495. T, 2,4,5- (Pesticide residues in food: 1979 evaluations)

PESTICIDE RESIDUES IN FOOD - 1979

Sponsored jointly by FAO and WHO

EVALUATIONS 1979

Joint meeting of the
FAO Panel of Experts on Pesticide Residues
in Food and the Environment
and the
WHO Expert Group on Pesticide Residues
Geneva, 3-12 December 1979

2,4,5-T

Explanation

2,4,5-T was reviewed in 1969; however, no recommendations for an
acceptable daily intake or for maximum residue limits were made.
Since that time, the results of additional toxicological and other
studies have become available and are reviewed in this monograph
addendum.

Purity

2,4,5-trichlorophenol, which is required for the preparation of
2,4,5-T, is now only available from very few manufacturers. All
manufacturers known to the meeting confirm that their product contains
less than 0.1 mg/kg of TCDD. Surveys of 2,4,5-T manufactured from
such material and marketed in many countries consistently show
contents considerably below 0.1 mg/kg of TCDD. For example, reports
from U.S.A. (U.S. Environmental Protection Agency, 1979) show that
they are generally below 0.02 mg/kg.

Methods for the determination of TCDD in 2,4,5-T and its formulations,
include procedures developed by the major manufacturer (Dow, 1975).

EVALUATION FOR ACCEPTABLE DAILY INTAKE

Biochemical aspects

Groups of 4 or 5 non-pregnant female Wistar strain rats were dosed
orally with [1-¹⁴C]-2.4.5-trichlorophenoxyacetic acid at dosage
levels of 0.04, 1.04 or 10.04 mg/rat (estimated to be equivalent to
0.17, 4.3 or 41 mg/kg). Four pregnant rats received 0.04 mg/rat.
Excretion, expressed as percent of administered dose, was comparable
in all groups, with 75 percent of the ¹⁴C appearing in urine and 8
percent appearing in faeces within 24 hours. By seven days, 85
percent of the administered ¹⁴C was excreted via the urine and 11
percent via the faeces. No ¹⁴C was detected in expired air.
Analysis of urine showed 90-95 percent of the ¹⁴C was unchanged
2,4,5-T. Three minor metabolites (2 nonpolar and 1 polar) were
detected but not identified. Following administration of 1 mg
[1-¹⁴C]-2,4,5-T to 9 non-pregnant rats, and of 0.04 mg to 6 pregnant
rats, single animals sacrificed at various time intervals, and tissue
analyses were performed. Radioactivity was detected in all tissue,
levels initially being highest in the stomach, but decreasing during
the first 13 hours. Kidney levels were also high and remained higher
than other tissues during the 24 hours (pregnant) or 72 hours
(non-pregnant) of the study. In non-pregnant rats, no radioactivity
was detected in any tissue except kidney at the 72 hours sacrifice.
The average radioactive half-life in adult female rat tissues was 3.4
hours. In pregnant rats, placental ¹⁴C was higher than in any tissue
other than kidney. Fetal ¹⁴C-levels increased with increasing size.
Average half-life of 2,4,5-T in the newborn was 97 hours. A final

experiment based on administration of multiple doses of 2,4,5-T before
and after parturition indicated transfer via the placenta was
considerably less than transfer via the milk. In addition,
distribution in pups differed from that in the adult, the highest
concentrations being in blood rather than in the kidney (Fang, et
al., 1973).

Studies on the pharmacokinetics of 2,4,5-T using [carboxyl-¹⁴C]
2,4,5-T were performed with groups of 3 male and 3 female rats, and 2
male and 2 female dogs. Sex differences were not apparent and data
were combined at each dose level for the two species. Rats received
single oral doses of 5, 50, 100 or 200 mg/kg, and dogs 5 mg/kg.
Plasma clearance rates decreased (half life 4-7, 4-2. 19.4 and 25.2
hours) and volume distribution increased with increasing dose in the
rat. Reversible plasma protein binding of 2,4,5-T was unaffected by
dose. Excretion was primarily via the urine regardless of dose.
However, increasing dose resulted in increased faecal excretion of
2,4,5-T. Half-life for elimination was 13.6, 13.1, 19.3 and 28.9
hours at 5, 50, 100 and 200 mg/kg respectively. At 5 and 50 mg/kg,
urinary ¹⁴C was mainly unchanged 2,4,5-T. A small amount of an
unidentified metabolite was detected, increasing with dose at 100 and
200 mg/kg. Thus, in the rat it was apparent that distribution,
elimination, and metabolism change with increasing dosage. In the
dog, plasma clearance and elimination of 2,4,5-T was much slower than
in the rat. The half-life of 2,4,5-T in plasma was 77 hours and the
elimination half-life was 86.6 after 5 mg/kg dosing. Urinary
excretion exceeded faecal excretion, but the latter was much greater
than in the rat. Three unidentified urinary metabolites were
detected. Thus, in the dog, distribution, elimination and metabolism
differed markedly from the same parameters in the rat (Piper, et al,
1973).

Rats dosed intravenously at levels of 5 or 100 mg ¹⁴C-2,4,5-T/kg
showed first order decrease of 2,4,5-T from plasma at 5 mg/kg, but a
non-linear relationship governed clearance at 100 mg/kg. Plasma
clearance indicated half-lives of 4.33 ± 0.27 hours at 5 mg/kg,
compared with 23.1 ± 4.9 hours (0.36 hours) and 5.30 ± 1.23 hours
(36-72 hours) at 100 mg/kg. Volume of distribution increased with
increased dose level. Excretion in urine was 96 percent of
administered 2,4,5-T in 84 hours at 5 mg/kg, but only 85.8 percent in
168 hours at 100 mg/kg. Faecal excretion (2.78% in 84 hours at 5
mg/kg expressed as percent of administered dose) increased with
increased dose (7.33 percent in 84 hours at 100 mg/kg). Urinary ¹⁴C
was mainly unchanged 2,4,5-T (Sauerhoff, et al., 1976).

In vitro experiments with rat and dog renal cortex slices indicate
that in both species, kidney uptake is due to an active anion
transport system with competitive inhibition of p-aminohippuric acid
transport. Plateau levels were attained in the tissue slices in the
presence of oxygen, but only limited uptake occurred in the presence
of nitrogen. Reduction of potassium levels in the media, in the case
of rat tissue, significantly reduced 2,4,5-T uptake. No effect

occurred in dog tissue with reduced media potassium levels. Acetate
did not alter accumulation of 2,4,5-T in rat tissue, but markedly
enhanced it in dog tissue. Reduced transport and accumulation in
newborn rat kidney slices was also noted, supporting the hypothesis of
renal elimination by active secretion of the compound (Hook, et al.,
1974).

TOXICOLOGICAL STUDIES

Special Studies on Reproduction

Four groups of Sprague-Dawley rats were fed 0 (16 males, 32
females/group), 3 (10 males, 20 females/group), 10 (10 males, 20
females/group) or 30 (16 males, 32 females/group) mg 2,4,5-T/kg body
weight in a three-generation reproduction study.

The 2,4,5-T was purified material containing less than 0.5 ppb
2,3,7,8-tetrachlorodibenzo-p-dioxin. The study design comprised
single breedings of F₀ and F₁ parents, but two breedings of F₂
parents. Gross and histopathology (as well as organ weights) of 5
animals of each sex in each group were performed with all generations.
No consistent effects of 2,4,5-T were noted with respect to parental
body weight, food consumption, fertility index or gestation duration.
Neither were consistent effects noted on litter size, sex ratio, birth
weight, weanling weight, or on gross or histopathology. Survival to
weaning was significantly reduced in all 30 mg/kg dose level offspring
and in F₁, F₂ and F3_a offspring at 10 mg/kg. Even so, except in
the F_3b litters, survival to weaning exceeded 90 percent. Weanling
liver weight ratios were increased in F₂, F_3a and F_3b offspring at
the 30 mg/kg dose level and thymus weight was decreased at 10 and 30
mg/kg in the F_3b offspring (Smith et al., 1978).

Four groups of 20 male and 20 female Sprague-Dawley rats were fed 0,
3, 10 or 30 mg 2,4,5-T/kg body weight in the diet in a standard
three-generation, 2 litter/generation reproduction study. The 2,4,5-T
contained 0.05 ppm 2,3,7,8-tetrachlorodibenzo-p-dioxin.
Histopathology was performed on 10 males and 10 females/dose level
from the F_3b generation at 9 weeks of age. All discarded parents and
offspring were subject to gross pathological examination. No
consistent effects were observed with respect to parental food intake,
water intake, body weight, fertility, or duration of gestation. In
the offspring, no consistent effects were noted with respect to litter
size, sex ratio, survival to weaning, incidence of stillbirths, runts,
or malformations, birth weights, weanling weight, viability or
lactation indices, post-natal development (as judged by time of onset
of hair growth, development of ears, cutting of teeth or opening of
eyes), or sensory function (as judged by consciousness, emotional
behaviour, activity and reactivity, central excitation, positions and
posture, muscle tone, or reflexes). Autopsies revealed no consistent
gross or histopathological effects including absolute or relative
organ weights (Leuschner, et al., 1978).

Special Studies on Teratogenicity

Mouse

A total of 199 NMRI mice (group size 12-23) were treated on days 6-15
of pregnancy with oral doses of 0, 20, 40, 80 or 120 mg/kg of 2,4,5-T
acid (containing 0.1 ppm 2,3,7,8-tetrachlorodibenzo-p-dioxin) or
2,4,5-T butoxyethylester, the dose for the latter being expressed as
free acid. At 80 and 120 mg/kg (toxic to the maternal animals),
malformations (7.9 and 22.3 percent, respectively) and fetal loss
(13.5 and 51.5 percent, respectively) were observed with 2,4,5-T acid.
The ester caused effects only at 120 mg/kg, resulting in 11.6 percent
malformations and 11.6 percent fetal loss (Frohberg, 1974).

In a series of experiments on about 700 MNRI mice sacrificed on day 18
of pregnancy (day 0 being the day when vaginal plugs were detected),
Neubert and Dillman (1972) considered the effects of 2,4,5-T, TCDD,
and the combination of the two compounds on induction of cleft palate.
Dose levels of 2,4,5-T containing less than 0.02 ppm TCDD on days 6-15
of gestation resulted in an increased cleft palate induction rate at
45 mg/kg/dy. No significant effects were noted at 30 mg/kg/day. A
sample of 2,4,5-T containing 0.055 ppm TCDD resulted in a significant
increase in cleft palate incidence at 60 mg/kg, but an insignificant
increase at 30 mg/kg. TCDD caused an increased cleft palate incidence
at 30 µg/kg, but not at 0.3 µg/kg. Combination studies with 2,4,5-T
containing less than 0.02 ppm TCDD with TCDD, using 30 mg 2,4,5-T/kg
with 0.3 or 3.0 µg TCDD/kg, or 60 mg 2,4,5-T/kg with 0.1, 0.3 or 3.0
TCDD/kg resulted in demonstration of potentiation in the cases where
teratogenic doses of 2,4,5-T (60 mg/kg) was combined with a
non-teratogenic dose of TCDD (0.3 µg/kg). No potentiation occurred
with 60 mg 2,4,5-T/kg in combination with 0.1 µg TCDD/kg.
Potentiation also occurred with 30 mg 2,4,5-T/kS combination with 3.0
µg TCDD/kg, but not at any other combination levels. The authors
concluded that for potentiation of doses of 30 or 60 mg 2,4,5-T/kg to
occur with TCDD, levels of TCDD contamination must exceed 1 ppm.

Rat

Groups of 25 female Sprague-Dawley rats were intubated with 1, 3, 6,
12 or 25 mg 2,4,5-T/kg body weight on days 6-15 of pregnancy (day 0
being the day of detection of positive vaginal smears). A group of 50
rats received the suspending vehicle (Methocel^(R)) on a similar time
schedule, at the maximum volume administered to test animals. The
2,4,5-T contained 0.5 ppm 2,3,7,8-tetrachlorodibenzo-p-dioxin. All
offspring were removed by Caesarean section on day 20. Resorption
rates were comparable in all groups, and no stillbirths were reported.
Mean pup weight was comparable to, or slightly greater than, controls
in all test groups. Gross, skeletal and soft tissue examination of
control and high dose offspring revealed minor abnormalities, the
incidence being greater in the controls than in the high dose test
group, except for delayed ossification of the fifth sternebra. The
increased incidence, with respect to this parameter, was within the
normal incidence range of Sprague-Dawley rats (Emerson, et al 1971).

Groups of 25 rats were dosed by intubation on days 6-15 of gestation
(day 0 being the day of detection of positive vaginal smears) with 50
mg 2,4,5-T/body weight, or on days 6-10 of gestation with 100 mg
2,4,5-T/kg body weight. Controls were given appropriate volumes of
vehicle (Methocel^(R)). The level of
2,3,6,7-tetrachlorodibenzo-p-dioxin in the technical 2,4,5-T was 0.5
ppm. Mortality of maternal animals was 80 percent at 100 mg/kg,
preceded by marked body weight loss. Resorption rate was slightly
increased at 50 mg/kg (12.1 percent or 6.6 percent in controls) and
markedly increased at 100 mg/kg. At 100 mg/kg, only one litter
provided viable fetuses. Reduced pup weight and delayed ossification
were noted in this litter. At 50 mg/kg, pup weight was comparable to
control values. An increased incidence of delayed ossification of the
skull was noted, as compared to controls (Sparschu, et al.,1971).

Four samples of 2,4,5-T containing less than 0.5 ppm
2,3,7,8-tetrachlorodibenzo-p-dioxin and one sample of the butyl ester
of 2,4,5-T were administered to groups of Wistar rats, at dose levels
up to 150 mg 2,4,5-T/kg body weight. Treated groups ranged from 6-14
pregnant females/dose level for 2,4,5-T and for the butyl ester, group
size comprised 3 (150 mg/kg) or 6 (50 mg/kg) pregnant rats. Dosing
was via intubation on days 6-15 inclusive of pregnancy. The day of
detection of positive vaginal smears was deemed to be day 1 of
gestation. Parental animals were killed and fetus removed on day 22
of gestation. At 150 mg 2,4,5-T/kg, both samples tested at this dose
caused reduced body weight gain in the gravidas, one of the two
samples causing 3/3 deaths. No signs of toxicity were observed with 3
samples tested at 100 mg/kg; maternal weights were also unaffected by
150 mg 2,4,5-T butyl ester/kg. Litter size (based on viable fetuses)
was unaffected by 2,4,5-T or its butyl ester. However, incidence of
dead fetuses, fetal weight and incidence of malformed fetuses
increased with dose at the 100 and 150 mg 2,4,5-T/kg levels. These
effects were not apparent in the limited studies with butyl ester.
Malformation observed with high doses of 2,4,5-T included wavy ribs,
additional ribs, retarded ossification of frontal and parietal bones,
a wide range of eternal defects, fused ribs, and micromelia. In a
second phase of the study, parents treated with 2 of the 4 samples of
2,4,5-T were permitted to litter, and offspring were maintained for 12
weeks. Maximum dose level was 100 mg/kg. Sex ratios, viability and
rate of body weight gain to maturity was unaffected (Khera and
McKinley, 1972).

Rabbit

Groups of 20 virgin New Zealand White rabbits, artificially
inseminated, were dosed orally by gelatin capsule at 0, 10, 20 or 40
mg 2,4,5-T/kg body weight on days 6-18 of gestation. The 2,4,5-T
contained 0.5 ppm 2,3,7,8-tetrachlorodibenzo-p-dioxin. Offspring were
removed by Caesarean section on day 29 of gestation. Incidence of
resorptions, stillbirth, and absorptions were not affected by 2,4,5-T
administration. Pup birth weight was non-significantly reduced in all
test groups compared to controls. The slight reduction was not dose
related. In the control and 40 mg/kg group, detailed visceral and

skeletal examination did not reveal any abnormal incidence of minor
malformation. No major malformations were reported. Postnatal
mortality in the first 24 hours was 7, 26, 11 and 16 percent at 0, 10,
20 and 40 mg/kg respectively. The significance of this non
dose-related effect is obscured by initially incorrect (low)
incubation temperatures. The cause of death appeared to be occluded
nares. On the last day of fetal collection, incidence of small and/or
non-patent nares was 36, 25, 26 and 22 percent in controls, 10, 20 and
40 mg/kg groups, respectively (Emerson et al., 1971).

Monkey

Four groups of ten pregnant Rhesus monkeys were dosed orally with 0,
0.05, 1 or 10 mg 2,4,5-T/kg on days 22-38 of pregnancy. The 2,4,5-T
contained 0.05 ppm 2,3,4,7-tetrachlorodibenzo-p-dioxin. Pregnancies
were permitted to go to term and young were examined within 24 hours
of birth and weaned at 4 months. Sacrifice was at 1 year post-partum.
During the study, no signs of maternal toxicity were reported.
Incidence of stillbirths (1/10 at 1 mg/kg), abortions (1/10 at 0, 1/10
at 1, and 2/10 at 10 mg/kg), duration of gestation, birth weight, and
post-natal development were normal for the colony. No malformation
was detected in any offspring, including stillbirths. (The abortions
at 1 and 10 mg/kg were prior to 50 days gestation and were not
examined). Clinical chemistry and hematology at 0, 6 and 12 months
post-partum were stated to be within normal limits for the colony
(Dougherty, et al., 1975).

Sheep

Eleven ewes, force fed 100 mg 2,4,5-T/kg body weight in ground alfalfa
meal on days 14-36 of gestation, all produced normal offspring. A
further group of five ewes were force fed 113 mg 2,4,5-T/kg body
weight for days 14-19 (one ewe), 14-27 (2 ewes) and 14-29 (2 ewes) of
gestation. These ewes also produced full-term normal lambs. The
2,4,5-T contained 1 ppm 2,3,4,7-tetrachlorodibenzo-p-dioxin. The
administration orally of 100 mg/kg body weight of the 2,4,5-T
propylene glycol butyl esters to an unknown number of ewes did not
result in any malformed offspring (Benns and Balls, 1971).

Special Studies on Carcinogenicity

Groups of XVII/G or C3Hf mice were given 2,4,5-T containing less than
0.05 ppm total dioxins (0.02-0.03 ppm
2,3,4,7-tetrachlorodibenzo-p-dioxin) in their drinking water at a
level of 100 mg/L, for 2 months, followed by dietary administration at
a level of 80 ppm in the diet for the remainder of their lifespan.
Average survival time was significantly increased in XVII/G males and
significantly decreased in C3Hf males. The effective group size (i.e.
surviving beyond 300 days), was between 32 and 44 for controls, and 19
and 25 for test groups. In the XVII/G mice, incidence of animals with
tumors was 53 and 78 percent in female and male mice, comparative
figures in the test groups being 84 and 75 percent. The majority of
tumors in all groups were lung tumors. In C3Hf mice, incidence of

animals with tumors was 21 and 49 percent in female and male controls,
and 48 and 55 percent in female and male test animals. The majority
of the tumors was spontaneous hepatomas. In females of the C3Hf test
group, tumors not seen in the control group included a sebaceous
squamous cell carcinoma, a squamous cell carcinoma and an osteogenic
tumor with pulmonary metastasis. It was concluded that 2,4,5-T was
not tumorigenic in XVII/G mice, but in C3Hf mice, a significant
increase occurred in the total yield of tumors in female mice
(Muranyi-Kovacs, et al., 1976).

Special Study on Mutagenicity

Groups of 5 male rats from the F_3b litters of a three-generation
study utilizing 0, 3, 10 or 30 mg 2,4,5-T/kg body weight dose levels
were sacrificed at 26 weeks of age, and metaphase chromosomes of
spermatogoneal cells (40 cells/animal) were examined for gaps, breaks,
atypical chromosomes, or pulverized metaphases. A low incidence
(comparable in all groups) of pulverized metaphases was recorded. All
other parameters were negative (Leuschner, 1978).

Short Term Studies

Monkey

Twelve mg 2,4,5-T/kg administered for 18 consecutive days to male and
female Rhesus monkeys produced toxic signs including loss of appetite,
vomiting, and loss of body weight (Dougherty, et al., 1975

Long-Term Studies

Rat

Groups of 50 male and 50 female Sprague-Dawley rats were fed 3, 10 or
30 mg 2,4,5-T/kg body weight for 2 years. Eighty-six rats/sex were
maintained as controls. An additional 10 rats/sex/group were
initiated to provide an interim kill at about 120 days. Dioxins
(tetra-, hexa-, hepta-, and octa-chlorodibenzo-p-dioxins) were not
detected in the 2,4,5-T. Analytical sensitivity for each dioxin was
at or below 0.4 ppb. No effects were noted on food consumption,
mortality, hematology, or clinical chemistry at any dose level. Body
weight was decreased in females at 30 mg/kg; male urine volume,
coproporphyrin, and uroporphyrin excretion were increased at 30 mg/kg,
and in the initial stages of the study, coproporphyrin excretion was
increased at 10 mg/kg. In females, coproporphyrin excretion was
increased at 30 mg/kg only. Organ weight ratios were increased in
males at 30 mg/kg in the case of kidney at 120 days, and at 2 years
the heart ratio only was increased. Gross and histopathology
indicated changes at 30 mg/kg in kidney in females (dose related
increase in mineralization in renal papillae or renal pelvis at 10 and
30 mg/kg), increased pigmentation (possibly iron, since the reaction
to Mallory's stain increased) and in proximal convoluted tubular
epithelium at 30 mg/kg); in males, decreased spontaneous chronic
nephritis, accompanied by increased mineralization of pulmonary

alveoli, myocardium, myocardial blood vessels, gastric mucosa, and
muscles at 30 mg/kg. Changes were also noted in liver and lung at 30
mg/kg. Tumor incidence was detailed and failed to indicate either
overall increase in tumor incidence, changes in site specific
incidence or changes in incidence of specific types of tumors (Kociba,
et al., 1979).

Groups of 60 male and 60 female Sprague-Dawley rats from the F_1a
generation of a reproduction study were selected (2-4 males and 2-4
females/litter) at 6 weeks of age and were fed 0, 3, 10 or 30 mg/kg
2,4,5-T/kg body weight via the diet for 130 weeks. An additional
group of 60 males and 60 females were fed untreated diet, the original
control group being fed diet treated with acetone volatized off prior
to feeding. The 2,4,5-T contained 0.05 ppm
2,3,4,6-tetrachlorodibenzo-p-dioxin. Ten rats/sex/group were subject
to an interim kill at 13 weeks. With respect to behaviour, condition
of faeces, mortality, water intake, food intake, body weight,
hematology, chemical chemistry urinalysis, ophthalmology, auditory
acuity, and dentition defects, all groups were comparable. No
consistent absolute or relative organ weight changes were noted at
either 13 or 130 weeks with respect to 12 organs. No dose or
compound-related non-neoplastic lesions were observed. Incidence of
tumor-bearing animals was high in all groups, being greatest in the
untreated controls (80 percent in males and 80 percent in females).
There was no evidence of 2,4,5-T induced tumors with respect to total
incidence, incidence of benign, or malignant tumors, altered tumor
induction time, site-specific tumors or particular tumor types
(Leuschner, et al., 1979).

Observations in Man

Seven males, 31-58 years of age, exposed to a single oral dose of 5 mg
2,4,5-T (99% purity, with less than 0.05 ppm
2,3,4,7-tetrachlorodibenzo-p-dioxin)/kg showed no clinical signs of
poisoning as assessed by neurological evaluation, blood pressure,
pulse rate, pulmonary function, electrocardiogram, chest X-ray, and a
complete battery of urological, hematological and clinical chemistry
parameters (Gehring, et al., 1973).

Seven human volunteers received 5 mg/kg, which was followed by
periodic blood sampling and urine and faecal collection. Plasma
elimination and excretion from the body followed first-order rate
processes with half-lives of 23.01 and 23.06 hours, respectively.
Distribution volume was low, the majority of the 2,4,5-T remaining in
plasma, largely reversible bound to protein. Excretion was mainly via
the urine 88.5 percent of administered 2A5-T being excreted unchanged
via this route in 96 hours. In three of faeces, collectively
accounting for a complete 48 hour voiding, less than 1 percent of the
administered dose was detected (Gehring, et al., 1973).

COMMENTS

A review of the new data available to this meeting showed that no
teratogenic effects of 2,4,5-T have been reported, at the highest dose
levels tested, in rabbit, monkey or sheep. However, at high dose
levels, terata can be induced in rat and mouse.

There are no data indicating carcinogenic potential of 2,4,5-T in rat
or in three strains of mice. In a fourth strain, a questionable
increase in tumor incidence occurred in females.

Pharmacokinetic and pharmacodynamic data suggest that the dog is an
inappropriate species for toxicological extrapolation to man. A rat
carcinogenicity study performed with 2,4,5-T containing 0.05 ppm
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), demonstrated a "no
observable effect" level of 3 mg/kg body weight/day.

The meeting felt that there were minimal concerns regarding the
presence of residues of 2,4,5-T in food, but could not ignore the
toxicological problems associated with the toxic contaminant
2,3,7,7-tetrachlorodibenzo-p-dioxin. The high safety margin utilized
in estimating the temporary acceptable daily intake reflects these
concerns.

TOXICOLOGICAL EVALUATION

Level Causing no Toxicological Effect

Rat: Dietary administration of 3 mg/kg/bw/day

Estimate of Temporary Acceptable Daily Intake for Man

0-0.003 mg/kg body weight.

RESIDUES IN FOOD AND THEIR EVALUATION

Use Pattern

2,4,5-T is a selective herbicide widely used in crop production and in
the management of forests, ranges and industrial, urban and aquatic
sites. Broad-leafed plants are generally susceptible whereas most
grasses, coniferous trees and certain legumes are relatively
resistant. It is widely used to control broad-leafed weeds in wheat,
barley, rice and grain sorghums to suppress unwanted hardwood trees
and brush, to reduce competition with conifers already established or
to prepare sites for the regeneration of conifers in forests; also on
grazing lands to control unpalatable and noxious plants and to kill
brush and small trees that reduce their productivity. In addition
there are various industrial and urban uses including the control of
brush on rights-of-way, of various noxious weeds.

The phenoxy herbicides, including 2,4,5-T, were discovered nearly 40
years ago, and despite the more recent development of many other
herbicides, they remain major tools in vegetation management (Emmelin,
1977). We can expect their continued use in each of these
applications (National Academy of Sciences, 1968).

2,4,5-T, a weak acid, is only slightly soluble in water and petroleum
oils (Crafts, 1961). Although the acid is biologically active, it is
normally converted to water-soluble esters or oil-soluble esters for
convenience in handling and application. The amino forms are diluted
with water and sprayed on foliage or injected undiluted into trees
(Bovey, 1977). Esters are sprayed as oil solutions or as emulsions
with water. Although the strengths of commercial formulations are
expressed in terms of the equivalent content of the parent acid,
esters generally have greater herbicidal activity than the amino
forms; but they are more expensive. Esters may evaporate from foliage
after application, releasing fumes that can move outside the treated
area and cause injury to sensitive plants elsewhere. This hazard can
be reduced by the use of low-volatile (long-chain) esters, but these
cost more than the high-volatile (short-chain) esters and are less
effective as herbicides in some situations (Craftes, 1961). Mixtures
of 2,4-D and 2,4,5-T are commonly employed in brush control (Crafts,
1975a).

A problem with grazing lands is that livestock often consume forage
plants and leave weedy plants untouched. The result is that valuable
species can be suppressed while unpalatable or noxious ones remain
free to prosper under reduced competition. In the absence of proper
management, weeds can come to predominate, often to the exclusion of
forage species. Because of their low cost, high activity, suitability
for low-volume application and ability to kill most broad-leafed
plants, including woody species, without injury to grasses and certain
legumes, 2,4,5-T herbicides are widely used in pasture and range
management (Way and Chancellor, 1976).

Uses of 2,4,5-T herbicides in forestry include the preparation of
sites for tree establishment, selective weeding to release preferred
species from competing woody plants (Byrnes, 1960) and to deal with
situations leading to populations of destructive animals (Marquis,
1975). They are applied from aircraft, by ground broadcast sprays and
by treating individual trees. Rates of herbicide application for both
aerial and ground broadcast treatments generally range from 2 to 4
kg/ha of 2,4,5-T. (Bovey, 1977).

RESIDUES RESULTING FROM SUPERVISED TRIALS

When 2,4,5-T herbicides are sprayed on vegetation, a residue of the
herbicide is deposited on plant foliage, on soil, on fences, poles and
structures, and often onto surface waters. Of the herbicide deposits
on leaves, some is absorbed into the living tissues, often killing the
plant (Audus, 1976; Kearney and Kaufman, 1975; Ashton and Crafts,
1973). The residue remaining in the tissues of dead plants is largely
decomposed as plant material rots; however, some is released into the

soil. The herbicide remaining in surviving plants is broken down over
a period of a few days to few weeks. Forage from pastures and ranges
treated with 2,4,5-T has initial residues in and on the plant material
of about 100 mg/kg per kg of chemical applied per hectare (Morton et
al., 1967). Initial residues in and on forage rarely exceed 300 mg/kg
and this only on sparse vegetation from the heaviest allowable rates
of use on grazing lands (Clark et al., 1975). Forage residues
decline with a half-life of one to two weeks. Thus, within two to
four weeks, levels have usually fallen into the range of one half to
one sixteenth of the initial value.

Residues on Grasses and Forage

Bovey and Hour (1972) detected from 27 to 140 mg/kg 2,4,5-T on the day
of application of 0.5 kg/ha and 53 to 144 mg/kg from 1 kg/ha
applications on native or tame pasture grasses. Similar amounts using
similar rates of 2,4,5-T per hectare have been reported in other
studies (Bovey et al., 1974; Bovey et al., 1975; Morten et al.,
1967).

Baur et al (1969) applied 2,4,5-T in the form of the 2-ethyl hexyl
ester at the rate of 2 kg/ha alone and with 0.5, 1 and 2 kg/ha of
picloram to pastures supporting infestations of woody plants.
Recovery of 2,4,5-T acid and ester from woody and grass tissues was
greatest when applied along with picloram. Residue concentration in
all treatments, however, was usually less than 10 and 0.1 mg/kg, 1 and
6 months, respectively, after application.

Bovey and Baur (1972) analysed forage grasses from 5 locations in
Texas with wide variations in grass species, soils and climate. These
areas had been treated with propylene glycol butyl ether esters of
2,4,5-T at 0.5 and 1 kg/ha. An average of 98% of the 2,4,5-T was lost
from all treated areas 6 weeks after treatment. After 26 weeks the
residue levels on grass ranged from 0 to 0.05 mg/kg.

In two separate studies, Bovey et al. (1974, 1975) applied a 1:1
mixture of triethylamine salt of 2,4,5-T and picloram at a total of 1
and 2 kg/ha on pasture land in central Texas. Repeat treatments were
made every 6 months to the same area for a total of 5 applications.
Herbicide content of native grasses was highest (28 to 113 mg/kg)
immediately after spraying, degraded rapidly after each treatment, and
tended to disappear before each new application was made. There was
no accumulation of 2,4,5-T in vegetation. Other investigators report
similar results (Scifres et al., 1977; Norris et al., 1977;
Radosevich and Winterlin, 1977).

Baur et al. (1969) found most of the 2,4,5-T applied at 2 kg/ha as
the 2-ethyl hexyl ester to live oak disappeared in 6 months. However,
small amounts, both the acid (0.09 mg/kg) and ester (0.23 mg/kg) of
2,4,5-T could be detected 6 months after application. More 2,4,5-T
was found in live oak tissue at 1 and 6 months from the top of the
plant than the middle and lower stem due to the top portion
intercepting more spray initially than lower regions.

Norris et al. (1977) determined residues of 2,4,5-T in 4 species of
forest vegetation after 2 successive annual applications of herbicide
(4 kg/ha as iso-octyl ester applied in diesel oil by helicopter).
Their results show a sharp decrease in herbicide concentration the
first month after application. The mean half-life of 2,4,5-T for all
species was about 2 weeks after both the first and the second
applications. The rate of residue decline slowed up after 3 months.
One year after application, residues ranged from 0.48 mg/kg in vine
maple foliage to 0.07 mg/kg in blackberry runners and foliage.
2,4,5-T residues were below detectable limits (0.01 mg/kg) in all
species except vine maple 2 years after the first application. The
rate of decline of 2,4,5-T residues in vegetation after the second
application was similar to the first except that 1 year after the
second application no detectable residues were present in any of the
sprayed vegetation.

Morton et al. (1967) studied the disappearance of 2,4,5-T over a
3-year period from a pasture containing several herbaceous species.
Most experiments showed half-lives to 2 to 3 weeks after application
in green tissue. The half-life in grass litter was slightly longer (3
to 4 weeks). Shorter persistence in green tissues was attributed to
dilution by growth. Rainfall was important in hastening herbicide
disappearance.

As a result of environmental and species differences encountered in
natural situations, modelling or predicting herbicide kinetics and
concentration in plants and hence potential exposures of herbivores,
is very difficult. However, generalised herbivore exposures may be
estimated by examining typical residue levels on plants after spray
operations. The maximum concentrations immediately after spraying are
found in grasses (40 to 160 mg/kg per kg/ha). While it might be
expected that residues from the volatile esters would initially fall
off more rapidly (i.e. until esters are hydrolyzed), the data show
greater variability among plant species than among formulations of
compounds. The residue-time pattern illustrates a 2-phase pattern of
persistence. A fast phase with a half-life of about 1 to 3 weeks,
probably represents volatilization and wash-off from plant surfaces.
The remaining low levels of herbicide may persist for longer than 5
months in some species.

In 1969, Dow conducted special studies to determine maximum residue of
phenoxy herbicides from direct application to grass in four U.S.A.
locations (Gentry, 1970, Leng 1972). The residues declined with a
half-life of 1 to 2 weeks depending upon geographic location and
within 16 weeks all residues had declined to 0.1 to 7.3 (average 3)
mg/kg for each kg of herbicide applied per hectare.

Morton et al. (1967) found 90 to 300 mg/kg 2,4,5-T on grasses
immediately following application to 2 kg/ha of 2,4,5-T. The range of
residues from a 0.5 kg/ha application varied from 50 to 110 mg/kg due
to the type and condition of grass at the time of application.
Obviously, more spray will be intercepted by a thicker stand of grass.

Radosevich and Winterlin (1978) set out to measure the persistence of
2,4-D and 2,4,5-T in chaparral brush growing in an environment
characterised by moist cool winters which are followed by about 5
months of hot dry conditions. Following the applications of 2,4,5-T
at the rate of 4. 5 kg/ha 1023 mg/kg of 2,4,5-T was recovered
immediately after application. Within 2 days the level of chamise and
grass had fallen to 18% and 32% respectively of the initial deposit.
At the end of 30 days the residue in these plant materials had
declined to 1.3 and 3% of the initial deposit. There was further
steady decline so that at the end of 12 months the deposit on chamise
was only 0.02% of the original deposits.

Residues in Berries

Spraying with 2,4,5-T is frequently recommended for control of brush
in woodland during summer when young conifers are likely to be least
susceptible to the herbicide. The danger of spraying at a time when
such bush fruits as raspberries are likely to be picked and consumed
was examined in trials in 1972 and 1973 by Olberg et al (Olberg 1973
and Olberg et al 1974). It appears that 2,4,5-T applied at 5kg/ha,
in 2 formulations in mid-summer, caused relatively fast leaf wilt, but
green berries continued to ripen and became "conspicuously large and
beautiful".

Residue levels were determined in fruits picked at various times
between 0 and 41 days after application. The results present a
confusing picture, possibly due to the shielding of fruit by leaves.
Initial residue levels were markedly different in the 2 years of the
study. The first year results with 1 formulation show a 4-fold
decrease in residue levels in 41 days, but virtually no change in
residue levels over the same period of the second formulation. In the
second year, initial residue levels were much higher by a substantial
margin. These levels declined relatively quickly, however, with a
mean half-life of 8.6 days for the first 15 to 17 days after
treatment. There was a marked reduction in the rate of decrease after
that time. By the end of the measurement period, which ranged from 29
to 41 days on different plots, residue levels varied from 0.05 to 22.2
mg/kg but the results were compounded to some degree by apparent
2,4,5-T residues in untreated fruits.

In Finland residues of 2,4,5-T from 0.07 to 15 mg/kg were found in
lingonberries when samples were collected 2 to 13 weeks after aerial
spraying of forests (Siltanen and Rosenberg, 1978). By contrast,
Maier-Bode (1972) found only 1 mg/kg 2,4,5-T on unidentified wild
berries in Sweden on the day of treatment by aircraft, due no doubt to
the shielding by overhead foliage. Work in Britain has shown that
blackberry fruit harvested 3 days after spraying with 2,4,5-T at 3
kg/ha contained 100 mg/kg of 2,4,5-T (Brown and MacKenzie, 1971).
Fully-ripened fruit remained in good condition for 3 to 4 days, but
then developed mold and began to drop from the bushes, while immature
fruit failed to ripen following treatment.

Blackberries which grow in forests, hedgerows and roadsides in many
countries are major weed pests in other countries where biological
constraints do not operate to prevent their proliferation and invasion
of pastures, range lands, orchards and similar situations. Donaldson
and Irvine (1979) reported observations on the effects of spraying of
2,4,5-T on the development of blackberry fruit and on the residue
levels in the fruit at various times after spraying of bushes bearing
ripe fruit. The bushes were sprayed to the point of run off with a
0.07% solution of the butoxyethanol ester of 2,4,5-T. Development of
the tagged fruit was followed over the next few weeks. Samples of
ripe fruit were collected just prior to spraying, immediately after
and 3, 7, hours, 1, 2, 3, 4 days, 1 and 2 weeks after spraying.

The initial effect of the 2,4,5-T which was a slight twisting of the
tips of the canes, was apparent 1 day after the treatment, but this
could easily escape the notice of a person unfamiliar with this
herbicide. After about a week the foliage began to turn yellow which,
together with the pronounced twisting of the ends of the canes and
leaf petioles, would indicate that the bushes had been sprayed. The
symptoms then became progressively more severe, until after about 6
weeks the bushes appeared to be dead.

The residues of 2,4,5-T present in ripe blackberry fruit at various
intervals after spraying ranged from 19.4 mg/kg immediately after
spraying to 11 mg/kg 2 weeks later. After 2 weeks the sprayed fruit
was no longer suitable for picking and no further analyses were
carried out.

Residues in Mushrooms

Residues of 2,4,5-T as high as 1.7 mg/kg have been detected in
mushrooms collected from woodland areas 3 to 11 days after spraying
with 2,4,5-T ester at 1.5 to 2.3 kg/ha (Olberg, Kallfass and Wolff,
1978). In Finland residues of 2,4,5-T from less than 0.02 mg/kg to
1.8 mg/kg were found in wild mushrooms when samples were collected 2
to 13 weeks after aerial spraying of forests (Siltanen and Rosenberg,
1978).

Residues in Rice

No residues of 2,4,5-T were detected in grain or hulls of rice treated
twice with 2,4,5-T at 0.75 and 1.5 kg/ha and harvested 50 or 84 days
after the last application. Residues found in rice straw ranged from
1 to 13 mg/kg using alkaline extraction and/or hydrolysis which is
about 10 times more than found using solvent extraction in the
presence of acid (Dow, 1973).

Residues in other cereals

At the 1970 meeting, data on the level and fate of 2,4,5-T residues on
barley, oats, rye and wheat were calculated. It was concluded that a
MRL of 0.05 mg/kg was needed. Likewise, a much higher limit was
required for cereal straws.

Residues on Sugarcane

Sugarcane growing in Florida was treated twice with 2,4,5-T at 1 kg/ha
using a triethylamine salt formulation. Samples of immature cane were
collected at intervals and analysed for residues using a gas
chromatographic method with a validated sensitivity of 0.05 mg/kg.
The residue in whole raw sugarcane decreased rapidly from 10 mg/kg at
1 day after the second application to less than 0.05 mg/kg at normal
harvest 26 weeks later. Traces of 2,4,5-T present in sugarcane at
early harvest were found to occur principally in the bagasse (fibre)
portion of the stalk and amounted to 0.1-0.4 mg/kg in that by-product.
The sugarcane juice contained less than 0.05 mg/kg. Samples of juice
spiked with 0.1 to 0.4 mg/kg 2,4,5-T were put through the sugar
process in a pilot factory and showed that traces of residue in mixed
juice would become concentrated 5-fold in factory syrup and 9-fold in
first molasses. The residue in raw sugar would be half the level (if
any) in the juice from which it was derived (Dow, 1970).

Residues in Apples

Data obtained by personnel at Cornell University indicated that
treatment of apples with a solution containing 20 to 40 mg/L of
2,4,5-T to prevent preharvest drop caused a residue of less than 0.3
mg/kg 2,4,5-T immediately after application. This residue decreased
to less than 0.1 mg/kg within 3 days of treatment even at double the
registered rate of application. Residues of 2,4,5-trichlorophenol
were not detected in treated fruit. Analyses were performed by
measurement of radio-activity and by gas chromatography (Dow, 1971).

Residues in Meat

Feeding studies were conducted during 1969 and 1970 with 2,4,5-T in
the total ration of dairy cows, beef cattle or sheep for intervals of
2 to 4 weeks (Leng, 1972, 1977). Groups of 3 beef calves were
maintained for 4 weeks on a complete ration containing 2,4,5-T and
were slaughtered the day following the last feeding. Additional
groups of calves were given the highest level of herbicide and were
slaughtered 1 week after replacement of treated feed with untreated
feed. The levels fed to treated calves were 100, 300, 900 and 1800
ppm. Samples of muscle, fat, liver and kidney were analysed for
residues of 2,4,5-T and its corresponding phenol. The methods of
analysis were based on gas chromatography of methyl esters of the
parent acid and methyl esters of the phenol. The methods were
validated to the sensitivity of 0.05 mg/kg in each tissue. The
residue data obtained were published (Jensen et al., 1972; Leng
1972).

Calves slaughtered while ingesting 300 ppm 2,4,5-T in the total ration
contained average residues of 0.1 to 0.28 mg/kg in muscle, fat and
liver and 3.3 mg/kg in kidneys. Proportionally higher average
residues were found in tissues of animals fed 900 and 1800 ppm of
2,4,5-T and slaughtered without withdrawal, but the levels varied
considerably among individual animals in each group. Nevertheless,

the highest residues found in beef kidney was equivalent to only 0.4%
of the daily dose of 2,4,5-T fed to that animal each day for 4 weeks
prior to slaughter. In cases where residues were found in certain
tissues 1 week after withdrawal, they amounted to only 5% of those
found in similar tissues of animals slaughtered without withdrawal
from rations containing 1800 ppm of 2,4,5-T. Residues decline rapidly
in tissues as soon as animals started to eat untreated feed.

No 2,4,5-trichlorophenol was found in the muscle and fat of animals
fed even at the highest level. The residues in kidney were generally
below 0.5 mg/kg for all levels of feeding and averaged residue of
2,4,5-T in the same tissue. As with the parent compound, residues of
the phenol disappeared rapidly when the animals were given untreated
feed.

Clark et al., (1975) reported studies aimed at determining the level
and fate of residues in tissues of sheep. Groups of sheep received
2000 ppm in their rations for 28 days after which some of the animals
were slaughtered and samples of muscle, fat, liver and kidney were
collected. 7 days after the treated feed had been replaced by
untreated feed, the remaining animals were killed and sampled. As
shown in Table 1, significant residues were found only in tissues
taken from animals at the end of the 28-day feeding period. The
highest residues occurred in kidney where 27.2 mg/kg of 2,4,5-T and
0.9 mg/kg of 2,4,5-trichlorophenol were found. This feeding level is
at least 100 and probably more than 500 times the maximum that sheep
would receive under practical conditions.

Clark and Palmer (1971) report that the residue of 2,4,5-T was less
than 0.1 mg/kg in tissues of a sheep given a single oral dose of 25
mg/kg body weight 2,4,5-T propylene glycol butyl ether ester or in
omental fat of sheep given 4 daily doses of 0.15 or 0.75 mg/kg of the
same formulation. Residues of 2,4,5-T as high as 368 mg/kg of tissues
were found in tissues of sheep acutely poisoned by repeated doses of
250 mg/kg of 2,4,5-T acid or the above ester formulation. Low levels
of apparent residues were found in the omental fat of cattle given
daily oral doses of 0.15 or 0.75 mg/kg propylene glycol butyl ether
ester of 2,4,5-T orally for up to 32 weeks of treatment.

Residues in Milk

St John et al., (1964) found that dairy cows given 2,4,5-T in their
ration at 5 ppm for 4 days, completely eliminated 2,4,5-T as soluble
salts in the urine 2 days after dosing stopped.

Leng (1972), Bjerke et al., (1972) report studies in which groups of
3 cows were fed 0, 10, 30, 100, 300 or 1000 ppm of 2,4,5-T in the
total ration continuously for intervals of 2 or 3 weeks at each level,
followed by untreated feed for 1 week after withdrawal from the 1000
ppm ration. Samples of milk and cream obtained at specific intervals
throughout the study were analysed. Average residues found in milk
and cream are given in Table 2.

Table 1. Residues of 2,4,5-T and 2,4,5-Trichlorophenol in Sheep Fed 2,4,5-T for 28 Days^a (Clark et al, 1975)

Residues found, ppm^b

Muscle Fat Liver Kidney

2,4,5-T in 2,4,5-T 2,4,5-T 2,4,5-T 2,4,5-T
feed, ppm 2,4,5-T phenol 2,4,5-T phenol 2,4,5-T phenol 2,4,5-T phenol

2000 1.00 0.13 0.27 <0.05 2.29 6.1 27.2 0.90
2000 (+ w)^c 0.05 <0.05 <0.05 <0.05 <0.05 4.4 0.06 0.81

^a Average of three animals per group (data for individual animals are available).
^b Not corrected for recovery.
^c (+ w) = 7-day withdrawal.

Table 2. Average Residues of 2,4,5-T and 2,4,5-Trichlorophenol in Milk and Cream from Cows Fed 2,4,5-T for 2 or
3 weeks at Each Level Followed by Untreated Feed for 1 Week

2,4,5-T,ppm 2,4,5-Trichlorophenol, ppm

upm Milk Cream Milk Cream
2,4,5-T Cow Number Composite Cow Number Composite
in Diet 36 41 30 36 41 30

10 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05
30 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05
100 0.05 0.05 0.05 0.05 0.06 0.06 0.05 0.06
300 0.05 0.06 0.20 0.07 0.08 0.12 0.10 0.10
1000 0.35 0.31 0.54 0.26 0.16 0.27 0.26 0.19
1000 + 0 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05

The data showed that no detectable residues occurred in milk of cream
of cows ingesting 10 to 30 ppm 2,4,5-T, but traces of
2,4,5-trichlorophenol (0.06 mg/kg) appeared in milk and cream at 100
ppm 2,4,5-T in the ration and of both 2,4,5-T and
2,4,5-trichlorophenol at levels of 2,4,5-T, equivalent to 300 ppm and
1000 ppm in the total ration; but no residues were found in milk or
cream when cows were given untreated feed for 1 to 3 days after 3
weeks on the high level of 1000 ppm in the total ration.

In the light of these findings and of the fact that total diets during
milk production seldom, if every, consist entirely of freshly-treated
forage containing maximum residues of phenoxy herbicides, it can be
concluded that no residues are likely to be found in milk or cream of
cows grazing pastures treated with 2,4,5-T.

Residues in Wildlife

Garcia et al., (1979) searched for residues of 2,4,5-T in aquatic
samples from a reservoir gathering water from a watershed in Texas
that was extensively treated with 2,4,5-T for brush control. No
2,4,5-T was detected in whole fish or in 5 tissues from turtles.
Seven of 22 preparations from turtles contained traces of 2,4,5-T, the
highest 0.013 mg/kg. The turtles containing 2,4,5-T were more
herbivorous than those in which 2,4,5-T was absent.

Newton and Norris (1968) studied blacktail deer whose habitat had been
treated with a combination of 2,4,5-T and 2,4-D. Residues of 2,4,5-T
were found in organs such as brain, kidney, lung, lymph nodes, spleen,
thyroid, as well as blood and urine. The highest concentration ranged
from 0.006 to 0.192 mg/kg. Concentrations in flesh rarely reached
detectable levels and the ruminant was able to degrade and eliminate
the herbicide soon after ingestion.

Residues in Food Commodities

Results of the FDA Market Basket Surveys for 1964 through 1974
indicate that residues of 2,4,5-T are not occurring in food
commodities. With the exception of 3 isolated values reported early
in the Market Basket Survey, no 2,4,5-T has been found using an
analytical method judged to have a limit of detection of 0.002 mg/kg
(Duggan et al., 1967, Martin and Duggan 1968, Corneliussen 1969,
1970, 1972).

FATE OF RESIDUES

In Animals

St John et al., (1964) showed that dairy cows receiving 2,4,5-T in
their feed completely eliminated 2,4,5-T as soluble salts in the urine
2 days after dosing stopped. Clark et al., (1975) showed that sheep
receiving massive doses of 2,4,5-T daily for 28 days in feed
eliminated the herbicide in the urine mainly unchanged although there
was a small conversion to 2,4,5-trichlorophenol. Clark and Palmer

(1971) showed that a sheep given a single oral dose of 25 mg/kg of the
propylene glycol butyl ether ester of 2,4,5-T showed a peak
concentration of 10 mg/L of the unmetabolised ester in blood 3 and 4
hours post-treatment. Within 72 hours, approximately 86% of the
administered dose was recovered from urine as the unmetabolised ester,
and 1.4% was recovered as free 2,4,5-T. Leng (1977) reported that
residues of the phenoxy herbicides in treated food or feed crops were
readily absorbed in the gut of animals and were excreted rapidly in
the urine, largely as unchanged phenoxy acid. Some conjugation
occurred, particularly at higher dosage levels, but the basic
structure of the herbicide was not readily altered in animals.

Haque et al., (1975) studied the binding of 2,4,5-T with the protein
of bovine serum albumin. A weak binding appears to be possible.
Herne (1966) reported the major route of elimination of 2,4,5-T from
pigs, calves and rats dosed with 100 mg/kg was in the urine. Repeated
doses did not result in the retention or accumulation of the
herbicide. A cow which received 5 ppm 2,4,5-T in its feed eliminated
substantially all of the chemical within 2 days following exposure and
no 2,4,5-T was found in the milk (St John et al., 1964).

In Plants

The persistence of 2,4,5-T residues in vegetation may vary from year
to year depending on weather conditions. The length of time required
for half of the 2,4,5-T residues to disappear from forage ranged from
1.6 to 2.6 weeks in one study (Morton et al., 1967). Precipitation
markedly reduced the residues, indicating they were primarily a
surface deposit. However, even in the absence of precipitation, the
residues diminished with time due to growth dilution and metabolism of
herbicide by the plant (Morton et al., 1967). Any 2,4,5-T that is
washed from the foliage into the soil will contribute very little to
residues in subsequent plant growth. The chlorophenoxy acetic acid
herbicides are poorly absorbed and translocated following exposure of
roots (Crafts and Yamaguchi, 1960).

Fitzgerald et al., (1967) studying the degradation of 2,4,5-T in
woody plants, reported that the n-butyl ester of 2,4,5-T is degraded
in sweet gum (liquid amber) and southern red oak (Querous) to yield
2,4,5-trichlorophenol. Basler et al., (1964) established that
2,4,5-T is decomposed in excised leaves from woody plants. Morton
(1966) showed that approximately 80% of the 2,4,5-T absorbed by
mesquite leaves was metabolised after 24 hours. Numerous other
investigations have also shown the importance of metabolism in
detoxification and loss of phenoxy herbicides within many plant
species.

Leaves and stems of plants are the main receptors of foliar-applied
herbicides. Apart from their function in decarboxylation, breakdown,
and conjugation of the herbicide, leaves and plant parts may abscise
from the plant and fall to the soil where the tissue and any residual
herbicide is subject to weathering and decay. Aerial parts of plants
may also be removed by mowing machines or clipped and consumed by

grazing animals. If the herbicide does not kill or stop growth of the
plant, the herbicide will be diluted by the growth and biomass
accretion of the organism. On plant surfaces, 2,4,5-T is lost by
photodegradation and the volatilisation in a manner similar to that
for bosphorum soils. Rainfall is also reported to be an important
means of accelerating herbicide loss from plant surfaces (Bovey et
al., 1974, Morton et al., 1967). Loos (1975) has recently reviewed
the degradation of 2,4,5,-T and other phenoxy herbicides in plants.
In general, because of the widely different degradative pathways, the
phenoxy herbicides do not persist in plants.

Investigations by Winston and Ritty (1972) indicated that 2,4,5-T is
decomposed to form carbon dioxide, inorganic chlorides and water;
chlorophenols are not end-products to this decomposition. Reinhart
(1965) provided supporting evidence. The upper half of a 10-hectare
timbered watershed in northern West Virginia was logged and then half
was treated with 10 kg/ha 2,4,5-T ester to kill all vegetation. No
odour contaminants (phenols or catechols) were found in numerous water
samples taken from the stream draining the treatment watershed.

Morton et al., (1967) using technical grade 2,4,5-T labelled in the
carboxyl position carbon-14, found its apparent half-life averaged 1.6
weeks in green tissues of native grasses in Texas and 1.7 weeks in
litter.

In Forest Litter

Montgomery and Norris (1970) have reviewed the information available
on the fate of 2,4,5-T in the forest environment, the forest floor
being a major receptor of aerially-applied 2,4,5-T. Norris (1966)
reported 5.3% decomposition of 2,4,5-T in 29 days in the highly
organic layers of the forest floor. In another study, 87% of the
2,4,5-T was degraded in 2 months (Norris 1969).

About 60% of the 2,4,5-T in solution was absorbed at equilibrium
(30°C) which was attained in a few hours (Norris 1970). The extensive
inter-reaction of 2,4,5-T with forest floor suggests that only limited
leaching should occur. A lack of 2,4,5-T residues in streams flowing
from treated areas (Norris 1967) suggests that a combination of rapid
degradation and resistance to leaching prevents stream contamination.
Newton (1971) has calculated from studies on the kinetics of
degradation by micro-organisms that 2,4,5-T has a half-life of 7 weeks
in the forest floor. Investigations by Winston and Ritty (1972) and
Reigner et al., (1968) indicate that 2,4,5-T is decomposed to form
carbon dioxide, inorganic chlorides and water; objectionable
chlorophenols are not end-products of this decomposition. Norris et
al., (1977) reported on the persistence of 2,4,5-T in a Pacific
Northwest forest. The authors found that 6 months after the
application at 2.24 kg/ha, the level of herbicide in the forest floor
declined 90%; after 1 year, less than 0.02 kg/ha remained in the
forest floor. The authors found little leaching from the forest floor
into soil.

Norris (1970) published extensive studies from which it appears that
the degradation of 2,4,5-T follows first-order kinetics when
recoveries of 2 concentrations are compared. A lag period,
characteristic of degradation of other herbicides, is found also with
2,4,5-T.

In Soil

The persistence of 2,4,5-T in soil varies, but it does not usually
carry over from one growing season to the next. Residual lifetime is
influenced by climatic conditions and populations of soil
micro-organisms (Alexander and Aleem 1961). Biological detoxication
may be complete within a few weeks or may require up to 9 months
(Newman et al., 1952, Warren, 1954). Where conditions are
favourable, 2,4,5-T may be detoxified in one month (Warren 1954). The
2,4,5-trichlorophenol, which is a degradation product of 2,4,5-T, is
even more readily metabolised than the parent compound (Alexander and
Aleem, 1961).

In Water

Current information indicates, although some 2,4,5-T may enter streams
flowing through or adjacent to areas being sprayed, residue levels in
streams will be very low.

Norris (1971) reported the results of an intensive study of stream
contamination from spray projects on range and forest lands in Oregon
which showed that peak concentrations of 2,4,5-T seldom exceeded 0.1
mg/L and that herbicide residues persisted for only a few hours in
nearly all streams. Norris speculated, however, that application of
2,4,5-T to marshy areas may result in residues at a higher level for a
longer period in nearby streams. Other papers on the fate of 2,4,5-T
in water under laboratory and field conditions have been published by
Kenaga, (1974); Bovey et al., (1975); Norris and Moore (1971); and
Manigold and Shulze (1969).

Photodecomposition

Photochemical decomposition of 2,4,5-T in aqueous media utilising
wavelengths in the region of 300-450 nm was reported by Crosby and
Wong (1973). The breakdown was slow, with approximately 10% of the
2,4,5-T undergoing photolysis after 180 hours of irradiation. In
sunlight, the photolysis of 2,4,5-T was very slow. However, the
presence of low levels of acetone or riboflavin in the solution
resulted in a marked increase in the rate of disappearance, with 80%
being degraded in 48 hours. In these experiments using sensitizers,
2,4,5-trichlorophenol was confirmed as the degradation product.

Presence and fate of the Dioxin, TCDD

In the 2,4,5-T manufacturing process, the especially toxic dioxin,
2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD), is formed when the
reaction temperature is in excess of temperatures above 160°C. The

formation of TCDD during the production of 2,4,5-trichlorophenol was
demonstrated by Kimmig and Schulz (1957). A number of researchers
have reported on the formation of TCDD by the thermal decomposition of
the sodium salt of 2,4,5-trichlorophenol under alkaline conditions
during the manufacturing process.

After concern arose in 1969 about the extremely toxic properties of
TCDD, manufacturing methods were changed and carefully controlled by
manufacturers. By 1971 industry had reduced the TCDD content in
commercial samples of 2,4,5-T to less than 1 mg/kg. Current
manufacturing specifications require 2,4,5-T to contain less than 0.1
mg/kg TCDD. Several countries now produce commercial 2,4,5-T
containing less than 0.05 mg/kg TCDD.

Getzendaner and Hummel (1975) reported on the disappearance of TCDD
from grass after spraying it with 12 kg/ha 2,4,5-T. The loss of TCDD
is consistent with the work on photodegradation by Crosby et al.,
(1971), Crosby (1977, 1977a) and Crosby and Wong (1976, 1977), Botre
1978, and Plimmer, 1978. Negative findings have been reported from
monitoring studies for TCDD in a variety of likely substrates using a
GC/MS method developed by Stehl et al., with low part per trillion
sensitivity. The results of these analyses include beef fat (Kocher
et al., 1978), cows milk (Mahle et al., 1977), fish, human milk,
rice, water and soil (Shandoff et al., 1977), all collected from
areas where herbicide 2,4,5-T had been used for up to 30 years for the
control of weeds and brush.

In a study (Jensen et al., 1978), sheep were fed on a diet
containing 300 parts per 10⁶ (i.e. ppm) of 2,4,5-T and 150 parts per
10¹² (i.e. trillion) of TCDD for 28 days. At the end of this period,
it was found that fat and liver contained the highest residue,
accumulating twice the diet level. Muscle contained the least at 20
parts per trillion or about 1/5 the diet level.

Koeher et al., (1978) have presented data on cattle taken from areas
where 2,4,5-T is known to have been used. These samples were
collected to represent typical situations from which beef might enter
commercial channels, as well as one case in which the potential for
residues for TCDD was exaggerated. In spite of major difficulties in
interpreting the data from the GC-MS technique at low parts per
trillion levels with much interference from other chlorinated residues
in fat (DDE, dieldrin, PCB's etc) it was generally concluded that the
samples were substantially free of TCDD even from the area where the
use pattern was exaggerated.

Another study was conducted in an attempt to find TCDD in milk of
cattle grazing on pastures or range which had been treated with
2,4,5-T (Mahle et al., 1977). The results of analysis of milk from
cows grazing on grass treated with 2,4,5-T were indistinguishable from
those from the control milk obtained from a supermarket remote from
areas where 2,4,5-T might be used. Shadoff et al., (1977) reported
the outcome of a search for TCDD in an environment exposed annually to

2,4,5-T herbicides. No evidence was found that TCDD is accumulating
in the environment under the conditions of annual 2,4,5-T use to
control weeds in rice in the USA.

Jensen et al., (1978d) reported the results of an investigation into
the possible presence of TCDD residues in rice grains from fields
treated with 2,4,5-T. No trace of TCDD could be found. Another
environmental sampling was conducted by Newton (1975). In a
reforestation project, 2,4,5-T was applied, and 10 mountain beavers (a
herbivorous rodent which collects succulent plants and stores them
underground) were collected from within the treated area 2 months
after the application. No TCDD was found in the beavers using a
method sensitive to 3 parts per trillion.

TCDD is immobile in soil (Helling et al 1973). The possibility of
ground water contamination in virtually non-existent (Kearney et al,
1972). A recent National Academy of Science report on drinking water
stated that 2,4,5-T and TCDD had never been detected in drinking
water; the limit of detection was in the parts per trillion (National
Research Council 1977). Following treatment of brush with 2,4,5-T in
Texas, soils, lake sediments, organic matter, turtles and fish tissues
were analysed for residues of TCDD. None of the samples collected
over a 13-month period contained TCDD (Garcia et al., 1979), when a
method of analysis sensitive to TCDD only at ppb level was used.

METHODS OF RESIDUE ANALYSIS

Methods for the determination of TCDD in 2,4,5-T and related materials
have been published by Dow Chemical Company (1975). These are capable
of determining TCDD at levels down to 0.01 mg/kg.

The various analytical techniques for the determination of 2,4,5-T
residues are documented and described in several reviews (Thier, 1974;
Cochrane and Purkayastha, 1973; Yip, 1975; National Research Council
of Canada, 1978). Gas chromatographic analysis is most commonly used
for the estimation.

Several studies have confirmed the conjugation of
chlorophenoxyalkanoic acids with plant substituents. Such conjugation
has occurred as ester linkages with glucose and as amide linkages with
amino acid and proteins. Therefore, tissues for analysis of 2,4,5-T
residues require a preliminary liberation of these "recalcitrant"
residues when present. This can be achieved by incorporating a
hydrolytic extraction step. However, extraction of 2,4,5-T by
acidified organic solvents has been used in the majority of published
methods with no provision for a hydrolysis step. Hence "recalcitrant"
residues have previously gone undetected.

For residue monitoring, conversion of the free acids to the methyl
ester using boron trifluoride has proved to be the most popular
derivatizing procedure. The methylation is simple to carry out, does
not require specialised equipment, gives almost 100% conversion to the
methyl ester and introduces the least contamination by interfering

compounds. A clean-up stage, commonly with a Florisil column, is
frequently included after derivatization.

Residues of TCDD might be expected to be found in environmental
components in the range of 1-10 ng/kg (parts per trillion). The only
methodologies developed to date which are capable of this sensitivity
are high resolution mass spectrometry and high resolution mass
spectrometry/gas chromatography (Stehl et al., 1979). The
time-consuming cleanup for the detection of dioxins and the expense of
the instrumentation for this detection indicate than an extensive
monitoring programme for dioxins in the environment is not too likely
in the immediate future.

NATIONAL MAXIMUM RESIDUE LIMITS

Few national governments appear to have established maximum residue
limits for 2,4,5-T in raw agricultural commodities. The following
limits were reported to the meeting.

mg/kg
Australia

potable water 0.02

Germany

wild mushrooms 2
other food of plant origin 0.05

Netherlands

fruit, vegetables (not potatoes) 0
spices 0

Switzerland

cereals 0.01

APPRAISAL

2,4,5-T herbicides have been used extensively for almost 30 years for
the control of woody weeds of range land, pasture, forests, some
cereal crops, rice, sugarcane, as fruit setting and stop-drop sprays
on certain crops such as apricots and apples and for the control of
unwanted vegetation on industrial land, rights-of-way, etc.

Commercial 2,4,5-T can contain traces of the toxic dioxin TCDD. The
meeting was informed that in recent years all known manufacture has
ensured that the TCDD content is below the upper limit recommended by
FAO (0.1 mg/kg).

Following the evaluation of 1970 extensive data have become available
on the nature and fate of 2,4,5-T and TCDD residues in many

environmental components including food crops, livestock and water.
These data indicate that approved uses of 2,4,5-T herbicides are
unlikely to give rise to residues in drinking water or in food at
levels above 0.02 mg/L and 0.05 mg/kg respectively. Wild mushrooms
and wild vaccinium berries gathered from recently sprayed forests may
contain residues at levels of the order of 2 mg/kg and 5 mg/kg
respectively. This view is confirmed by extensive monitoring
programmes which have failed to detect residues in food components or
water at levels much above the limit of determination.

In the case of food crops on which 2,4,5-T is applied, the meeting
recommended that the MRL be at or about the limit of determination.

Following the request of the previous meeting, methods for the
determination of TCDD in 2,4,5-T and formulations, have become
available with a limit of determination in the region of 0.01 mg/kg.
These are being employed to monitor the quality of 2,4,5-T herbicides
on the world market. In view of the low level of TCDD in technical
2,4,5-T and in formulated 2,4,5-T herbicides (0.01 mg/kg), the rate of
use of 2,4,5-T, the situations in which it is used and the knowledge
that TCDD is readily degraded in sunlight, the meeting agreed that
there was no likelihood of TCDD residues occurring in food.

RECOMMENDATIONS

The following limits apply to 2,4,5-T determined and expressed as
2,4,5-trichlorophenoxy acetic acid:

Commodity MRL (mg/kg)

Apples, apricots 0.05*
Barley, oats, rice, rye, wheat 0.05*
Sugarcane 0.05*
Milk, meat, meat by-products, eggs 0.05*
Cereal straw 2

(* At or about the limit of determination.)

Further Work of Information

Required by 1981:

1. Information on the level of 2,3,7,7-tetrachlorodibenzo-p-dioxin in
2,4,5-T from a wide range of manufacturers;

2. Studies on the potential of bioaccumulation of the 2,4,5-T
contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin in mammalian
tissues.

Desirable:

1. Studies to investigate the possibility of interaction between
2,4,5-T and 2,3,7,8-tetrachlorodibenzo-p-dioxin with respect to
carcinogenic potential;

2. Data on epidemiological studies with 2,4,5-T.

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    See Also:
       Toxicological Abbreviations
       T, 2,4,5- (AGP:1970/M/12/1)
       T, 2,4,5- (Pesticide residues in food: 1981 evaluations)