeks of age, at dosage levels of 8, 64, 500 and 4000 ppm
(concentrations were found to be 7.5-7.8, 57.7-68.5, 469-547 and
3910-4150 ppm in an analysis for homogeneity). Ten animals of each
sex were sacrificed after a 4-week withdrawal period. The actual
calculated doses were 0.5, 4, 32 and 263 mg/kg bw/day for males and
0.6, 5, 39 and 311 mg/kg bw/day. Apart from the death of one
high-dose male on day 71 with a miliary tumour in the thoracic cavity,
no treatment related changes were observed. Body weight gain was
suppressed in top-dosed animals in the first 3 weeks and a concomitant
decrease in food consumption was noted. Water consumption was
decreased in animals of both sexes dosed with 4000 ppm during the
first week of administration and was thereafter increased in males
until termination of administration. Increased water consumption was
not observed during the recovery period. No dose-related changes were
found in haematological investigation. Blood chemistry after 47 days
showed a slight dose-related decrease in calcium and a decrease, not
dose-related, in uric acid in all treated males. The corresponding
investigation in females revealed a decrease in LDH, total bilirubin,
Cl and direct bilirubin in high-dose animals, an increase in albumin
and A/G (Albumin/Globulin) in the two highest dosage groups and the
low-dose group and an increase in creatinine in the 64 ppm and 4000
ppm groups. After 13 weeks, cholesterol was increased in high-dose
males and uric acid decreased in a dose-related manner in all treated
males, while no significant changes were found in females. Liver
glutamine synthetase in liver decreased significantly in top-dosed
animals of both sexes and in females dosed at 500 ppm after 13 weeks,
however, returning to normal after a 4-week recovery period. No
dose-related changes were found in serum levels of ammonia. Urinalysis
showed a decrease in pH in high-dose animals and an increase in
specific gravity in females fed 4000 ppm. The pH remained low in
high-dose animals of both sexes after the 4 week recovery period. No
compound-related changes were found at necropsy. Absolute and
relative kidney weight were increased in males and females in all dose
levels except the low dose in which males had an increase in absolute
weight. The effect in kidneys was present even after a 4 weeks
recovery period with both absolute and relative weights being affected
in males in the two highest dosage groups. Other changes in organ
weight were increased thymus weight in the 500 ppm and the 4000 ppm
group and an increase in the weight of the adrenals in all treated
males and a decrease in both absolute and relative brain weights in
females dosed 500 and 4000 ppm after 13 weeks. No compound-related
effects were observed in the histological examination. The NOAEL was
64 ppm for males equivalent to 4.1 mg/kg bw/day and 500 ppm for
females, equivalent to 39 mg/kg bw/day (Ohtaka et al., 1981g).
Dogs
Groups of 4 male and 4 female Beagle dogs, 33-37 weeks old, were
fed glufosinate (purity 92.1%) in dietary concentrations 0, 4, 8, 16,
64 or 256 ppm for 13 weeks. The calculated doses were 0, 0.1, 0.3,
0.5, 2, and 7.8 mg/kg bw/day, respectively. Analysis for homogeneity
of the substance in diet was acceptable and the compound remained
stable in the diet for a period of 2 weeks at room temperature.
Apart from 2 high-dose males which exhibited aggressive behaviour, no
treatment-related changes in behavior or health condition were
observed. A slight reduction in body weight occurred in high-dose
females and food intake was slightly diminished in high-dose animals
of both sexes. Water intake was similar in all groups. No
treatment-related changes were noted in opthalmoscopy, haematology,
clinical chemistry or urinalysis. Organ weights showed no marked or
statistically significant differences between the various test groups
and the controls. Both the absolute and relative weights of the
thyroids were lowered in all test groups, especially in the 64 and 256
ppm groups of females. Gross and microscopic examination did not
reveal any abnormalities considered to be of toxicological
significance. The NOAEL was 64 ppm, equal to 2 mg/kg bw/day (Til & de
Groot, 1982).
Glufosinate ammonium (purity 95.3 %) was administered to groups
of 4 male and 4 female Beagle dogs, 4-6 months of age in the diet at
levels equal to 0, 1.8, 4.5 and 8.4 mg/kg bw/day for 6 or 12 months.
The high dose was adjusted from 10.8 to 8.4 mg on day 11 and
afterwards. Tests showed homogeneity to be within +/- 10 %, and
stability of the substance in the diet up to 21 days at room
temperature. Clinical symptoms manifested by triasmus, salivation and
hyperactvity followed by somnolence and hypoactivity, as well as
stereotypic gait, tremor, ataxia, whining, urinating, and tonic-clonic
spasms were seen in one male and two females receiving the high dose
between days 9 and 14 of treatment. Two of these animals died, one of
each sex, and the one male was replaced by another male, which was
treated for 12 months. The deaths of the two dogs in the highest
dosage group were caused by heart and circulatory failure due to
myocardial necrosis. Low-dosed females showed a decrease in food
intake, whereas food intakes for the mid- and top-dosed females were
increased when compared to controls. No changes were seen in males
apart from a decrease in food consumption during the first week of
treatment. The mean body weight gains of the treated males,
especially high-dose males, was slightly reduced during the first 6
months of treatment. No dose-related changes were found in hearing
tests, ophthalmoscopic examinations or examinations of teeth and
membranes. Electrocardiogram (ECG) values showed some increase in P
wave (P wave ampl. = 0.6 mV, upper normal limit = + 0.45 mV) in one
high-dose male after 12 months and this effect is characterized as a
questionable compound-related effect. A slight decrease in heart
rate, within the normal range, was observed in groups receiving the
test compound after 6 months in the highest dosage group. Haematology,
clinical biochemistry and urinalysis indicated no changes of
toxicological significance, the variations being within the range of
values of historical controls. No treatment-related changes in organ
weights were noted. The pathomorphological findings that were reported
are considered to be spontaneous lesions usually observed in dogs of
this strain and age. The NOAEL in this study is 5 mg/kg bw/day
(corrected value is 4.5 mg) for dog (Bathe & Sachsse, 1984).
Rats (Metabolites)
3-methylphosphinico-propionic acid (purity >99%), the principal
metabolite in plant residues and also a relevant metabolite in
mammalian organisms, was administered in the diet to groups of 5 male
and 5 female SPF Wistar rats, average weight 103 g and 102 g
respectively for 28 days in concentrations 0, 50, 500, 2500 and 5000
ppm. Analysis showed stability of the test substance in the diet for
a period of 30 days and concentrations corresponded satisfactorily to
the nominal concentrations; 36-51, 359 and 3660-4914 ppm. The
calculated doses were 0, 6, 57, 286 and 554 mg/kg bw/day for males and
0, 6, 55, 282 and 561 mg/kg bw/day for females. No substance-related
effect was found in behaviour, clinical observations or body weights,
food intake and water consumption. Changes in haematological
parameters gave no indication of substance-related effects. An
increase in uric acid in high-dose males and in triglycerides in
top-dosed females, which was within normal biological variation, were
the only treatment-related changes found in clinical chemistry. Apart
from the appearance of the urine (clear and light to dark yellow in
colour), no substance-related effects were observed on urinalysis.
Glutamine synthetase activity in the liver was unaffected by
treatment. Apart from an increase in liver weights in top-dosed
females, the pathological examinations did not reveal any effect.
Histological examinations were performed in controls and high-dose
animals only. The NOAEL is 2500 ppm equivalent to 284 mg/kg bw/day
(286 for males and 282 for females) (Ebert et al., 1986a).
Long-term/carcinogenicity studies
Mice
Glufosinate ammonium (purity 95.3%) was administered for 2 years
in the diet to groups of 50 male and 50 female SPF NMRI mice, 5-6
weeks old in levels 0, 20, 80, ppm and 160 ppm for males and 0, 20,
80, and 320 for females. In addition, 10 mice/sex/group were dosed for
52 weeks. The calculated doses were 2.8, 10.8 and 22.6 mg/kg bw/day
and 4.2, 16.2 and 64 mg/kg bw/day, respectively (animal dosed 2
years). Analysis of the diets showed the mean concentrations to be
103%, 99% and 99% of nominal doses in the low, medium and high level.
Homogeneity varied in the range of + 20% to - 18% and the substance
remained stable in the diets for 21 days at room temperature. The
mortality rate in top-dosed males during the study was significantly
increased and this was considered treatment-related even though the
cause of higher mortality could not be established. No
treatment-related clinical symptoms nor signs of toxicity were noted.
Body weights were lowered in high-dose males scheduled for sacrifice
at week 52, and in high-dose females between weeks 7 and 31. Food
intake was not affected. Ophthalmoscopic examinations, hearing tests
and examination of teeth and mucous membranes revealed no
treatment-related effects. No changes of toxicological significance
were noted in haematological values. Clinical biochemistry showed a
slight increase in glucose level in top-dosed animals at week 52, an
increase in aminotransferase in top-dosed females after 52 weeks and
a decrease in glutathion level in top-dosed males after 104 weeks of
treatment. Other changes were within the range of biological
variation of historical controls. After 52 weeks treatment the
absolute and relative spleen weight in top-dosed females was slightly
but not significantly increased. After 104 weeks of treatment, no
treatment-related organ weight changes were detected. Neoplastic and
non-neoplastic lesions noted in this study were commonly observed in
mice of this strain and age, and the type and incidence were
considered to be similar in treated and control animals. The NOAEL is
80 ppm, equivalent to about 11 mg and 16 mg/kg bw/day for males and
females, respectively (Suter & Sachsse, 1986b).
Rats
Groups of 80 male and 80 female SPF Wistar rats, 5 1/2 weeks of
age, were administered glufosinate ammonium (purity: 95.5%) in test
diets in concentrations of 0, 40, 140 and 500 ppm for 52 weeks (10
rats/sex/group), 104 weeks (20 rats/sex/group), or 130 weeks (50
rats/sex/group). The doses for males and females were 0, 2.1, 7.6 and
26.7 mg/kg bw/day. Analysis showed the mean concentrations to be 96,
97 and 99% of the nominal doses respectively and homogeneity varied in
the range of +/- 22% of mean concentration. The substance remained
stable over a period of at least 21 days, at room temperature.
Females in the 140 and 500 ppm groups displayed a significantly
increased intercurrent mortality. Treatment-related clinical signs of
toxicity were not observed. No effect was seen in ophthalmoscopic
examinations, hearing test nor examination of teeth and mucous
membranes. Body weights of males dosed at 140 and 500 ppm were
increased in males on weeks 6-51 and weeks 10-51, respectively. Food
consumption was com-parable between groups when expressed in g/kg
bw/day. Females dosed at 140 and 500 ppm showed an increase in body
weight in weeks 4-35 and weeks 4-79, respectively. Food intake in g/kg
bw/day was similar in all groups. A decrease in erythrocyte count,
haemoglobin concentrations and haematocrit value were noted in
top-dosed animals only after 52 weeks of treatment. Special
biochemical investigations on liver, kidneys and brain showed a slight
inhibition of liver and brain glutamine synthetase activity in animals
dosed at 140 and 500 ppm at week 52 and in weeks 52 and 104,
respectively. The kidney glutamine synthetase activity was slightly to
moderately increased in animals in all dosage groups. Ammonia levels
were unaffected in all treatment groups. Glutathione (GSH, reduced;
GSSG, oxidized) in liver was lowered in males (GSSG) and in females
(GSH and GSH+GSSG) in groups dosed at 140 and 500 ppm. GSH in blood
was decreased in top-dosed animals and in females dosed at 140 ppm,
and GSSG was up in high-dose males. Changes in other biochemical
parameters were all within the range of normal biological variation.
Absolute and relative kidney weights were slightly increased in males
dosed at 140 and 500 ppm and in top-dosed females. At week 130 a
slight increase in relative kidney weight was noted in all treated
females.
An increased incidence of benign medullary tumours (adrenal
gland) was observed in males at 130 weeks. However, a positive trend
was not found in statistical analysis. No other treatment-related
effect was found in the pathological examination. The substance is
not oncogenic in rats in doses up to 500 ppm equivalent to 24.4 mg/kg
bw/day. The NOAEL in this study is 40 ppm equivalent to 2.1 mg/kg
bw/day (Suter & Sachsse, 1986a).
Reproduction studies
In a preliminary study to the multigeneration study, glufosinate
ammonium (purity 95.3%) was administered in the diet to groups of 10
male and 10 female SPF Wistar rats, 8-9 weeks of age in dose levels 0,
50, 500, 2500 and 5000 ppm during a three-week premating period
continuing throughout the mating, gestation and lactation period. Mean
concentrations were found to be in the range 78-83%, 87-89%, 93-97%
and 90-91% of nominal doses, respectively. Homogeneity of all samples
was found to be 5.1 +/- 2.2%. Supplementary groups of 10 males were
dosed 0, 500, 2500 and 5000 ppm for 9 weeks and during the period of
mating with non-dosed females. No signs of toxicity nor clinical
symptoms were noted in any animal in any group. Food consumption was
reduced in the premating period in males in the 2500 and 5000 ppm
groups and in high dose females. Reduction in food consumption was
recorded in females in the 2500 and 5000 ppm groups during gestation
and only the low-dosed females and the controls had comparable food
intake during lactation. A slight, significantly reduced body weight
was noted in high-dose males in the premating period. In the gestation
and lactation period only the low-dose females and their controls
showed overall comparability. Duration of gestation in the 500 pm
group was 0.9 day less than that of the controls. Females in the 2500
and 5000 ppm groups delivered no pups, although implantation sites
were noted. A significantly increased post-implantation loss was seen
in dams of the 500 ppm groups. The findings in the supplementary
groups showed that the effect on reproduction was mediated via the
dams. The NOAEL was 50 ppm. Based upon this study, doses of 40, 120
and 360 ppm were selected for the multiple-generation study (Becker &
Sachsse, 1986).
In a two-generation study, groups of 30 male and 30 female SPF
Wistar rats, 7 weeks of age (F0) were administered glufosinate
ammonium (purity 95.3%) in their diet in concentrations 0, 40, 120 and
360 ppm for a period of 80 days preparing and during pairing,
gestation and lactation for breeding of the F1a and F1b groups. The
F1b rats were dosed similarly to the F0 for a period of 101 days
including lactation for breeding F2a and F2b. Analysis showed the
concentration of the test substance in the diet to be 109, 102, and
104% of the nominal concentrations 40, 120 and 360 ppm respectively.
Homogeneity varied between +16% to -17%, and the substance was stable
for 21 days at room temperature. Concentration of the metabolites (see
Biotransformation) was lower than 0.2% during a period of 6 months.
A slightly reduced food intake was noted in F0 and F1 high-dose
females during lactation periods. There was a decrease in litter size
in the 360 ppm group, and increased weights of kidneys in males dosed
at 120 and 360 ppm and in top-dosed females. No other treatment-
related changes were found. The NOAEL for reproduction was 120 ppm
(equivalent to 12 mg/kg bw) due to reduced litter size in the
top-dosed group (Becker & Sachsse, 1987).
Special studies on embryotoxicity
Glufosinate ammonium (purity: 97.7%) was administered orally to
groups of 20 mated female SPF Wistar rats, about 70 days of age in
doses 0, 10, 50 and 250 mg/kg bw/day (in redistilled water, 5 ml/kg
bw) days 7-16 of pregnancy (day one = sperm detection). Caesarean
section was performed on day 21. Dose-related clinical signs of
toxicity were observed at all dose levels and consisted of motor
unrest accompanied in the two highest dosage groups by hyperactivity,
piloerection, vaginal haemorrhages, and reduction in body weights.
Average food consumption and body weight gain was lowered in top-dosed
animals. Number of dams carrying live fetuses to term in the 50 and
250 mg groups was 16 and 10, respectively, compared to 20 in low-dosed
animals and controls. Number of corpora lutea and implantations was
comparable with that of the controls. Examination of the fetuses
revealed a dose-related increased incidence of distension of renal
pelvis and ureter in all three dose groups, and a slight retardation
in ossification in the 250 mg/kg bw/day group was observed. The
autopsy of the dams revealed no changes in the low-dose group when
compared with the controls (large adrenals and a noticeable small
spleen in the 50 and 250 g/kg bw/group were seen in dams with vaginal
haemorrhages or only dead implantation), and the only effect on organ
weights (decreased liver weight) was seen in the high dose dams. No
NOAEL was identified for maternal or embryonic/fetal toxicity (Baeder
& Kramer, 1985a).
Glufosinate ammonium (purity: 97.2%) was administered orally to
groups of 21-24 mated female SPF Wistar rats, 70 days of age in doses
0, 0.5, 2.2 and 10 mg/kg bw/day (in distilled water, 5 ml/kg bw) from
days 7-16 in pregnancy (day 1 = sperm detection). Caesarian section
was performed day 21. No clinical signs of intoxication were
observed. Food consumption and body weights were not affected in any
dosed groups. The only malformations observed were a diaphragmatic
hernia in one control fetus, gastroschisis in one fetus in the 2.24 mg
group and one fetus with cleft palate and two fetuses in one litter
from the 10 mg/kg bw/day dose level with haematocysts on both hind
paws accompanied of aplasia in the corresponding toes. A slight
increase in weights of kidneys and spleen was found in high dose dams.
The NOAEL for both maternal or embryonic/fetal toxicity is 2.24 mg/kg
bw/day (Baeder & Kramer, 1985b).
Glufosinate ammonium (purity: 96.9%) was administered orally to
groups of 20-25 mated female SPF Wistar rats, 65-70 days of age in
doses of 0, 0.5, 2.2 and 10 mg/kg bw/day (in distilled water, 5 ml/kg
bw) from day 7 to 16 in pregnancy (Day 1 = sperm detection). The
animals were allowed to deliver normally and rear their offspring for
21 days. Two dams in the 10 mg group were found in lateral position
with extended limbs, one on day 7 and one 3 days after treatment.
Piloerection was observed in two dams in low and mid-dose group and
one in the high-dose group. No other disturbances were observed in
behaviour and general health condition. The NOAEL is 10 mg/kg bw/day
for maternal, embryonic and fetal toxicity (Pensler et al., 1986).
Glufosinate ammonium (purity: 95.3%) was administered orally to
groups of 15 mated female Himalayan rabbits, 6-7 months of age in
doses of 0, 2, 6.3 and 20 mg/kg bw/day (in distilled water, 5 ml/kg
bw) from day 7-19 in pregnancy (the day of pairing = day 0). Caesarian
delivery was performed on day 29 of pregnancy and the fetuses were
kept in an incubator for 24 hours and subsequently examined for
abnormalities. A decrease in water consumption and/or quantity of
faeces was observed between days 13 and 25 of pregnancy in 4 dams in
the low-dose group, 2 in the mid-dose group, 7 in the high-dose group
and 1 in the controls. Premature birth occurred in one animal in the
6.3 mg group and one in the 20 mg/kg bw/day. Food intake was
significantly lowered in the 6.3 and 20 mg groups. Only in the
high-dose group was a significant reduction in average body weight
observed. The mean number of dead fetuses was significantly different
than the control group at the high dose level. Body weight in live
fetuses of high-dose animals was slightly but significantly reduced.
Morphological examination of the offspring revealed no
treatment-related effect. An increase in kidney weights was observed
in the high dose dams. The NOAEL in rabbit is around 6.3 mg/kg bw/day
(Baeder & Kramer, 1984).
Special studies of genotoxicity
Genotoxicity
Special studies of neurotoxicity
Glufosinate ammonium, in a formulation containing 40% active
ingredient, was administered to groups of 6 Leghorn hens, weighing
1214-1728 g once orally in the dose 10 000 mg/kg bw with
administration repeated 21 days after the first treatment with or
without antidote (10 mg/kg bw atropine + 4 mg/kg bw
1,1'-oxydimethylenebis (4-formylpyridinium chloride) dioxime)). No
substance-related effect was found in tests for neurotoxicity or on
morphology in brain, spinal marrow and peripheral nerves (Leist &
Weigand, 1979).
Table 2. Results of genotoxicity assays on glufosinate-ammonium
Test system Test object Concentrations Purity Results Reference
(%)
Procaryotic systems
in vitro
Ames test (with and S. typhimurium 5-1000 µg/plate 92.1 Negative Othaka et al., (1981)
without activation) TA98, TA100, (500 µg/plate
TA1535, TA1537, cytotoxic)
TA1538
Reverse mutation E. coli WP2H 5-1000 µg/plate 92.1 Negative Othaka et al., (1981)
(with and without (500 µg/plate
activation) cytotoxic)
Rec assay B. subtilis, 50-10 000 µg/ 92.1 Negative Othaka et al., (1981)
H17, M45 disc
Gene conversion/ S. cerevisiae 1000-10 000 µg/ 95.3 Negative Mellano & Milone (1984a)
DNA repair test D4 plate
(with and without
activation)
Forward mutation Schizosaccharomyces 125-1000 µg/ml 95.3 Negative Mellano & Milone (1984b)
test (with and without pombe
activation)
Table 2 (contd).
Test system Test object Concentrations Purity Results Reference
(%)
Mammalian test systems
in vitro
Unscheduled DNA Primary rat 26.2-5240 µg/ml 95.3 Negative Cifone & Myhr (1984)
synthesis assay hepatocytes
Forward mutation Mouse lymphoma 50-5000 µg/ml 95.3 Negative Cifone & Myhr (1985)
assay (with and L51784
without activation)
Structural chromosome Human lymphocytes 1-1000 µg/ml 95.3 Negative Pirovano & Milone (1985)
aberration (with and
without activation)
Mammalian test systems
in vivo
Micronucleus test Male and female 0, 100, 200 & 96.9 Negative Jung & Mayer (1986)
NMRI mice 350 µg/g bw
(15/sex/group) (period: 10 ml/
kg bw)
Special studies on pharmacological actions
Mice, rabbits and guinea-pigs
Pharmacological actions of glufosinate ammonium (purity: 97%)
were investigated in mice, rabbits and guinea-pigs SPF ICR male and
female mice weighing 30-40 and 20-30 g, respectively, were
administered a single peroral dose of 0, 200, 400, 800 and 1600 mg
glufosinate ammonium (in isotonic sodium chloride solution/kg bw.
Neuropharmacological changes (multidimensional observation) were
measured in groups of 3 mice of each sex. Male mice dosed with 800 mg
or above and females dosed with 400 mg or above showed signs
indicating CNS excitation after a latency period of 8 hours.
Hexorbarbital sleeping time was measured in groups of 10 males/group.
Prolonged sleeping time was observed in animals dosed with 800 mg.
SPF male rabbits of a Japanese white strain weighing 2.5-3.5 kg,
3 animals/group were administered (in isotonic sodium chloride
solution, 1 ml per kg bw) a single intravenous dose of 0, 2.5, 10 or
40 mg glufosinate ammonium. Neurological signs such as convulsion,
decreased spontaneous activity, motor incoordination were observed
after a latency period of 8 hours in high dose animals. Abnormal EEG
indicating convulsions appeared more than 4 hours after dosing in
animals at 10 or 40 mg/kg bw. The effect disappeared almost within 4
days. Body temperature was increased 1-2 °C in 2 top-dosed animals 8
hours and 1 day after dosing, respectively. A decrease in respiratory
rate and an increase in respiratory tidal volume was observed. Blood
pressure and ECG were unaffected. Glufosinate ammonium had no effect
on contraction of anterior tibialis muscle caused by direct or
indirect stimulations.
Effect of the substance on haemolysis and blood coagulation was
investigated in an in vitro study using blood from rabbits. No
treatment-related effect was seen on haemolysis, prothrombin time nor
activated partial thromboplastin time at doses of 10-5, 10-4 or 10-3
g/ml. No effect of the substance on isolated guinea-pig vas deferens
(male Hartley, SPF, 6 weeks of age) was observed at doses 10-5, 10-4
or 10-3 g/ml. However, the high concentration increased the
noradrenaline or high K+-induced contraction of the vas deferens. A
concentration of 10-3 g of the substance/ml increased the muscle tone
and the spontaneous contraction of the isolated guinea-pig ileum. No
effect was measured on the acetylcholine, histamine or high K+
-induced contraction in concentrations 10-5, 10-4 and 10-3 g/ml
(Takahashi et al., 1986).
Observations in humans
Workers involved in the optimization of the production process
and formulation of glufosinate ammonium since 1984 were exposed to
very low levels of the substance. These persons were subject to
routine examinations by the manufacturer's department of industrial
medicine in accordance with the Principles 10, 33 and 83 of the
"Berufsgenossenschaft Chemie". Neither clinical nor laboratory
examinations showed findings deviating from the standard values.
There are no reports of adverse effects on health caused by poisoning
at the workplace or by exposure under the conditions of the
recommended use or any published cases of accidental poisoning. A few
cases of suicidal poisoning were described after drinking of large
amounts of the formulated product (200 g/l). The profile of
intoxication observed in suicides corresponded to that observed in the
acute toxicity studies in rodents and dogs (Ebert & Leist, 1989).
COMMENTS
The toxicokinetics of glufosinate-ammonium were investigated in
rats and dogs as well as in livestock (goats and hens). The substance
was rapidly excreted in all test species regardless of the route of
administration. About 80-90% of an oral dose of glufosinate-ammonium
remained unabsorbed and was eliminated unchanged in the faeces over 48
hours, while about 10-15% was eliminated in the urine.
The main metabolite of glufosinate-ammonium found in urine and in
faeces was 3-[hydroxy(methyl)phosphinoyl] propionic acid1. Its
half-life was 6-7 hours in vivo. Rats given a single oral dose of 20
mg/kg bw 3-[hydroxy(methyl) phosphinoyl] propionic acid excreted 92%
in the urine and 3.5% in faeces after 4 days.
Glufosinate-ammonium competitively inhibits glutamine synthetase
in mammals. However, even at high (sublethal) doses, glutamate,
ammonia and glutamine levels in brain, liver and kidney tissues were
unaffected. No effect was seen on enzymes which have glutamate as a
substrate nor on the metabolism of amino acids, glutathione or
carbohydrates. The substance did not impair the oxidative metabolism
in mitochondria in vitro.
The compound showed slight to moderate acute oral toxicity in
rats, mice and dogs; dogs were the most sensitive species.
Short-term toxicity studies were performed in rats, mice and
dogs. In mice, the NOAEL was 80 ppm, equal to 17 and 19 mg/kg bw/day
in males and females respectively, based upon increased plasma
potassium levels at the next highest dose (67 mg/kg bw/day). In rats,
effects on absolute kidney weights were seen at dose levels as low as
0.52 mg/kg bw/day. These effects on kidney weight were not found in
the long-term bioassay in rats. In dogs, the NOAEL was 4.5 mg/kg
bw/day, based on decreased body weight at higher doses. CNS
excitation was seen only in dogs.
When 3-[hydroxy[methyl]phosphinoyl]propionic acid, the primary
metabolite of glufosinate-ammonium, was administered in the diet to
rats for 28 days at concentrations of 50-5000 ppm, the NOAEL was 2500
ppm, equal to 280 mg/kg bw/day. An increase in liver weight was seen
in the high-dose females. Hepatic glutamine synthetase was unaffected
by treatment.
1 The name 3-methylphosphinico-propionic acid was used in reports
provided to the Meeting.
Glufosinate-ammonium was not teratogenic in rats or rabbits. The
NOAELs for maternal and embryo/fetal toxicity was 6.3 mg/kg bw/day in
rabbits and 2.2 mg/kg bw/day in rats.
Glufosinate-ammonium was not carcinogenic in long-term/
carcinogenicity studies in rats and mice. In mice fed 0, 20, 80, or
160 ppm (males) and 0, 20, 80, or 320 ppm (females), the NOAEL was 80
ppm (equal to 11 mg/kg bw/day), with increased male mortality at
higher dietary concentrations. In rats fed 0, 40, 140 or 500 ppm, the
NOAEL was 40 ppm (equal to 2.1 mg/kg bw/day) with increased kidney
weight at 140 ppm. Additional effects noted at higher doses were a
reduction in glutathione level in liver and blood and significant
increases in renal weight.
In a two-generation study in rats the only effect on reproduction
was a reduction in litter size in animals fed 360 ppm
glufosinate-ammonium. The NOAEL was 120 ppm, equivalent to 6 mg/kg
bw/day.
After reviewing the available in vitro and in vivo
genotoxicity data, it was concluded that there was no evidence of
genotoxicity.
The ADI was based upon the NOAEL determined from the long-term
study in rats, using a 100-fold safety factor.
TOXICOLOGICAL EVALUATION
Level causing no toxicological effect
Mouse: 80 ppm in the diet, equal to 11 mg/kg bw/day
Rat: 40 ppm in the diet, equal to 2.1 mg/kg bw/day
Rabbit: 6.3 mg/kg bw/day
Dog: 4.5 mg/kg bw/day
Estimate of acceptable daily intake for man
0-0.02 mg/kg bw
Studies which will provide information valuable in the
continued evaluation of the compound
1. Further observations in humans.
2. Clarification of the biological significance of the increased
renal glutamate synthetase activity observed in rats.
REFERENCES
Baeder, C. & Kramer, M. (1984) Testing for embryotoxicity in
Himalayan rabbits following oral administration. Hoechst Report
84.0177. Submitted to WHO by Hoechst A.G., Frankfurt-am-Main,
Germany.
Baeder, C. & Kramer, M. (1985) Testing for embryotoxicity in Wistar
rats following oral administration. Hoechst Report 85.0748. Submitted
to WHO by Hoechst A.G., Frankfurt-am-Main, Germany.
Baeder, C. & Kramer, M. (1985) Testing for embryotoxicity in Wistar
rats following oral administration. Hoechst Report 85.0771. Submitted
to WHO by Hoechst A.G., Frankfurt-am-Main, Germany.
Bathe, R. & Sachsse, K. (1984) 12-month oral toxicity (feeding) study
in Beagle dogs. Research and Consulting Company A.G. Project 019203.
Submitted to WHO by Hoechst A.G., Frankfurt-am-Main, Germany.
Becker, H. & Sachsse, K. (1986) Preliminary study to the multiple
generation study in rats. Research and Consulting Company A.G. Project
018472. Submitted to WHO by Hoechst A.G., Frankfurt-am-Main, Germany.
Becker, H. & Sachsse, K. (1987) Multiple generation study in rats.
Research and Consulting Company A.G. Project 018483. Amended version.
Submitted to WHO by Hoechst A.G., Frankfurt-am-Main, Germany.
Cifone, M.A. & Myhr, B.C. (1984) Rat primary hepatocyte - unscheduled
DNA synthesis assay. Litton Bionetics, Inc. Project 20991. Submitted
to WHO by Hoechst A.G., Frankfurt-am-Main, Germany.
Cifone, M.A. & Myhr, B.C. (1985) Mouse lymphoma forward mutation
assay. Litton Bionetics, Inc. Project 20989. Submitted to WHO by
Hoechst A.G., Frankfurt-am-Main, Germany.
Dorn, E., Künzler, K., Steinau, M. & Kellner, H.M. (1983) Hoe
039866-14-c, metabolism study on female rats after a single oral dose
of the active ingredient. Fo. 321/83, Analytisches Laboratorium,
Hoechst Aktiengesellschaft. Submitted to WHO by Hoechst A.G.,
Frankfurt-am-Main, Germany.
Ebert, E. & Weigand, W. (1983) Experimental assessment of the
therapeutic action of atropine sulfate + 2-PAM+iodide and
phenobarbital sodium in the case of an acute intoxication by Hoe
039866 in Wistar rats. Hoechst Report 83.0625. Submitted to WHO by
Hoechst A.G., Frankfurt-am-Main, Germany.
Ebert, E. & Kramer, M. (1985) Hoe 039866 - active ingredient
technical examination of the mode of action following single oral
administration of doses up to the sublethal range to female Wistar
rats and NMRI mice. Hoechst Report 85.0066. Submitted to WHO by
Hoechst A.G., Frankfurt-am-Main, Germany.
Ebert, E., Leist, K.H., Mayer, D. & Langer, K.H. (1986) Hoe 061517 -
active ingredient technical testing for subacute oral toxicity (28-day
feeding study). Hoechst Report 86.0012. Submitted to WHO by Hoechst
A.G., Frankfurt-am-Main, Germany.
Ebert, E., Leist, K.H., Mayer, D. & Langer, K.H. (1986) Hoe 039866 -
active ingredient technical studies on the mechanism of action
following subchronic oral feeding of Wistar rats. Hoechst Report
86.0772. Submitted to WHO by Hoechst A.G., Frankfurt-am-Main,
Germany.
Ebert, E. & Leist K.H. (1986) Testing the therapeutic effect of
atropine sulfate + 2-PAM-iodide after acute intoxication with Hoe
039866 in the male and female Wistar rat. Hoechst Report 86.0973.
Submitted to WHO by Hoechst A.G., Frankfurt-am-Main, Germany.
Ebert, E., Leist, K.H., Mayer, D. & Langer, K.H. (1986) Hoe 039866 -
active ingredient technical examination of the mode of action
following a single oral dose in female Wistar rats. Hoechst Report
86.1003. Submitted to WHO by Hoechst A.G., Frankfurt-am-Main,
Germany.
Ebert, E. & Leist, K.H. (1989) Glufosinate ammonium - substance
technical (code: Hoe 039866). Summary and evaluation of the toxicity
data. Report 88.1909, Hoechst. Submitted to WHO by Hoechst A.G.,
Frankfurt-am-Main, Germany.
Ellgehausen, H. (1984) Distribution and excretion of the equimolar
mixture of 14C-Hoe 039866/14C-Hoe 061517 after repeated oral
administration to laying hens. Report to RCC-project 025573,
Itingen/Schweiz. Submitted to WHO by Hoechst A.G., Frankfurt-am-Main,
Germany.
Ellgehausen, H. (1984) Distribution, degradation and excretion of the
equimolar mixture of 14C-Hoe 039866/14C-Hoe 061517 after repeated
oral administration to lactating goats. Report to RCC-project 027562,
Itingen/Schweiz. Submitted to WHO by Hoechst A.G., Frankfurt-am-Main,
Germany.
Ellgehausen, H. (1986) Analysis of radioactivity in liver and kidney
of laying hens after repeated oral administration of the equimolar
mixture of 14C-Hoe 039866/14C-Hoe 061517. Attachment I to
RCC-project 025573, Itingen/Schweiz. Submitted to WHO by Hoechst
A.G., Frankfurt-am-Main, Germany.
Ellgehausen, H. (1986) Absorption, excretion and metabolism of
14C-Hoe 039866 by Beagle dogs after repeated administrations of the
unlabelled test article followed by repeated administrations of the
14C-labelled test article. Attachment I to RCC-project 048734,
Itingen/Schweiz. Submitted to WHO by Hoechst A.G., Frankfurt-am-Main,
Germany.
Ellgehausen, H. (1986) Pharmacokinetic study with 14C-Hoe 039866 on
various organs of male and female Beagle dogs and excretion pattern of
radioactivity after single oral administration of the test article.
Report to RCC-project 050185, Itingen/Schweiz. Submitted to WHO by
Hoechst A.G., Frankfurt-am-Main, Germany.
Ellgehausen, H. (1986) Pharmacokinetic study with 14C-Hoe 039866 on
various organs/tissues of male rats and excretion pattern of
radioactivity after single dermal administration of the test article.
Report to RCC-project 056597, Itingen/Schweiz. Submitted to WHO by
Hoechst A.G., Frankfurt-am-Main, Germany.
Gerhards, G. & Köcher, H. (1986) Pharmacological screening of Hoe
039866 - substance technical and Hoe 061517 - substance technical
following i.c.v. or i.v. Application in male Wistar rats. Hoechst
Report 86.1190. Submitted to WHO by Hoechst A.G., Frankfurt-am-Main,
Germany.
Hollander, H. & Weigand, W. (1982) Aerosol inhalation to the male and
female SPF Wistar rat (4 h - LC50). Hoechst Report 564/82. Submitted
to WHO by Hoechst A.G., Frankfurt-am-Main, Germany.
Hollander, H. & Weigand, W. (1985) Testing for acute dust inhalation
toxicity in male and female SPF Wistar rats (4 h - LC40). Hoechst
Report 84.0889. Submitted to WHO by Hoechst A.G., Frankfurt-am-Main,
Germany.
Inoue, H. & Okamura, T. (1982) Acute oral toxicity in mice. Report
276 AN-PYO Center. Submitted to WHO by Hoechst A.G.,
Frankfurt-am-Main, Germany.
Inoue, H. & Okamura, T. (1982) Acute subcutaneous toxicity study in
mice AN-PYO Center, Report 277. Submitted to WHO by Hoechst A.G.,
Frankfurt-am-Main, Germany.
Inoue, H. & Okamura, T. (1982) Acute intraperitoneal toxicity study
in mice AN PYO Center, Report 278. Submitted to WHO by Hoechst A.G.,
Frankfurt-am-Main, Germany.
Jung, R. & Mayer, D. (1986) Micronucleus test in male and female NMRI
mice after oral administration. Hoechst Report 86.1307. Submitted to
WHO by Hoechst A.G., Frankfurt-am-Main, Germany.
Kellner, H.M. & Dr Eckert (1983) Hoe 039866-14C, study on kinetics
and residue analyses in rats. 01-L42-0400-83. Radiochemisches Labor,
Hoechst Aktiengesell-schaft. Submitted to WHO by Hoechst A.G.,
Frankfurt-am-Main, Germany.
Kellner, H.M. & Dr Eckert (1984) Hoe 061517, Untersuchungen zur
Resorption und Ausscheidung bei der Ratte nach oraler Gabe.
01-L42-0413-84. Radiochemisches Labor, Hoechst Aktiengesellschaft.
Submitted to WHO by Hoechst A.G., Frankfurt-am-Main, Germany.
Kellner, H.M. & Dr Eckert (1985) Hoe 039866-14C. Studies of kinetics
and residue determinations in male and female rats after repeated oral
doses of 2 mg/kg body weight x day on 15 consecutive days.
01-L42-0465-85. Radiochemisches Labor, Hoechst Aktiengesellschaft.
Submitted to WHO by Hoechst A.G., Frankfurt-am-Main, Germany.
Kellner, H.M. & Dr Eckert (1985) Hoe 039866-14C. Studies of kinetics
and residue determinations in rats following oral administration of 30
mg/kg body weight. 01-L42-0467-85. Radiochemisches Labor, Hoechst
Aktiengesellschaft. Submitted to WHO by Hoechst A.G.,
Frankfurt-am-Main, Germany.
Köcher, H. & Schulze, E.-F. (1986) Investigating the effect of the
herbicides Hoe 039866 and Hoe 035956 on various enzymes in vitro.
Hoechst Report Kö 3/1986. Submitted to WHO by Hoechst A.G.,
Frankfurt-am-Main, Germany.
Lacoste, A.M., Mansour, S., Cassaigne, A. & Neuzil, E. (1985) Effect
of phosphonic analogues of glutamic acid on glutamate decarboxylase.
Experientia, 41: 643-644.
Leist, K.-H. & Weigand, W. (1979) Neurotoxicity study with White
Leghorn hens. Hoechst Report 275. Submitted to WHO by Hoechst A.G.,
Frankfurt-am-Main, Germany.
Leist, K.-H. & Weigand, W. (1979) Neurotoxicity testing of Hoe 039866
- active ingredient technical in White Leghorn hens. Hoechst Report
79.0275. Submitted to WHO by Hoechst A.G., Frankfurt-am-Main,
Germany.
Lejczak, B., Starzemska, H. & Mastalerz, P. (1981) Inhibition of rat
liver glutamine synthetase by phosphonic analogues of glutamic acid.
Experientia, 37: 461-462.
Mayer, D. & Kramer, M. (1980) Acute oral toxicity to the male and
female Beagle dog. Hoechst Report 543/80. Submitted to WHO by Hoechst
A.G., Frankfurt-am-Main, Germany.
Mayer, D. & Weigand, W. (1980a) Acute oral toxicity to the male
mouse. Hoechst Report 547/80. Submitted to WHO by Hoechst A.G.,
Frankfurt-am-Main, Germany.
Mayer, D. & Weigand, W. (1980b) Acute oral toxicity to the female
mouse. Hoechst Report 546/80. Submitted to WHO by Hoechst A.G.,
Frankfurt-am-Main, Germany.
Mayer, D. & Weigand, W. (1980c) Acute oral toxicity to the male rat.
Hoechst Report 587. Submitted to WHO by Hoechst A.G.,
Frankfurt-am-Main, Germany.
Mayer, D. & Weigand, W. (1980d) Acute oral toxicity to the female
rat. Hoechst Report 588. Submitted to WHO by Hoechst A.G.,
Frankfurt-am-Main, Germany.
Mayer, D. & Weigand, W. (1982a) Acute percutaneous toxicity to the
male rat. Hoechst Report 495. Submitted to WHO by Hoechst A.G.,
Frankfurt-am-Main, Germany.
Mayer, D. & Weigand, W. (1982b) Acute percutaneous toxicity to the
female rat. Hoechst Report 496. Submitted to WHO by Hoechst A.G.,
Frankfurt-am-Main, Germany.
Mayer, D. & Weigand, W. (1982c) Acute intraperitoneal toxicity to the
male rat. Hoechst Report 497. Submitted to WHO by Hoechst A.G.,
Frankfurt-am-Main, Germany.
Mayer, D. & Weigand, W. (1982d) Acute intraperitoneal toxicity to the
female rat. Hoechst Report 498. Submitted to WHO by Hoechst A.G.,
Frankfurt-am-Main, Germany.
Mellano, D. & Milone, M.F. (1984) Study of the mutagenic activity
with Saccharomyces cerevisiae. Gene conversion - DNA repair test.
Istituto di Ricerche Biomediche. Experiment M 709. Submitted to WHO
by Hoechst A.G., Frankfurt-am-Main, Germany.
Mellano, D. & Milone, M.F. (1984) Study of the mutagenic activity
in vitro with Schizosaccharomyces pombe. Istituto di Ricerche
Biomediche. Experiment M 710. Submitted to WHO by Hoechst A.G.,
Frankfurt-am-Main, Germany.
Metzger, H. (1986) Studies on the influence of Hoe 039866 - active
ingredient technical on the oxidative phosphorylation in rat liver
mitochondria. Hoechst Report 86.1395. Submitted to WHO by Hoechst
A.G., Frankfurt-am-Main, Germany.
Ohashi, H., Nakayoshi, H. & Abe, M. (1982) The effect of Hoe 039866
on glutamine synthetase activity in rat liver. Nomura Research
Institute Report 81-7454. Submitted to WHO by Hoechst A.G.,
Frankfurt-am-Main, Germany.
Ohtake, T., Takahashi, T. & Nakayoshi, H. (1981a) Acute oral toxicity
in male rats. Nomura Research Institute 81-7840. Submitted to WHO by
Hoechst A.G., Frankfurt-am-Main, Germany.
Ohtaka, T., Takahashi, T. & Nakayoshi, H. (1981b) Acute oral toxicity
in female rats. Nomura Research Institute 81-7840. Submitted to WHO
by Hoechst A.G., Frankfurt-am-Main, Germany.
Ohtaka, T., Takahashi, T. & Nakayoshi, H. (1981c) Acute
intraperitoneal toxicity in male rats. Nomura Research Institute, Exp.
81-7840. Submitted to WHO by Hoechst A.G., Frankfurt-am-Main,
Germany.
Ohtaka, T., Takahashi, T. & Nakayoshi, H. (1981d) Acute
intraperitoneal toxicity in female rats. Nomura Research Institute,
Exp. 81-7840. Submitted to WHO by Hoechst A.G., Frankfurt-am-Main,
Germany.
Ohtaka, T., Takahashi, T. & Nakayoshi, H. (1981f) Acute subcutaneous
toxicity in male rats. Nomura Research Institute, Exp. 81-7840.
Submitted to WHO by Hoechst A.G., Frankfurt-am-Main, Germany.
Ohtaka, T., Takahashi, T. & Nakayoshi, H. (1981g) Acute subcutaneous
toxicity in female rats. Nomura Research Institute, Exp. 81-7840.
Submitted to WHO by Hoechst A.G., Frankfurt-am-Main, Germany.
Ohtaka, T. & Nakayoshi, H. (1981) Two-week subacute toxicity in rats.
Nomura Research Institute, Exp. 81-7850. Submitted to WHO by Hoechst
A.G., Frankfurt-am-Main, Germany.
Ohtaka, T., Takahashi, T. & Nakayoshi, H. (1981) 13-week subchronic
toxicity in rats. Nomura Research Institute, Exp. 81-7860. Submitted
to WHO by Hoechst A.G., Frankfurt-am-Main, Germany.
Othaki, Y., Nomura, A., Nakayoshi, H. & Nakasawa, M. (1981) In vitro
microbial assay for mutagenicity testing. Nomura Research Institute,
Exp. 81-7359. Submitted to WHO by Hoechst A.G., Frankfurt-am-Main,
Germany.
Parcell, B.I. & Kynoch, S.R. (1986) Acute dermal toxicity to rabbits.
Huntingdon Research Centre Ltd. Report 86475 D/HST290/AC. Submitted
to WHO by Hoechst A.G., Frankfurt-am-Main, Germany.
Pensler, M., Baeder, C., Mayer, D. & Langer K.-H. (1986) Testing for
embryotoxicity and effects on postnatal development in Wistar rats
following oral administration. Hoechst Report No. 86.0713. Submitted
to WHO by Hoechst A.G., Frankfurt-am-Main, Germany.
Pirovano, R. & Milone, M.F. (1985) In vitro study of chromosome
aberration in cultured human lymphocytes. Istituto di Ricerche
Biomediche. Experiment M 711. Submitted to WHO by Hoechst A.G.,
Frankfurt-am-Main, Germany.
Sachsse, K. (1986) 28-day oral toxicity (capsule) study in the dog
with Hoe 039866 technical, 14C - Hoe 039866 with special reference
to mode of action and target organ. Part 1. RCC project 048734.
Submitted to WHO by Hoechst A.G., Frankfurt-am-Main, Germany.
Schacht, U. (1986) Hoe 039866 - substance technical: Testing the mode
of action by neurotransmitter receptor binding assays in vitro.
Hoechst Report 86.1243. Submitted to WHO by Hoechst A.G.,
Frankfurt-am-Main, Germany.
Schwalbe-Fehl, M., Steinau, M., Scheinkönig, U., Kellner, H.M. &
Eckert, H.G. (1985) Hoe 039866-14C, metabolism and residue
determinations in rats after single oral administration of 800 mg/kg
body weight. CM008/85, Analytisches Laborat-orium, Hoechst
Aktiengesellschaft. Submitted to WHO by Hoechst A.G.,
Frankfurt-am-Main, Germany.
Schwalbe-Fehl, M. (1986) Hoe 039866, ammonium-DL-homodanin-4-yl
(methyl)-phosphinate. Summary on pharmacokinetics and metabolism in
animal (Analytishes Laboratorium, Hoechst Aktiengesellschaft.
Submitted to WHO by Hoechst A.G., Frankfurt-am-Main, Germany.
Schwalbe-Fehl, M., Steinau, M., Scheinkönig, U., Kellner, H.M. &
Eckert, H.G. (1986) Hoe 039866-14C, metabolism and residue
determinations in female rats after repeated oral administrations of
10 and 100 mg/kg body weight/day, respectively. CM007/85, Analytisches
Laboratorium, Hoechst Aktiengesellschaft. Submitted to WHO by Hoechst
A.G., Frankfurt-am-Main, Germany.
Suter, P. & Sachsse, K. (1984) 28-day range finding study in rats.
Research and Consulting Company A.G. Project 018494. Submitted to WHO
by Hoechst A.G., Frankfurt-am-Main, Germany.
Suter, P. & Sachsse, K. (1986) Combined chronic toxicity/oncogenicity
study in the rat. Dietary administration. Research and Consulting
Company A.G. Project 018505. Submitted to WHO by Hoechst A.G.,
Frankfurt-am-Main, Germany.
Suter, P. & Sachsse, K. (1984) 13-week oral toxicity (feeding) study
in mice. Research and Consulting Company A.G. Project 018516.
Submitted to WHO by Hoechst A.G., Frankfurt-am-Main, Germany.
Suter, P. & Sachsse, K. (1986) 2-year oncogenicity study in mice.
Dietary administration. Research and consulting Company A.G. Project
018527. Submitted to WHO by Hoechst A.G., Frankfurt-am-Main, Germany.
Takahashi, H., Tsuda, S., Ikeda, T., Tanaka, J., Elbino, K. & Shirasu,
Y. (1986) Hoe 039866 OH ZC97 0003 - general pharmacology study. The
Institute of Environmental Toxicology. Submitted to WHO by Hoechst
A.G., Frankfurt-am-Main, Germany.
Til, H.P. & de Groot, A.P. (1982) Sub-chronic (90-day) toxicity study
in dogs. CIVO TNO V82.318/201720. Submitted to WHO by Hoechst A.G.,
Frankfurt-am-Main, Germany.
Wink, O., Haberkorn, B., Künzler, K. & Kellner, H.M. (1986) Hoe
039866-14C, metabolism in male and female rats after a single oral
administration of 2 mg/kg body weight each. CMO82/85I, Analytisches
Laboratorium, Hoechst Aktiengesellschaft. Submitted to WHO by Hoechst
A.G., Frankfurt-am-Main, Germany.
Wink, O., Haberkorn, B., Künzler, K. & Kellner, H.M. (1986) Hoe
039866-14C, metabolism in male and female rats after repeated oral
administrations of 2 mg/kg body weight each on 15 consecutive days.
CMO82/85II, Analytisches Laboratorium, Hoechst Aktiengesellschaft.
Submitted to WHO by Hoechst A.G., Frankfurt-am-Main, Germany.
Wink, O., Dorn, E., Künzler, K., Haberkorn, B. & Kellner, H.M. (1986)
Hoe 039866-14C, metabolism in male and female rats after a single
administration of 30 mg/kg body weight each. Doc. A33895 CMO83/85,
Analytisches Laboratorium, Hoechst Aktiengesellschaft. Submitted to
WHO by Hoechst A.G., Frankfurt-am-Main, Germany.
See Also:
Toxicological Abbreviations
Glufosinate-ammonium (JMPR Evaluations 1999 Part II Toxicological)