Document gG90B3jZy55apr2aOr5DXnmQ
A literature review and evaluation
Central Institute for Nutrition and Food Research T.N.O.
Zeist, The Netherlands PCB-ARCH-EXT0375992
Central Institute for Nutrition and Food Research T.N. O.
Report No. R 1838
THE TOXICITY OF THE CITRUS FUNGISTAT DIPHENYL
A LITERATURE REVIEW AND EVALUATION
' x
' ' . .' ' by P. G. C. van Stratum
M. Sc. Biol.
'v ,
Zeist, The Netherlands November, 1964
P
PCB-ARCH-EXT0375993
.......
.ftS--^ 'i. c
ABSTRACT AND CONCLUSIONS
The available literature data on the toxicity of diphenyl have been
studied and reviewed extensively. This review comprises-, the results
of acute, short-term, and long-term feeding studies with laboratory
animals as well as skin and eye irritation tests and studies of the
metabolism of diphenyl.
.
From available data, no evidence emerged that diphenyl exerts
cumulative effects. Also there was no evidence from .these .data .that
diphenyl is carcinogenic (cancer producing). No major differences
between different animal species were found as to sensitivity or meta
bolism of diphenyl. In two-year feeding tests with rats, 0;05% diphenyl
in the diet appeared to be the highest level which did not cause any
detectable ill effects. The level corresponds to a daily intake of about
30 milligrams (mg) per kilogram (kg) of body weight; hence, when
applying the usual margin of safety of 100, the acceptable daily intake
is 0.3 mg per kg of body weight for human beings. This means that a
person weighing 70 kg may consume up to 20 mg diphenyl a day with
out any reasonable health risk. .
. . . .. . .. ..... ......
The average present ingestion of diphenyl from citrus -fruits and
citrus products in European countries was calculated to be about 0.06
mg per person a day, therefore, the average daily intake is only about
one three-hundredth of the acceptable amount. An adult.human Using
must consume, for example, peeled fruit equivalent to a total ofabout 40
oranges, 30 lemons, and 20 grapefruits of medium size-daily, together
with 600 grams of jam or marmalade prepared from diphenyl pro
tected citrus fruits, in order that the intake of diphenyl would approach
the acceptable level.
From these data it appears that it is not reasonable to expect any
danger to public health from the present or feasible future consump
tion level of fresh oranges, lemons, and grapefruits protected with
diphenyl and of products manufactured from citrus fruit treated in the
same way.
' \ =tr>
vf
- ...................
PCB-ARCH-EXT0375994
CONTENTS
ABSTRACT AND CONCLUSIONS
CONTENTS
1. INTRODUCTION
2. ORAL TOXICITY
2.1. Acute oral toxicity-studies*
.
2.1.1. Rat
2.1.2. Rabbit
2.1.3. Cat
2.1.4. Conclusion of acute oral toxicity studies
2.2. Short-term oral studies
2.2.1. Rat
2.2.2. Rabbit
2.2.3. Monkey
... . 2-2,4. Dog
2.2.5. Mail
........ - w
2.2.6... Conclusion of short-term oral toxicity studies
2.3. Long-term oral studies
2.3.1. Rat
2.3.2. Conclusion of long-term oral toxicity studies
2.4. Conclusion of oral toxicity studies
3. NON-ORAL TOXICITY
3.1. Inhalation studies
3.1.1. Rat
'
3.1.2. Mouse
3.1.3. Rabbit
3.1.4. Conclusion of inhalation studies
3.2. Skin studies
3.2.1. Guinea pig
3.2.2. Rabbit
3.2.3. Rat
3.2.4. Mouse
3.2.5. Man
PCB-ARCH-EXT0375995
CONTENTS
3.3. Eye irritation tests - Rabbit ,3.4. Conclusion of non-oral toxicity tests 4. CARCINOGENIC ACTION
Page 13 13
14
5. METABOLIC STUDIES
5.1. Experiments
5.1.1. Rat.
-
5.1.2. Rabbit
5.1.3. Dog
5.1.4. Miscellaneous experiments,- .
5.2. Conclusion of metabolism experiments
.
14
T4
14
16
16
16,
17
6. DIPHENYL RESIDUES IN CITRUS PRODUCTS
i7
6.1. Fruits, peels and juices
17
6.2. Home made marmalade
20
6.3. Diphenyl intake of humans consuming citrus products
20
6.3.1. Average daily intake
20
6.3.2. High citrus consumption
21
6.3.3. Consumption of citrus-peel
22
7. INTERPRETATION OF DATA PRESENTED
23
8. SUMMARY
'
24
9. LITERATURE
25
PCB-ARCH-EXT0375996
A LITERATURE REVIEW AND EVALUATION
23
7. INTERPRETATION OF DATA PRESENTED
The animal experiments carried out did not reveal any cumulative effects from diphenyl ingestion, inhalation, or skin application. The effects evoked by the lowest toxic levels - viz. nephrotoxic lesions -- were demonstrated to be reversible, even after several- months- of intoxication. Diphenyl was not shown to be a carcinogen..,Skin.application and eye irritation tests did not show that human health is at risk in the handling of diphenyl-treated citrus fruits. Both from feeding experiments and from metabolism studies, it was seen that- no-maj or differences in susceptibility between animal species occur. Therefore, it seems justified to calculate the safe level for human-- beings -on- the basis of the results of the animal experiments.
In the long-term oral feeding tests (see section 2.4.) the highest "no ill-effect" level was found to be 30 mg per kg body weight a day. Using a 100-fold margin of safety the acceptable highest level for human beings would be 0.3 mg per kg a day or about 20 mg a day for a human being weighing 70 kg.
The average daily intake of diphenyl by human beings in- European countries (see Table 4) is about 0.06 mg, which is very muchlower tfian the acceptable intake of 20 mg. Even in cases of continuous high citrus fruit consumption (i.e. ten times the average consumption level ;.sec Table 5), the daily amount is no more than one thirtieth of'the accept able daily intake. On the basis of the above mentioned data, it means that a daily consumption of peeled fruit equivalent to about 20 kg of citrus fruits and citrus products (for example, the daily consumption of a total of 40 oranges, 30 lemons, and 20 grapefruits ofmedium-size, together with 600 grams of orange marmalade) would be needed for an intake of 20 mg diphenyl, i.e. the acceptable amount.
The Joint FAO/WHO Expert Committee (22) estimated the highest daily unconditionally acceptable intake for man using, a 500-fold safety margin as 3.5 mg diphenyl for a human weighing:70 kg (0.05 mg per kg body weight). Even at this high safety margin, the actual average daily intake (0.06 mg per capita a day) is only one fiftieth of this unconditionally acceptable intake.
From the available data collected in this report no evidence was obtained that the present consumption of diphenyl protected citrus fruits might give rise to any public health danger. There is-no reason to change this conclusion as regards feasible future consumption of citrus fruits.
PCB-ARCH-EXT0375997
24
THE TOXICITY OF DIPHENYL
8. SUMMARY
1. A survey was made, of the literature on the toxicity of diphenyl.
2. The oral LD50 of diphenyl for rats and rabbits was found to be between 2.5 and 5.0 g per kg body weight. In short-term oral studies with rats, dogs, and monkeys lasting up to one year, the highest level of diphenyl causing no effect was found to be 0.1 % of the diet or more. In long-term oral rat studies, 0.05% ofdiphenyl in the diet appeared to be the highest "no ill-effect" level, i.e. 30 mg per kg rat a day.
3. No cumulative effects were observed at feeding, inhalation, and skin applicauon tests of diphenyl. Diphenyl, was notjfound to be carcinogenic. In metabolism experiments, it appeared that rats, rabbits, and dogs had common detoxication mechanisms.
4. By applying a safety margin of .100 to the results of animal experi ments, the acceptable dose of diphenyl for human beings was calculated to be about 20 mg per capita a day (0.3 mg per kg body weight).
5. From residue studies in consumer-type citrus fruits and products, ...it was calculated that the European consumer has an average diphenyl intake of about 0.06 nig a day. This quantity is about one three-hundredth of the calculated acceptable intake.
i