Document ID: EPA-HQ-OPP-2005-0306-0006
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-04-04T04:00Z

COMPANY FEDERAL REGISTER DOCUMENT SUBMISSION TEMPLATE (7/1/2006)

EPA Registration Division contact: [insert name and telephone number
with area code]

 

INSTRUCTIONS:  Please utilize this outline in preparing tolerance
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TEMPLATE:

[BASF Corporation]

[PP 5E6996]

	EPA has received an amendment to pesticide petition ([PP5E6996]) from
[BASF Corporation], [100 Campus Drive, Florham Park, NJ 07932]
proposing, pursuant to section 408(d) of the Federal Food, Drug, and
Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180.

(Options (pick one)

	2. to establish an exemption from the requirement of a tolerance for

	[Vitamin E (CAS no. 1406-18-4) in the form of Vitamin E Alcohol
(d-alpha tocopherol, CAS no. 59-02-9 and dl-alpha tocopherol, CAS no.
10191-41-0) and Vitamin E Acetate (d-alpha tocopheryl acetate, CAS no.
58-95-7 and dl-alpha tocopheryl acetate, CAS no. 7695-91-2)] in or on
raw agricultural commodities when used as an ingredient in pesticide
formulations used in accordance with good agricultural practices.
[Vitamin E is a chemical complex that includes eight naturally occurring
homologues having a chromanol ring and a twelve-carbon aliphatic side
chain containing two methyl groups in the middle and two or more methyl
groups on the end.  Vitamin E is found in many plant-derived foods and
is believed to be necessary for human health.  Vitamin E alcohol in the
form of d-alpha tocopherol has the highest biological activity of the
compounds in the Vitamin E complex.  Vitamin E alcohol and its ester,
Vitamin E acetate, are commonly consumed as dietary supplements. 
Vitamin E alcohol and Vitamin E acetate are common food additives. 
Vitamin E alcohol is used as an antioxidant for foods or food chemicals.
Vitamin E acetate is a common animal feed additive and is used widely in
topical skin care products.]  EPA has determined that the petition
contains data or information regarding the elements set forth in section
408 (d)(2) of the FDDCA; however, EPA has not fully evaluated the
sufficiency of the submitted data at this time or whether the data
supports granting of the petition. Additional data may be needed before
EPA rules on the petition.

A. Residue Chemistry

]

	3. Magnitude of residues. [Residues of Vitamin E were evaluated using
the EPA Tier I exposure level screening method, which is being used for
inert ingredients.  By the Tier I method, the maximum estimated chronic
exposures range from 0.087 mg/kg/day for adults to 0.422 mg/kg/day for
children ages one to two years.  Taking the chronic toxicity endpoint of
50 mg/kg/kay for adults (see toxicity data below), and using a safety
margin of 100, gives a calculated chronic population adjusted dose
(cPAD) of 17% for adults.  All other population subgroups give cPAD <100
except for children one to two years, where a chronic toxicity limit of
20 mg/kg/day gives a cPAD of 210%.  This subgroup therefore requires a
higher level of analysis.  The Tier I analysis assumes that the inert is
used at the same levels as active ingredients; in reality, the level of
Vitamin E use in a pesticide formulation would be far less than half
that of the typical active ingredient.  Therefore, the estimated
exposure can safely be reduced to less than 0.2 mg/kg/day for children
one to two years, giving a cPAD of <100%. 

The estimated acute exposures at the 95th percentile of exposure range
from 0.199 mg/kg/day for adults to 0.939 mg/kg/day for children one to
two years.  An NOAEL for acute toxicity is not known, but the LD50 for
rats is >4,750 mg/kg.  Scaling this by 100 to estimate for humans, and
using a safety margin of 100 gives an acute PAD (aPAD) of 42% for
adults.  For children one to two years, this gives an aPAD of 198%. 
Using similar rationale as with the cPAD analysis, the aPAD calculated
with a more realistic formulation use level would be <100% for all
population subgroups.  

]

B. Toxicological Profile

Vitamin E in supplements is usually consumed as alpha-tocopheryl
acetate, a more stable form.  The body converts the esters to
tocopherols. Therefore, toxicology data presented for alpha-tocopherol
can be reliably bridged to alpha-tocopheryl acetate and vice versa.  

Alpha-tocopherol and mixed tocopherol concentrate were evaluated for
acceptable daily intake at the sixth and seventeenth meetings of the
Joint FAO/WHO Expert Committee on Food Additives.  These evaluations are
summarized in the sections that follow.  

 

	Alpha-tocopherol may be an essential nutrient.  The Institute of
Medicine, Food and Nutrition Board has published recommended daily
allowances (RDAs) and Tolerable Upper Intake Levels (ULs), listed below.
 A Joint FAO/WHO expert consultation report, Human Vitamin and Mineral
Requirements, was published in 2002, covering the 1998 consultation in
Bangkok.  It describes the difficulty in determining Recommended
Nutrient Intake (RNI) levels for vitamin E, but states that vitamin E
appears to have very low toxicity, with 100 to 200 mg/day of the
synthetic (dl-alpha-tocopherol) commonly taken as dietary supplements. 
They note that pro-oxidant damage has been associated with feeding of
vitamin E supplements, but typically only at very high levels, e.g.,
exceeding 1,000 mg/day.

]

	2. Genotoxicty. [According to the Joint FAO/WHO committee reports,
alpha-tocopherol was nonmutagenic.  Ames salmonella assay: Not mutagenic
(BASF MSDS).]

	3. Reproductive and developmental toxicity. [According to the Joint
FAO/WHO committee reports, the results of reproduction/teratology
studies did not indicate that alpha-tocopherol had adverse effects on
reproductive function.  90-day study on d-alpha-tocopherol polyethylene
glycol 1000 succinate (TPGS), a water-soluble form of vitamin E:
Reproductive indices (mean gestation period, litter size, sex ratio, and
mortality of pups or parents) were unaffected by treatment.  Clinical
chemical and hematological parameters were normal in the Fo generation
10 days before terminal sacrifice.]

	4. Subchronic toxicity. [From The European Commission, Opinion of the
Scientific Committee on Food on the Tolerable Upper Intake Level of
Vitamin E, April 4th 2003:  In rats given alpha-tocopheryl acetate by
gavage at doses of 125 to 2,000 mg/kg bw/day, TSH levels were elevated
by 30 to 100%.  At a dose of about 100 mg/kg bw/day, biochemical indices
of hepatotoxicity (serum alkaline phosphatase, alanine aminotransferase,
and aspartate aminotransferase) were elevated and liver weight was
increased.  The NOAEL for these effects was 125 mg alpha-tocopherol
acetate/ kg body weight (Abdo et al., 1986).]

	5. Chronic toxicity. [Ingestion of large amounts of alpha-tocopherol
over long periods of time may cause gastrointestinal distress, muscle
weakness, and fatigue.  The following is reported in the FAO/WHO report
(complete references are listed in the original summary report):

Rats

Groups of weanling female Wistar rates were fed diets containing 0; 25;
250; 2,500; 10,000; or 25,000 IU vitamin E/kg diet for eight and 16
months. [1 IU=0.67 mg alpha-tocopherol].  Vitamin E depressed
body-weight gain at concentrations of 10,000 and 25,000 IU/kg diet, and
increased relative heart and spleen weights were seen at eight months
and 16 months, respectively.  There was an increase in plasma alkaline
phosphatase and a decrease in the ash content of bone after 16 months at
these two dose levels.  Prothrombin time was reduced at 12 months, but
not at nine or 16 months.  Urinary excretion of creatine and creatinine
was normal at 11 months.  No histological examinations were reported
(Yang & Desai, 1977).

Groups of 60 male and 60 female Charles River CD rats, initial body
weight 134 g (males) or 130 g (females), were fed a diet supplemented
with dl-alpha-tocopheryl acetate at levels calculated to give a dose of
500; 1,000; or 2,000 mg/kg bw/day.  Occasional difficulties in arresting
bleeding were observed when blood samples were collected after eight
weeks and frank hemorrhages were observed in males only from week 15
(high-dose), week 16 (intermediate-dose), or week 18 (low-dose). 
Hemorrhages occurred variously in the gut, urinary tract, orbit and
meninges, and from minor injuries to the claws or vibrissal pits. 
Vitamin K supplementation was effective in bringing about recovery
within one to three days.  In all other respects, the appearance and
behavior of treated animals were similar to controls, and food
consumption and body-weight gain were similar to or slightly greater
than controls.

Mortality due to hemorrhage in males during the first 26 weeks,
maximally 10% in the high-dose group, was balanced by a similar number
of deaths in control males between weeks 26 and 52, and thereafter
alpha-tocopherol did not adversely affect survival.  At termination,
there were no significant differences in mortality between any treatment
groups of either sex and their respective controls.  Prothrombin times
were prolonged in males of all treatment groups at week four until week
13, but these returned to normal by week 26 (after initiation of vitamin
K supplementation in week 24); females were unaffected.  No other
hematological differences between treated and control animals were seen
except for a transient, slight lowering of the hematocrit and hemoglobin
at week eight in both males and females in the highest dose group. 
Serum alkaline phosphatase was occasionally significantly elevated
(p<0.05) in the high-dose group, but the differences were not consistent
nor progressive with time; no such changes were seen at lower-dose
levels.  A dose-related elevation of alanine aminotransferase was
observed in treated males at week four, persisting to week 26, but later
it lost statistical significance.  Aspartate aminotransferase and all
other blood chemical parameters were unaffected, and not significant
changes were seen on urinalysis.

At necropsy, no macroscopic changes related to treatment were observed.
 In females (but not males) of the high-dose group, a slightly elevated
absolute liver weight was seen at the interim sacrifice, but the
relative liver weight was not increased and no significant differences
in relative or absolute organ weights were seen at termination of the
study.  Histopathological examination of the livers did not reveal any
treatment-related changes with the exception of agglomerations of
vacuolated (“foamy”) macrophages in the centriacini of some treated
rats, distributed among the treated rats without dose-relation, but
never occurring in controls.  The foamy macrophages stained strongly
with periodic acid schiffs (PAS) and Oil Red O, which distinguished them
from occasional peribiliary macrophages seen in controls; they were seen
in 17% of treated males and 77% of treated females across the study as a
whole.  No other treatment-related effects were observed.  Whether
considered separately by tumor type, or in aggregate, the tumor
incidence did not reveal any neoplastic effects of treatment.  In both
sexes, there were indications of an inverse relationship between dosage
and incidence of mammary fibroadenomas, but this effect was
statistically significant only in females (Wheldon et al., 1983).

Humans

Adult humans have tolerated 1 g per day alpha-tocopherol for months or
larger doses for shorter periods with no undesirable effects. 
Therapeutically, daily doses of 20 to 600 mg of alpha-tocopherol or its
acetate salt are often taken with no toxic effects (Finkler, 1949;
McLaren, 1949; Sebrell & Harris, 1954). 

The clinical literature contains references to complaints of gastric
distress and other symptoms in patients receiving much smaller dosages;
these symptoms are probably attributable to fatty substances present in
alpha-tocopherol concentrates or, in some instances, to psychic factors
(Sebrell & Harris, 1954).

Side effects reported in clinical use of vitamin E supplements include
severe weakness and fatigue induced in healthy adults by daily doses of
around 720 mg alpha-tocopherol (Cohen, 1973a, b).  These side effects
were observed in a double-blind study on two healthy young males
receiving 720 mg alpha-tocopherol daily (Briggs, 1974; Briggs & Briggs,
1974).  In the latter study, the symptoms were associated with an
increase in serum creatine kinase activity and greatly increased 24-hour
urinary creatine excretion; asymptomatic creatinuria was reported in a
young male taking high doses of vitamin E (Hillman, 1957).

A 55 year-old patient presented with ecchymoses and prolonged
prothrombin time after self-administration of a vitamin E preparation at
up to 1,200 IU/day for two months while receiving warfarin and
clofibrate therapeutically.  The prothrombin time returned to its
baseline value after vitamin E administration was stopped while warfarin
and clofibrate treatment continued.  In a subsequent challenge study,
vitamin E (90% alpha-tocopherol) was given for seven weeks at a daily
dose of 800 IU/day; at the same time the patient received his normal
medication of digoxin (0.25 mg/day), sodium warfarin (5 mg/day
alternating with 2.5 mg/day), clofibrate (500 mg four times a day), and
procainamide (500 mg four times a day).  By the fourth week the
prothrombin time was increased from an initial value of 20.7 seconds to
24 seconds and continued to increase to 29.2 seconds after seven weeks;
levels of Factors II, VIII, IX, and X were depressed.  At this time,
multiple ecchymoses and a small hematoma were evident, so vitamin E was
discontinued.  The prothrombin time and levels of clotting factors
returned to baseline values within seven days and clinical signs of
hemorrhage disappeared (Corrigan & Marcus, 1974).

The hematological response to iron therapy by children with
iron-deficiency anemia has been reported to be significantly impaired if
vitamin E supplements are given simultaneously (Melhorne & Gross, 1969).

Allergic reactions shown by some individuals to topical creams or sprays
containing vitamin E were shown by patch tests to be due to
alpha-tocopherol (Brodkin & Bleiberg, 1965; Minkin et al., 1973; Aeling
et al., 1973).

Skin rashes and gastrointestinal irritation were reported in early
studies of oral vitamin E supplementation in the form of wheat-germ oil,
but it is not known whether this was due to alpha-tocopherol (Shute,
1938).

Effects of alpha-tocopherol on some biochemical parameters have been
reported in man.  A group of 52 patients (average age 72 years) showed a
mean increase in serum cholesterol of 74 mg/dl while receiving 300 mg
alpha-tocopherol daily (Dahl, 1974), but no such increase was seen in a
small group of healthy young men taking 800 mg daily (Briggs, 1974;
Briggs & Briggs, 1974).  

When patients with porphyria cutanea tarda were given daily doses of
1,000 mg alpha-tocopherol for three months, there were marked increases
in 24-hour urinary excretion of androsterone and etiocholanone +
dehydroepiandrosterone and a large decrease in 24-hour excretion of
pregnanediol (Pinelli et al., 1972).

The Institute of Medicine, Food and Nutrition Board has determined the
following Tolerable Upper Intake Levels (UL) values for
alpha-tocopherol, reported in mg of alpha-tocopherol equivalents (ATEs):



Table 1: ULs for alpha-tocopherol.

Age (years)	

Males

 (mg/day)	

Females 

(mg/day)	

Pregnancy (mg/day)	

Lactation (mg/day)

1-3	

200 (=300 IU)	

200 (=300 IU)	

N/A	

N/A

4-8	

300 (=450 IU)	

300 (=450 IU)	

N/A	

N/A

9-13	

600 (=900 IU)	

600 (=900 IU)	

N/A	

N/A

14-18	

800 (=1,200 IU)	

800 (=1,200 IU)	

800 (=1,200 IU)	

800 (=1,200 IU)

19-70	

1,000 (=1,500 IU)	

1,000 (=1,500 IU)	

1,000 (=1,500 IU)	

1,000 (=1,500 IU)

>70	

200 (=300 IU)	

200 (=300 IU)	

N/A	

N/A

	6. Animal metabolism. [When rats were given 3.5 mg alpha-tocopherol
daily by mouth, three to 15% appeared in the feces.  With larger doses,
up to 25% appeared in the feces.  There is practically no urinary
excretion of tocopherol but, from studies with labeled material, it
appeared that one or more metabolites of tocopherol are excreted in the
urine.  When more than the daily requirement is administered, there is
some storage of tocopherol in the liver.  The major pathway of
tocopherol metabolism is via phytyl side chain oxidation, leaving
carboxyethylhydroxychromans (CEHC) as metabolites.  Tocopheryl quinone
is also formed in animal metabolism via oxidation, followed by
conjugation to the glucuronate, which is excreted in the bile or further
degraded in the kidneys to alpha-tocopheronic acid, which is then
excreted in bile (2002 Joint FAO/WHO expert consultation report, Human
Vitamin and Mineral Requirements).]

	7. Metabolite toxicology. [Alpha and gamma CEHC are water soluble,
renally excreted, with known potent anti-inflammatory and antioxidative
properties.  (Himmelfarb et al., Kidney International, Volume 64 Issue 3
Page 978; September 2003).]

	8. Endocrine disruption. [Based upon the available data,
alpha-tocopherol is not anticipated to disrupt the endocrine system.]

C. Aggregate Exposure

	1. Dietary exposure. [Various forms of vitamin E are present in many
foods and consumed as dietary supplements.  Exposure to vitamin E within
reasonable limits is considered beneficial.]

	i. Food. [Vegetable oils, nuts, green leafy vegetables, and fortified
cereals are common food sources of vitamin E in the US.  The NIH Office
of Dietary Supplements lists the following sample of foods providing
vitamin E (Table 2).  Food values are listed in alpha-tocopherol
equivalents (ATE) to account for the variation in biological activity of
the different forms of vitamin E.

Table 2: Selected Food Sources of vitamin E

FOOD	

Milligrams (mg) Alpha-tocopherol pre serving	

Percent DV*

Wheat germ oil, 1 tablespoon	

20.3	

100

Almonds, dry roasted, 1 oz	

7.4	

40

Sunflower seed kernels, dry roasted, 1 oz	

6.0	

30

Sunflower oil, over 60% linoleic, 1 tablespoon	

5.6	

30

Safflower oil, over 70% oleic, 1 tablespoon	

4.6	

25

Hazelnuts, dry roasted, 1 oz	

4.3	

20

Peanut butter, smooth, fortified, 2 tablespoons	

4.2	

20

Corn oil, 1 tablespoon	

1.9	

10

Spinach, frozen, chopped, boiled, ½ cup	

1.6	

6

Vitamin E in supplements is usually consumed as alpha-tocopheryl
acetate, a more stable form.  The body converts the esters to
tocopherols.  Recommended daily allowances of vitamin E are:

Table 3: Recommended Dietary Allowances for vitamin E for Children and
Adults

Age (years)	

Children (mg/day)	

Men (mg/day)	

Women (mg/day)	

Pregnancy (mg/day)	

Lactation (mg/day)

1-3	

6 mg

(=9 IU)	

	

	

	

4-8	

7 mg (=10.5 IU)	

	

	

	

9-13	

	

11 mg (=16.5 IU)	

11 mg (=16.5 IU)	

15 mg (=22.5 IU)	

19 mg (=28.5 IU)

14+	

	

15 mg (=22.5 IU)	

15 mg (=22.5 IU)	

15 mg (=22.5 IU)	

19 mg (=28.5 IU)

]

	ii. Drinking Food. [No significant exposure of vitamin E via drinking
water is anticipated, except in bottled water that contains dietary
supplements, where vitamin E may be added intentionally.]

	2. Non-dietary exposure. [Vitamin E is used in skin creams and lotions,
from small concentrations up to 100% vitamin E in some skin care
products.  Some absorption through the skin is expected.]

D. Cumulative Effects

	[Vitamin E has no significant toxic effects for consideration of
cumulative effects.]

E. Safety Determination

	1. U.S. population. [Alpha-tocopherol is a low toxicity vitamin that is
used as a food chemical antioxidant.  Alpha-tocopherol is utilized by
the body and is part of the current US diet.  Therefore the proposed new
use of alpha-tocopherol as an ingredient in pesticide formulations is
not anticipated to contribute significantly to the amount of
alpha-tocopherol in the US diet and has a reasonable certainty of no
harm to the US population.]

	2. Infants and children. [Alpha-tocopherol has no significant toxic
effects that are specific to infants or children.  The proposed new use
of alpha-tocopherol as an ingredient in pesticide formulations has a
reasonable certainty of no harm to infants or children.]

F. International Tolerances

	[In the 2002 Joint FAO/WHO Expert Consultation Report, a lack of
sufficient data was cited for not determining a global agreed-upon
Recommended Nutrient Intake (RNI).  This report, however, comments that
100 to 200 mg/day intake of supplements is common, and that toxicity is
not thought to be a problem except at high intake levels, e.g., >1000
mg/day.]

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