EFSA Updates Opinion on Endosulfan Toxicity in Fish

The EFSA Journal (2005) 234, 1 - 31

Please note that this opinion, published on 7 April 2006, replaces the earlier version published
7 July 2005. The revision was considered necessary because the only study of oral toxicity of
endosulfan in fish listed in the original opinion was found to be actually a study with
endosulfan exposure of fish via water. Furthermore, two additional studies on fish exposed to
endosulfan in feed became available to the Panel.

The following items have been changed:
• Section 5.2, 1st paragraph has been replaced by 3 new paragraphs,
• Conclusion, Adverse effects in animals, bullet on fish is replaced.
• Reference list: Naveed et al., 2004 has been replaced by Braunbeck and Appelbaum, 1999
and Coimbra et al., 2005.

The Panel on contaminants in the food chain is informed that there is an on-going oral toxicity
study on Atlantic salmon exposed to endosulfan in the feed (Marc Berntssen, personal
communication, The National Institute of Nutrition and Sea Food Research, Bergen, Norway,
2006). Based on the results of this study, the opinion might be updated again. This study is
expected to be finalised in 2006.

http://www.efsa.eu.int Page 1 of 31


OPINION OF THE SCIENTIFIC PANEL ON CONTAMINANTS IN THE FOOD CHAIN
ON A REQUEST FROM THE COMMISSION RELATED TO ENDOSULFAN AS
UNDESIRABLE SUBSTANCE IN ANIMAL FEED

Question N° EFSA-Q-2003-066

Adopted on 20 June 2005
SUMMARY

Endosulfan is a non-systemic organochlorine pesticide that was developed and introduced in
the mid 1950s. Endosulfan consists of α- and β-isomers that could be metabolised to
endosulfan sulfate and endosulfan diol. In contrast to α- and β- endosulfan these metabolites
are susceptible to photolysis. Endosulfan containing products still hold authorisation in seven
member states of the European Community, but it is foreseen that the authorization of
endosulfan will be withdrawn by the Member States before 1 February 2006. The use of
endosulfan within the EU has steadily decreased during the recent years. Endosulfan is
released into the environment mainly as a result of its use as a pesticide and is found in
atmosphere, soil and sediment. Direct uptake from soil to plant as well as transport in plants is
negligible.

In contrast to most related organochlorine pesticides, endosulfan has a less pronounced
affinity to lipids. Consequently, biomagnification and accumulation of endosulfan, in
terrestrial food chains, is less likely to occur.

Endosulfan is readily absorbed from the gastrointestinal tract and distributed to the kidneys
and liver and to a lesser extent to other tissues. However, differences in distribution pattern
between the isomers as well as metabolites have been reported.

Endosulfan residues are normally found in food and feed at low levels only. Detailed data on
occurrence and temporal trends of endosulfan in feed are scarce.

Based on the limited data on animal exposure via feed produced according to good
agricultural practice, it is not likely that terrestrial animals will be exposed to levels that could
cause toxic effects.

Neurotoxic effects of endosulfan in both humans and animals are well documented. Exposure
can induce a number of effects including liver and kidney toxicity, haematological effects,
alterations in the immune system, and alterations in the reproductive organs.

Data from a limited number of samples suggest that intake of endosulfan by the general
population, are far below the ADI of 6 µg/kg b.w. established by JMPR in 1998.

KEY WORDS: Endosulfan, α-endosulfan, β-endosulfan, endosulfan sulfate, analysis, toxicity,
residues in feed and food, carry-over, ADI, environmental fate.



TABLE OF CONTENTS

LIST OF ABBREVIATIONS ............................................................................................................... 4
BACKGROUND ............................................................................................................................... 5
1. General Background............................................................................................................... 5
2. Specific Background .............................................................................................................. 6
TERMS OF REFERENCE ................................................................................................................... 8
ASSESSMENT ................................................................................................................................. 9
1. Introduction ............................................................................................................................ 9
1.1. Chemistry and use ......................................................................................................... 9
1.2. Environmental fate ...................................................................................................... 10
1.3. Toxicological findings in laboratory animals and hazard assessment for humans ..... 12
2. Methods of analysis.............................................................................................................. 14
3. Statutory limits ..................................................................................................................... 14
4. Occurrence in food and feed ................................................................................................ 14
5. Adverse effects on fish, livestock and pets, and exposure-response relationship................ 16
5.1. Introduction ................................................................................................................. 16
5.2. Fish .............................................................................................................................. 16
5.3. Ruminants.................................................................................................................... 17
5.4. Birds ............................................................................................................................ 18
5.5. Rabbits......................................................................................................................... 18
5.6. Dogs ............................................................................................................................ 18
6. Toxicokinetics and tissue disposition................................................................................... 19
6.1. Absorption................................................................................................................... 19
6.2. Distribution.................................................................................................................. 20
6.3. Metabolism.................................................................................................................. 20
6.4. Excretion ..................................................................................................................... 21
7. Carry over and tissue concentration ..................................................................................... 21
8. Human dietary exposure and comparison with ADI............................................................ 23
CONCLUSIONS ............................................................................................................................. 23
RECOMMENDATION ..................................................................................................................... 25
REFERENCES ............................................................................................................................... 26
SCIENTIFIC PANEL MEMBERS....................................................................................................... 31
ACKNOWLEDGEMENT .................................................................................................................. 31
DOCUMENTATION PROVIDED TO EFSA ....................................................................................... 31



LIST OF ABBREVIATIONS

ADI Acceptable daily intake
ATSDR Agency for Toxic Substances and Disease Registry
B.w. Body weight
CAS Chemical abstracts service
ECD Electron capture detector
FAO Food and Agricultural Organization
FEFAC European Feed Manufacturers' Federation
GABA Gamma-aminobutryic acid
GC Gas chromatography
IPCS International Programme on Chemical Safety
JMPR Joint FAO/WHO meetings on pesticide residues
LD50 Lethal dose that causes 50 % death of a group of test animals
LOAEL Lowest observed adverse effect level
Log Kow Logarithm of octanol-water partition coefficient
MRL Maximum residue levels
MS Mass spectrometry
NOAEC No observed acute effect concentration
NOAEL No observed adverse effect level
PCB Polychlorinated Biphenyls
POPs Persistent organic pollutants
SCAN Scientific Committee on Animal Nutrition
ULV Ultra-low volume
WHO World Health Organization
W.w. Wet weight



BACKGROUND

1. General Background

Directive 2002/32/EC of the European Parliament and of the Council of 7 May 2002 on
undesirable substances in animal feed1 replaces since 1 August 2003 Council Directive
1999/29/EC of 22 April 1999 on the undesirable substances and products in animal nutrition2.

The main modifications can be summarised as follows

- extension of the scope of the Directive to include the possibility of establishing
maximum limits for undesirable substances in feed additives.

- deletion of the existing possibility to dilute contaminated feed materials instead of
decontamination or destruction (introduction of the principle of non-dilution).

- deletion of the possibility for derogation of the maximum limits for particular local
reasons.

- introduction the possibility of the establishment of an action threshold triggering an
investigation to identify the source of contamination (“early warning system”) and to
take measures to reduce or eliminate the contamination (“pro-active approach”).

In particular the introduction of the principle of non-dilution is an important and far- reaching
measure. In order to protect public and animal health, it is important that the overall
contamination of the food and feed chain is reduced to a level as low as reasonably achievable
providing a high level of public health and animal health protection. The deletion of the
possibility of dilution is a powerful mean to stimulate all operators throughout the chain to
apply the necessary prevention measures to avoid contamination as much as possible. The
prohibition of dilution accompanied with the necessary control measures will effectively
contribute to safer feed.

During the discussions in view of the adoption of Directive 2002/32/EC the Commission
made the commitment to review the provisions laid down in Annex I on the basis of updated
scientific risk assessments and taking into account the prohibition of any dilution of
contaminated non-complying products intended for animal feed. The Commission has
therefore requested the Scientific Committee on Animal Nutrition (SCAN) in March 2001 to
provide these updated scientific risk assessments in order to enable the Commission to
finalise this review as soon as possible (Question 121 on undesirable substances in feed)3.

It is worthwhile to note that Council Directive 1999/29/EC is a legal consolidation of Council
Directive 74/63/EEC of 17 December 1973 on the undesirable substances in animal nutrition4,

1
OJ L140, 30.5.2002, p. 10
2
OJ L 115, 4.5.1999, p. 32
3
Summary record of the 135th SCAN Plenary meeting, Brussels, 21-22 March 2001, point 8 – New questions (
http://europa.eu.int/comm/food/fs/sc/scan/out61_en.pdf)
4
OJ L 38, 11.2.1974, p. 31



which has been frequently and substantially amended. Consequently, several of the provisions
of the Annex to Directive 2002/32/EC date back from 1973.

The opinion on undesirable substances in feed, adopted by SCAN on 20 February 2003 and
updated on 25 April 20035 provides a comprehensive overview on the possible risks for
animal and public health as the consequence of the presence of undesirable substances in
animal feed.

It was nevertheless acknowledged by SCAN itself for several undesirable substances and by
the Standing Committee on the Food Chain and Animal Health that additional detailed risk
assessments are necessary to enable a complete review of the provisions in the Annex,
including the establishment of maximum levels for undesirable substances currently not
listed.

2. Specific Background

Endosulfan is an organochlorine insecticide. Contrary to some other organochlorine
pesticides, endosulfan does not accumulate in the food chain and is eliminated rapidly from
the body. Endosulfan is highly toxic for some aquatic species, particular fish.

Contrary to the other pesticides listed in the Annex to Directive 2002/32/EC, endosulfan is
still in use as a pesticide.

Current EU legislation on maximum residue levels (MRLs) for pesticides is derived
from/based on four Council Directives

- Council Directive 76/895/EEC of 23 November 1976 relating to the fixing of
maximum levels for pesticide residues in and on fruit and vegetables6

- Council Directive 86/362/EEC of 24 July 1986 on the fixing of maximum residue
levels for pesticide residues in and on cereals7

- Council Directive 86/363/EEC of 24 July 1986 on the fixing of maximum residue
levels for pesticide residues in and on foodstuffs of animal origin8

- Council Directive 90/642/EEC of 27 November 1990 on the fixing of maximum
residue levels for pesticide residues in and on certain products of plant origin,
including fruits and vegetables9.

- Regulation (EC) No 396/2005 of the European Parliament and of the Council of 23
February 2005 on maximum residue levels of pesticides in or on food and feed of

5
Opinion of the Scientific Committee on Animal Nutrition on Undesirable Substances in Feed, adopted on 20
February 2003, updated on 25 April 2003 (http://europa.eu.int/comm/food/fs/sc/scan/out126_bis_en.pdf)
6
OJ L 340, 9.12.1976, p.26
7
OJ L 221, 7.8.1986, p. 37
8
OJ L 221, 7.8.1986, p. 43
9
OJ L 350, 14.12.1990, p. 71



plant and animal origin and amending Council Directive 91/414/EEC which will
repeal the four Council Directives10.

Until 1997, MRLs were fixed only for raw commodities. Council Directive 1997/41/EC of 25
June 199711 amending the above mentioned Directives, provided for a system applicable from
1 January 1999 to set MRLs in processed products and composite foodstuffs, based on the
MRLs fixed for the raw agricultural products. MRLs for processed products and composite
foodstuffs are calculated on the basis of the MRL set for the agricultural commodity by
application of an appropriate dilution or concentration factor and for composite foodstuffs
MRLs are calculated taking into account the relative concentrations of the ingredients in the
composite foodstuffs.

As the consequence of the coming into force of Directive 1997/41/EC, the pesticide residue
legislation applies also to animal feeding stuffs since 1 January 1999. However some
problems have been observed in implementing the pesticide residue legislation. The following
problems have already been identified:

- compound feed is composed of a relatively high number of ingredients of which
several are processed products (by-products). It is not obvious to know what MRL is
applicable to such compound feed as it involves many calculations and uncertainties
and “unknowns” (processing factors).

- pesticide residue legislation does not cover products of marine origin which are
regularly used in animal feed (no direct application).

- pesticide residue legislation does not cover products typically for animal feed (no food
use) such as pastures, roughages, forages, fish oil and fish meal.

Therefore it is appropriate to include in the list of undesirable substances maximum levels for
some pesticides, in particular those of relevance for animal health or for public health through
carry over from feed to food of animal origin

As already mentioned, endosulfan is listed in the Annex to Directive 2002/32/EC. For
comparison the current provisions in the EU-pesticide residue legislation are mentioned.

10
OJ L 70, 16/03/2005, p. 1
11
OJ L 184, 12/07/1997, p. 33



Directive 2002/32/EC EU-Pesticide residue legislation
ML relative to a feeding stuff with a MRL applicable to the product as marketed
moisture content of 12 %
Product mg/kg Product mg/kg
Maize 0.2 Cotton seeds 0.3
Oilseeds 0.5 Soybean seeds 0.5
Complete feeding stuffs for fish 0.005 Other oilseeds 0.1*
All other feeding stuffs 0.1 Potatoes 0.05*
Tea 30
Hops 0.1*
Cereals 0.05*
Citrus, berries 0.5
Pome fruit 0.3
Tree nuts 0.1*
Peppers 1
Tomatoes 0.5
Other vegetables 0.05*
Meat (fat) 0.1
Milk 0.004
Eggs 0.1*
*lower limit of analytical determination

In the current provisions in Directive 2002/32/EC there are apparently some inconsistencies.
Whereas for example a maximum level for endosulfan is fixed at 0.5 mg/kg for soybean seeds
(oilseeds) the resulting soybean oil (in which endosulfan concentrates) has to comply with 0.1
mg/kg (all other feeding stuffs) in case it is used for animal feed. For foodstuffs a processing
factor can be applied.

It is important that these provisions concerning endosulfan are completely reviewed in the
framework of Directive 2002/32/EC. A risk assessment on the presence of endosulfan in
animal feed, in particular fish feed and fish feed ingredients, should be undertaken as a
priority.

TERMS OF REFERENCE
The European Commission requests the EFSA to provide a scientific opinion on the presence
of endosulfan in animal feed.

This scientific opinion should comprise the

- determination of the toxic exposure levels (daily exposure) of endosulfan for the
different animal species of relevance (difference in sensitivity between animal species,
with particular attention to farmed fish species) above which

- signs of toxicity can be observed (animal health/impact on animal health)



- the level of transfer/carry over of endosulfan from the feed to the products of
animal origin results in unacceptable levels of endosulfan or of its metabolites
in the products of animal origin in view of providing a high level of public
health protection.

- identification of feed materials which could be considered as sources of contamination
by endosulfan and the characterisation, insofar as possible, of the distribution of levels
of contamination

- assessment of the contribution of the different identified feed materials as sources of
contamination by endosulfan

- to the overall exposure of the different relevant animal species (with particular
attention to farmed fish species) to endosulfan,

- to the impact on animal health,

- to the contamination of food of animal origin (the impact on public health),
taking into account dietary variations and carry over rates.

- identification of eventual gaps in the available data which need to be filled in order to
complete the evaluation.

ASSESSMENT
1. Introduction

1.1. Chemistry and use

Endosulfan is an organochlorine pesticide that was developed and introduced in the mid
1950s. World wide production of endosulfan in the middle of the 1980’s was estimated at
10,000 tons/year (ATSDR, 2000). Within the European Union there is currently only one
producer located in Frankfurt (Germany) which produces endosulfan. The manufactured
volume of endosulfan at this site currently amounts for approximately 4,000 tons/year and a
major part is exported for use in tropical and subtropical regions such as Latin America,
Caribbean and Southeast Asia. Endosulfan has also been reported to be produced in Israel,
India, South Korea, and China (Umweltbundesamt, 2004).

CAS numbers are for technical endosulfan 115-29-7, α-endosulfan 959-98-8, β-endosulfan
33213-65-9, and endosulfan sulfate 1031-07-8.

Technical endosulfan is obtained through the Diels-Alder addition of
hexachlorocylopentadiene and cis-butene-1,4-diol, followed by reaction of the addition-
product with thionyl chloride. It mainly consists of a mixture of two stereoisomers named α-
and β- endosulfan in the approximate ratio of 70:30 (Figure 1). As minor impurities technical
grade endosulfan may also contain up to 2 % endosulfan alcohol and 1 % endosulfan ether.



The technical product is a brownish crystalline solid and has a slight sulfur dioxide odour.
Endosulfan is practically insoluble in water but soluble in most organic solvents. Log Kow
values for technical endosulfan is 3.55 and 3.62, for α-endosulfan 3.83, for β-endosulfan 3.52,
and for endosulfan sulfate 3.66. It is hydrolysed slowly by water, more rapidly by acids and
bases. Decomposition is catalysed by iron, which it corrodes.

α - endosulfan β - endosulfan

Figure 1. Structure of α- and β-endosulfan.

Endosulfan is a non-systemic insecticide and acaricide with contact action. Formulations of
endosulfan include emulsifiable concentrate, wettable powder, ultra-low volume (ULV)
liquid, and smoke tablets. It is used in the control of sucking, chewing and boring insects and
mites on a very wide range of crops, including fruit, vines, olives, vegetables, ornamentals,
potatoes, cucurbits, cotton, tea, coffee, rice, cereals, maize, sorghum, oilseed crops, hops,
hazels, sugar cane, tobacco, alfalfa, mushrooms, forestry, glasshouse crops, etc. In addition to
its agricultural use, and its use in the control of the tsetse fly, endosulfan is used as a wood
preservative and for the control of home and garden pests.

Endosulfan containing products are authorised for use in seven member states of the
Community. But use of endosulfan within the EU has seen a steadily decrease lasting recent
years. Almost 90 % of 490 tons/year used in 1999, were applied in Mediterranean parts of the
EU (Umweltbundesamt, 2004). A draft Commission Decision has been notified by the
European Communities to the WTO proposing not to include endosulfan in the positive
Community list (Annex I of Directive 91/414/EEC) because it does not satisfy the minimum
safety requirements in particular the environmental fate, eco-toxicological profile and the
operators’ exposure risk. The foreseen date of entry into force is 1 August 2005 and Member
States have to withdraw all existing authorisations for plant protection products containing
endosulfan within 6 months from that date12.

1.2. Environmental fate

Endosulfan is released into the environment mainly as a result of its use as a pesticide. The
compound partitions to the atmosphere and to soils and sediments. Endosulfan can be

12
Notification G/SPS/N/EEC/260 of 3 May 2005. http://www.wto.org/english/tratop_e/sps_e/sps_e.htm



transported over long distances in the atmosphere, but is relatively immobile in soils
(ATSDR, 2000). Direct uptake from soil to plant as well as transport in the plant is negligible.

Both α- and β- endosulfan are fairly resistant to photo degradation, but the metabolites
endosulfan sulfate and endosulfan diol (Figure 2) are susceptible to photolysis. The half-life
of both isomers in water are estimated to be in the range of 4 to 7 days, but at low pH and
anaerobic conditions it could be up to 5 months (ATSDR, 2000). In laboratory experiments
with two soil types half time of 14C-endosulfan was estimated between 90 and 180 days based
on 14CO2 production (Peres et al., 2004).

Figure 2. Chemical degradation of endosulfan in the environment (WHO, 1984).

In soil, the α-isomer has a shorter half-life (60 days) than the β-isomer (900 days). Endosulfan
sulfate was found to be the major degradation product in soil and on plant surfaces. It is found
to be more stable than the two endosulfan isomers, but the transport of all three compounds is
slow in soil. Biodegradation in soil and water is dependent on climatic conditions and on the
type of micro organisms present. In plants sprayed with endosulfan, initial residues on fruits
and vegetables can vary from about 1 to 100 mg/kg; after 1 week, residues generally decrease
to 20 % or less of the initial amount (WHO, 1984).

Due to its potential for long range transport, environmental persistence, bioconcentration in
various aquatic organisms and ecotoxicity, there is agreement that endosulfan and its
metabolite endosulfan sulfate meet the criteria for future inclusion into the list of persistent
organic pollutants (POPs). However, unlike most other organochlorine pesticides of the Diels-



Alder class, such as chlordene, chlordane, heptachlor, heptachlorepoxide, aldrine and dieldrin,
endosulfan has a less pronounced affinity to lipids. Consequently, biomagnification and
accumulation of endosulfan, in terrestrial food chains, is unlikely to occur. Endosulfan is still
in use in some countries.

1.3. Toxicological findings in laboratory animals and hazard assessment for
humans

Endosulfan was evaluated by JMPR in 1998 (FAO/WHO, 1998). ATSDR published a
toxicological profile for endosulfan in 2000 (ATSDR, 2000).

The neurotoxic effects of endosulfan are well documented in both humans and animals, and
extensive research has been conducted in recent years aimed at elucidating its mechanism of
neurotoxicity. Possible mechanisms of toxicity include (a) alteration of neurotransmitter
levels in brain areas by affecting synthesis, degradation, and/or rates of release and reuptake,
and/or (b) interference with the binding of neurotransmitter to their receptors. In addition to
neurotoxicity, exposure to endosulfan has induced a wide array of effects in animals including
liver and kidney toxicity, hematological effects, alterations in the immune system, and
alterations in the reproductive organs of males. There are just a few studies on possible
mechanisms of the effects on organ or systems other than the nervous system.

As summarized in 6.3. Metabolism, the biotransformation of endosulfan can give rise to a
number of both polar and nonpolar metabolites. There is little and inconclusive information
on whether the toxicological properties of endosulfan are due to the parent compound or to
any of its metabolites.

The more lipophilic parent compound of endosulfan will be able to cross cell membranes
more easily than its polar metabolites, accumulate to a greater extent, and therefore possibly
be the most neurotoxic. Differential toxicity could also be related to differential affinity for
the GABA receptor. What is known from oral acute lethality studies in rats and mice is that α-
endosulfan is approximately 3 times more toxic than β-endosulfan (Dorough et al., 1978;
Hoechst, 1975, 1990; Maier-Bode, 1968). In addition, in mice, the acute toxicity of
endosulfan sulfate was comparable to that of α-endosulfan (Dorough et al., 1978). Also in
mice, the metabolites endosulfan α-hydroxy ether, endosulfan lactone, and endosulfan ether
had lethal doses 10 - 20 times higher than the α-or β-isomers; the lethal dose for
endosulfandiol was two orders of magnitude higher than that of the α-or β-isomer (Dorough et
al., 1978).

Most studies are carried out with technical products and if purity is given it is generally 97 -
99 % but purity as low as 91.4 % is also reported.

Acute toxicity

Acute exposure to high doses of endosulfan results in hyperactivity, muscle tremors, ataxia,
and convulsions.



The LD50 of endosulfan varies widely depending on the route of administration, species,
vehicle, and sex of the animal. Female rats are clearly more sensitive than male rats, and, on
the basis of a single study, this sex difference appears to apply to mice also. The lowest oral
LD50 value is 9.6 mg/kg b.w. in female Sprague-Dawley rats (Hoechst, 1990; Reno, 1975).

Long term toxicity

In a 78 week oral study with mice non-neoplastic changes were observed in both sexes in
kidneys and sex organs. Based on these findings a NOAEL was identified for female mice at
3.9 mg/kg diet; equal to 0.58 mg/kg b.w./day (US National Cancer Institute, 1978).

In a corresponding 78 week oral study with rats given diets containing 220 mg/kg technical-
grade endosulfan (purity, 98.8 %) or higher, non-neoplasic effects were seen in all dose
groups and thus a NOAEL could not be established (US National Cancer Institute, 1978). In
an other study groups of 50 five-to-six-week-old rats of both sexes were fed diets containing
endosulfan (purity, 97.1 %) at concentrations of 0, 3, 7.5, 15, or 75 mg/kg diet, equal to 0, 0.1,
0.3, 0.6, and 2.9 mg/kg b.w./day for males and 0, 0.1, 0.4, 0.7, and 3.8 mg/kg b.w./day for
females, for 104 weeks. Reductions in body weights and body-weight gains were observed in
males and females at 75 mg/kg diet, but no clinical signs of poisoning were seen at any dose.
No increase in mortality rates was observed in treated groups. Increased incidences of
enlarged kidneys in females and of aneurysms, enlarged lumbar lymph nodes and marked
progressive glomerulonephrosis in males were seen at 75 mg/kg diet. The NOAEL was 15
mg/kg diet, equal to 0.6 mg/kg b.w./day, on the basis of reduced body weights and
pathological findings at higher doses (Ruckman et al., 1989; Gopinath and Cannon, 1990;
Hack et al., 1995).

Human data as well as studies in animals did not provide unequivocal evidence of
carcinogenicity for endosulfan (Hack et al., 1995; Hoechst, 1988, 1989). However,
endosulfan promoted the development of altered hepatic foci in rats initiated with
nitrosodiethylamine (Fransson-Steen et al., 1992). Although the mechanism of tumour
promotion of endosulfan is not known, it has been suggested that it involves inhibition of
cellular communication (Kenne et al., 1994).

JMPR (FAO/WHO, 1998) established an ADI of 0 - 0.006 mg/kg b.w. for technical
endosulfan on the basis of the NOAEL of 0.6 mg/kg b.w./day in the two-year dietary study of
toxicity in rats and a safety factor of 100. The ADI is supported by similar NOAEL values in
the 78-week dietary study of toxicity in mice (NOAEL of 0.58 mg/kg b.w./day), a one-year
dietary study of toxicity in dogs (NOAEL of 0.8 mg/kg b.w./day, see chapter 5.6 for further
details), and a study of developmental toxicity in rats (NOAEL of 1.5 mg/kg b.w./day)

Endosulfan has been tested for genotoxicity in a wide range of assays. There was however no
evidence on genotoxicity in most of these assays. In one assay for dominant lethal mutation in
mice, late effects were observed at high doses (16.6 mg/kg b.w./day). The technical
endosulfan used was reported to have a purity of 97.3 % (FAO/WHO, 1998, Pandey et al.
1990).



2. Methods of analysis

Analysis of endosulfan residues in food and feed samples should include detection of α- and
β- endosulfan plus the major degradation product endosulfan sulfate. Currently, high
resolution gas chromatography with electron capture detection (GC/ECD) or mass
spectrometric detection (GC/MS) after extraction of samples with organic solvents, various
clean-up steps to remove lipids and other possible co-extractives are the analytical methods of
choice. These methods not only allow differentiation between the different isomers but also
separate them from possible superimposing co-extractives. An efficient separation of the two
endosulfan isomers and endosulfan sulfate from other interfering compounds, such as other
organochlorine pesticides and polychlorinated biphenyls (PCBs) is especially important. In
routine monitoring programmes it has therefore proven necessary to perform the gas
chromatographic separation on two capillary columns of different polarity.

3. Statutory limits

Endosulfan is listed in the Annex to Directive 2002/32/EC of the European Parliament and of
the Council of 7 May 2002 on undesirable substances in animal feed13 which replaces since 1
August 2003 Council Directive 1999/29/EC of 22 April 1999 on the undesirable substances
and products in animal nutrition14. The maximum levels which apply to the sum of the α- and
β- isomer and of endosulfan sulfate, expressed as endosulfan each pertain to a feedingstuff
with a moisture content of 12 %. See also specific background.

Minimum time intervals between the last application and harvesting are prescribed in most
countries and vary between 0 and 42 days, depending on the crop, type of formulation used,
the mode of application, tolerances, and agronomic needs.

4. Occurrence in food and feed

Endosulfan is released to the environment mainly as the result of its use as a pesticide. It has
been found at low levels in numerous food and feed samples.

Annually, some 40,000 – 50,000 food samples are analysed for, on average, 151 different
pesticides within national monitoring programmes of 15 EU Member States and the three
EFTA States Norway, Iceland and Liechtenstein in order to check the compliance of different
food commodities with the corresponding pesticide maximum residue levels. The condensed
results are regularly submitted to the Commission, which compiles and collates the data.
Besides national monitoring programmes, the Commission recommends the participation of
each Member State in a specific EU co-ordinated monitoring programme. These programmes
which have existed since 1996 include the analysis of major components of the standard
European diet of plant origin (so far: mandarins, pears, bananas, potatoes, oranges, peaches,
carrots, spinach, cauliflower, wheat grains, peppers, melons, rice, cucumber, head cabbage,
peas, apples, tomatoes, lettuce, strawberries, table grapes and nectarines) for an increasing

13
OJ L140, 30.5.2002, p. 10
14
OJ L 115, 4.5.1999, p. 32



number of pesticides. Endosulfan became part of the pesticide spectrum to check for in 1997.
Between 1997 and 2002 a total of 35,152 food samples of plant origin have been analysed for
endosulfan in the frame of these EU co-ordinated monitoring programmes. While 33,785
(96.1 %) samples contained no endosulfan residues, this pesticide could be determined in
1367 samples (3.9 %) below or at the MRLs. In 55 cases (0.16 %), the MRLs were exceeded.
Endosulfan and endosulfan sulfate were found mainly on pepper, melons, strawberries and
lettuce15.

Endosulfan levels in food can be reduced by food processing. For example, endosulfan can be
removed by physical refinement treatment during oil refining using bleaching and
deodorization (Riuz Mendez et al., 2005) or by peeling of apples (Rasmussen et al., 2003).

Thousands of feed samples are analysed annually in the Member States within the frame of
official feed control, with the aim to check compliance with legal limits. As the Commission
only requires the Member States to report their results as compliant and non-compliant, these
condensed summaries give almost no information on actual levels in feed. Furthermore, it is
often not specified which compounds are covered by the analytical method applied nor are the
limits of detection reported. When comparing the summary reports it is often difficult to
differentiate between numbers of individual analyses on the one hand and number of samples
on the other hand. Concentration levels for individual substances analysed rather than
condensed summaries for compound groups would be essential for a better understanding of
the occurrence situation of undesirable substances in different feed materials and compound
feeds as a prerequisite for a meaningful risk assessment and finally for a derivation of a
possible temporal trend of the respective compounds in the feed chain.

Analysis of 104 feedingstuffs performed in 2003/2004 as part of official feed control in
Germany revealed that endosulfan was detected in two samples only and then at a
concentration of 7 µg/kg. In all other samples which included crops, maize, oil seeds, tubers,
roots, mineral feed and compound feed for ruminants, pigs, poultry, horses and pets, α-, β-
endosulfan and endosulfan sulfate could not be detected at a limit of detection of 1 µg/kg.

In the Czech Republic, 10 samples of fish meal have been analysed in 2004. The samples
were analysed for α- and β-endosulfan. All results were below the limit of detection of 1
µg/kg. Data on endosulfan sulfate were not reported.

Data on fish feed (9 samples) provided by European Feed Manufacturers' Federation showed
levels of 0.08 – 0.23 µg/kg for α-endosulfan, whereas the levels for β-endosulfan and
endosulfan sulfate were < 0.1 µg/kg.

A survey of pesticide residues in animal feed ingredients has been conducted in the UK in
1998, where 151 samples of cereals (barley grain and malting, wheat grain, maize gluten and
distillers), fodder (barley and wheat straw, grass and maize silage, sugar beet pulp) and beans
(rapeseed, cotton seed, sunflower seed, cocoa meal, palm kernel and soy bean meal, copra)

15
European Commission, Food and Veterinary Office, pesticide annual reports
http://www.europa.eu.int/comm/food/fvo/specialreports/pesticides_index_en.htm



where analyzed for 28 different pesticides including endosulfan. None of these samples
contained endosulfan at concentrations over the detection limit (50 µg/kg) (MAFF-UK,
1998).

5. Adverse effects on fish, livestock and pets, and exposure-response relationship

5.1. Introduction

The effect of any dose of endosulfan varies with the route of exposure and with the vehicle
used. The lethal dose is lower if the insecticide is given in vegetable rather than in mineral oil,
or as suspensions or dry powder (Humphreys, 1988). The sensitivity to endosulfan exposure
varies with species, strain, age, gender and health status.

Acute intoxication with endosulfan is expressed through stimulation of the nervous system.
The symptoms vary considerably but are predominantly neuromuscular. The onset of clinical
signs may occur after a few minutes to days depending on the dose and route of exposure.
Most animals show signs within 24 hours after exposure (Humphreys, 1988).

The signs of chronic endosulfan toxicity are principally similar to those of acute poisoning but
develop more gradually, and tremors, convulsions, and depression may occur for weeks
(Humphreys, 1988).

5.2. Fish

In a recently published study on Nile tilapia of about 140 g b.w., the effects of endosulfan at
100 and 500 µg/kg diet during 21 or 35 days exposure on thyroid hormone levels and
metabolism were investigated (Coimbra et al., 2005). The plasma levels of T4 and of the
inactive metabolite reverse T3 were decreased compared to levels in control fish, the effect
was most prominent at the lowest dose. Furthermore, the hepatic deiodinase type I activity
was reduced and the hepatic deiodinase type III (D3) was increased compared with controls.
In the gills, D3 activity was increased in fish fed both levels of endosulfan. There was no clear
dose-response pattern. It is therefore difficult to interpret the consequences of these effects on
a long term; in addition, the authors claim that these might be adaptive responses.

In the common carp (on average 62.5 g b.w.) fed a diet containing technical endosulfan
(thiodan, 35 % w./v.) at an endosulfan concentration of 0.5 µg/kg diet dry weight (0.015
µg/kg b.w.) for 5 weeks. No alterations in behaviour, feeding activity, growth and
macroscopically overt signs of pathology upon dissection were observed. Cytological and
ultrastructural alterations in hepatocytes and enterocytes were investigated by means of light
and electron microscopy (Braunbeck and Appelbaum, 1999). The liver cells showed
enlargement of the nucleolus, increased number and size of both Golgi fields and rough
endoplasmic reticulum (ER) lamellae, as well as proliferation of peroxisomes and lysosomes,
all together representing morphological equivalent of a general stimulation of hepatic
metabolism. Furthermore, proliferation of smooth ER, glycogen and lipid depletion, invasion
of phagocytic macrophages and accumulation of myelinated bodies in endothelial cells of



hepatic sinusoids were found. In the intestinal tract, lack of chylomicrons in the epithelial
lining was observed, indicating a disturbance of absorption. These subtle biological changes
were considered by the Panel as not to represent adverse effects.

Endosulfan is toxic to fish through exposure via water, and generally the LC50 values lie
within the concentration range of 1 to 10 µg/L water (Goebel et al., 1982). The α-isomer was
more toxic and the β-isomer less toxic, than technical grade endosulfan when examined in
two freshwater fish species (Rao et al., 1980; Devi et al., 1981). Sulfur-free metabolites
possess a significantly lower toxicity against fish with LC50 values in the range 1 to 10 mg/L
(Knauf and Schulze, 1973). The effect of endosulfan in fish is temperature-dependent with
decreased action at low temperatures, demonstrated in rainbow trout (Macek et al., 1969).

Short time endosulfan exposure of different fish species in sub lethal water concentrations
(0.1 - 10 µg/L), have triggered increased swimming activity and raised blood glucose levels
(Van Dyk et al., 1977; Gopal et al., 1980; Singh and Srivastava, 1981; Verma et al., 1983).
Histopathological changes in the gills are reported after exposure to toxic water
concentrations (Dalela et al., 1979). Histopathological changes in the liver and brain have
been found in fish exposed to endosulfan contaminated water from insect spraying
(Matthiessen and Roberts, 1982).

5.3. Ruminants

In an experimental study, groups of two steers were given endosulfan in the rations at doses
0.15, 1.1, 2.5 and 5.0 mg/kg b.w. After 60 days, no signs of toxicity were found in the pairs of
steers receiving endosulfan at 0.15 and 1.1 mg/kg, One of the steers in the pairs receiving 2.5
mg/kg and 5.0 mg/kg showed toxic symptoms (muscle convulsions, excessive salivation, and
incoordination) after 13 and 2 days, respectively, and both pairs were removed from the
experiment (Bech et al., 1966). This indicates a NOAEL for clinical toxicity of 1.1 mg/kg
b.w., and with a dry matter feed intake to body weight of approximately 3 % (Pond et al.
1995) this correspond to a no observed acute effect concentration of 40 mg/kg diet.

A study of endosulfan effects in goats orally dosed with 5 mg/kg b.w/day for 36 days revealed
reduced body weight gain and depleted fat stores compared to controls. Other toxic symptoms
were not reported (Amin and Abdalla, 1995).

There are several reports on endosulfan poisoning in cattle. In one case fatal poisoning
appeared among cows fed peanut hay contaminated with endosulfan. Three cows died within
15 hours after the ingestion, and the dose was calculated to be approximately 30 mg of
Thiodan (presumed to contain 35 % endosulfan)/kg b.w. (Terblanche and Minne, 1968). In
another accidental case in cattle, Thiodan (also presumed to contain 35 % endosulfan)
resulted in convulsions and death. The dose ingested was not determined, but residues were
determined in liver (4.4 mg/kg w.w.), kidney (1.1 mg/kg w.w.) and muscle tissue (0.66 mg/kg
w.w.) consisting predominantly of the metabolite endosulfan sulfate (Braun and Lobb, 1976).



Spraying of animals with accidental high endosulfan concentration (Thiodan emulsion of 0.12
% endosulfan) for treatment against ectoparasites, produced acute nervous symptoms in 50 of
250 cattle and 11 animals died (Thomson, 1966). Spraying or applying powder with the
pesticide at the animal skin are the main causes to endosulfan poisoning in cattle and such
cases are still occurring (Aslani, 1996; Kelch and Kerr, 1997; Mor and Ozmen, 2003).

5.4. Birds

In broiler chicken fed 30, 60 and 120 mg endosulfan/kg diet from age one day to eight weeks,
a slight inhibitory effect on body weight gain relative to controls was found at all endosulfan
levels, but no significant effect on feed consumption was revealed. Furthermore, increased
serum glucose and decreased serum albumin was found in the chicken at all endosulfan levels.
The hyperglycemia tended to be dose-related (Selvaraj et al., 2001a,b). The daily feed intake
of broiler chicken after hatching is approximately 15 % relative to the body weight, reduced
to approximately 10 % within few days (Pond et al., 1995), hence the levels in feed
correspond to daily doses of 3 - 4.5, 6 - 9 and 12 - 18 mg/kg b.w., respectively.

Hudson et al. (1972) examined the effects of age of mallard ducks on their acute susceptibility
to endosulfan. The oral LD50s of animals of 36 hours after birth, the age of 7 days, 30 days
and 6 months were 28, 6.5, 7.9 and 34 mg/kg b.w., respectively.

Reported lethal feed concentrations (< 10-d LC50) of endosulfan in young mallard, ring-
necked pheasant and bobwhite quail are 350, 175 and 100 mg/kg diet (WHO, 1984). Based on
a daily feed intake of approximately 6 % relative to body weight, the feed concentrations
correspond to approximately 20, 15 and 6 mg/kg b.w., respectively.

5.5. Rabbits

Mated New Zealand white rabbits were given endosulfan by gavage on days 6 - 28 of
gestation at doses of 0.3, 0.7 or 1.8 mg/kg b.w. The highest dose was associated with signs of
maternal toxicity that included noisy, rapid breathing, hyperactivity and convulsions, but no
teratogenic or developmental effects. No clinical signs of toxicity in does or foetal effects
were found at the two other dose levels. Thus, the NOAEL of endosulfan in rabbits was 0.7
mg/kg b.w./day (Dickie et al., 1981).

5.6. Dogs

Dogs dosed endosulfan 200 or 500 mg/kg b.w. as a single dose in gelatine capsules showed
increased saliva formation, vomiting, and tonic and clonic cramps. The animals which did not
vomit during these tests died (Maier-Bode, 1968). LD50 in dogs is reported 77 mg/kg
(FAO/WHO, 1998)

Beagle dogs of both sexes were fed endosulfan at concentrations of 3, 10 and 30 mg/kg diet
for one year, calculated by the authors to be 0.23, 0.77 and 2.3 mg/kg b.w./day. At the 30



mg/kg diet some animals had violent contractions of the abdominal muscles, and males at this
dose had reduced body weight gains throughout the study in comparison with controls, and
cholinesterase activity was increased in the brain. No other effects related to treatment were
observed. In addition, one group was given a diet containing 30 - 60 mg/kg endosulfan,
increasing in stages from 30 mg/kg for 54 days, to 45 mg/kg for 52 days, and 60 mg/kg for 19
- 40 days. These dogs were killed in extremis before the scheduled completion of the
experiment due to a number of neurotoxic symptoms (FAO/WHO, 1998). The results from
this study gives a NOAEL of 10 mg/kg feed, corresponding to 0.8 mg/kg b.w.

Mongrel dogs of both sexes were given endosulfan in gelatine capsules at feed levels 3, 10
and 30 mg/kg for one year. No clinical signs or treatment related effects on body weight gain,
clinical chemical or haematological parameters, or gross or histopathological changes at these
concentrations were noted (FAO/WHO, 1998). Middle sized adult dogs have daily
maintenance requirement of dry feed of approximately 2 % relative to body weight (Pond et
al., 1995), corresponding to 0.06, 0.2 and 0.6 mg/kg b.w./day.

6. Toxicokinetics and tissue disposition

6.1. Absorption

Several animal studies provided evidence of endosulfan absorption following oral exposure
(Goebel et al., 1982; FAO/WHO, 1998; ATSDR, 2000). In metabolic studies with 14C-
endosulfan in mice (Deema et al., 1966) approximately 65 % of the administered radioactivity
was recovered from the excreta and tissues 24 hours after ingestion of a single dose (0.3
mg/animal), suggesting that gastrointestinal absorption occurred to a significant extent in this
species. More than 90 % of a single oral dose of 14C-endosulfan (2 mg/kg b.w.) was absorbed
in rats with a maximum plasma concentration occurring after 3 – 8 hours in males (0.25
µg/mL) and about 18 hours in females (0.18 µg/mL). The half-life in plasma was 75 hours in
females. Males show a biphasic curve with an initial half-life of 8 hours followed by a half-
live of 110 hours (FAO/WHO, 1998).

When 14C-endosulfan was administered as a single oral dose (0.3 mg/kg b.w.) to lactating
sheep (Gorbach et al., 1968), blood radioactivity reached a maximum after 24 hours (0.064
µg/mL). The metabolic balance performed on day 22 suggested that absorption of endosulfan
was > 42 % of the dose, based on radioactivity excreted in urine and milk.

Although no specific studies were carried out to determine the absorption of endosulfan in
humans, residues of endosulfan were found in the fat, brain and kidney of a man who had
ingested a single oral dose (260 mg/kg b.w.) of endosulfan. 150 minutes after ingestion, the
levels of α- and β-endosulfan and endosulfan sulfate in blood were 644, 101 and 876 µg/L
respectively (Boereboom et al., 1998). α-Endosulfan and endosulfan sulfate were also found
in urine but at levels of 1.0 µg/L or lower. The patient died 91 hours after ingestion. Post
mortem, the highest levels of α-endosulfan were found in adipose tissue and stomach content,
4.1 and 3.5 mg/kg respectively, whereas lower levels were found in brain and kidney, 0.08
and 0.06 mg/kg respectively. β-endosulfan was found in brain and stomach content at 0.07



and 1.4 mg/kg respectively and endosulfan sulfate was found in liver, brain and kidney at 3.0,
1.3 and 0.4 mg/kg respectively. β-endosulfan and endosulfan sulfate were not analysed in
adipose tissue. Even if this report concerns an extreme case, it gives evidence of absorption,
metabolism and distribution of endosulfan in humans.

6.2. Distribution

Studies using radiolabelled endosulfan administered to rat and mice indicate that the tissue
concentration of residues of parent compound and metabolites were generally highest in the
kidneys and liver and lower in other tissues, including fat. Male rats exposed daily for 60 days
to 2.5 or 3.75 mg/kg/day of endosulfan containing α- and β-isomers in a ratio of 2:1 produced
different disposition patterns for the two isomers (Ansari et al., 1984). For both doses, the
concentrations of the α-isomer were as follows: kidney > epididymis > prostate ≈ spleen >
testes > brain > liver. The β-isomer was found predominantly in seminal vesicle > epididymis
> heart > prostate > spleen > liver. Overall, the greatest levels of both isomers were located in
the kidney, seminal vesicle, and epididymis, with the liver having the least amount. Hoechst
(1987) investigated the tissue residues in rats consuming 34 or 68 mg endosulfan/kg/day over
4 weeks. The predominant substances found in the liver were endosulfan sulfate and
endosulfan lactone. Traces of α- and β-endosulfan were measured in the liver, whereas
approximately 200 times more α-endosulfan than β-endosulfan was found in the kidney.

In lactating cows and sheep (Keller, 1959; Gorbach et al., 1968) residues were predominantly
found in fat, kidney, and liver; all of the remaining tissues had considerably lower
concentrations.

Because Spain is a main user of endosulfan within EU several reports focused on residues of
endosulfan in humans from this country especially from southern Spain where extensive areas
are devoted to intensive farming, including plastic greenhouse production.

In the mid-1990ties remarkable high levels of endosulfan residues were determined in the
adipose tissue from 52 children from the Granada area in Spain, and showed the following
results, based on a limit of quantification of 1 - 5 ng/g of lipid: α-endosulfan was detected in
seven individuals: distribution, percentile 25, 50 and 75 were: 8.6, 58.9 and 105 ng/g of lipid.
β-endosulfan was detected in three individuals with levels of 115, 2450 and 9060 ng/g of
lipid. Endosulfan sulfate was found in one individual at 42.9 ng/g of lipid (Olea, personal
communication).

In women of reproductive age the highest concentration of α-endosulfan, β-endosulfan and
endosulfan sulfate were found in fat corresponding to 11 ± 86 µg/kg fat, 6.5 ± 20 µg/kg fat
and 16 ± 93 µg/kg fat, respectively (Cerrillo et al., 2005).

6.3. Metabolism

Biotransformation in mammals is by oxidation, hydrolysis and subsequent conjugation of α-
and β-endosulfan. The major portion of metabolites in the excreta and/or tissues consisted of



unidentified polar metabolites that could not be extracted from the matrix, whereas the non-
polar metabolites including sulfate, diol, α-hydroxyether, and ether derivatives of endosulfan,
represented only minor amounts (Dorough et al., 1978). In sheep, endosulfan sulfate was
detected in the faeces and endosulfan diol and α-hydroxyether were detected in urine
(Gorbach et al., 1968).

Of all the metabolites of endosulfan, the sulfate appears to be the one that accumulates,
predominantly in the liver and kidneys. The β-isomer is more resistant to oxidation to
endosulfan sulfate than the α-isomer and hence is more persistent in living organisms
(Sutherland et al., 2004). Residues associated with endosulfan comprise both isomers and
endosulfan sulfate, the latter being the major residue detected in animal tissues after exposure
(Sutherland et al., 2004). This has important consequences in regard to the monitoring issue
since endosulfan sulfate has equivalent mammalian toxicity to α-endosulfan (Goebel et al.,
1982).

Endosulfan is slowly metabolised in fish and endosulfan sulfate is the main metabolite (Rao et
al., 1981). Other metabolism data for fish dietary exposed to endosulfan were not identified.

6.4. Excretion

Elimination occurs mainly in the faeces and to lesser extent in urine, less that 15 % is retained
after 5 days. In a study using rats treated with a single oral dose of 14C-endosulfan (2 mg/kg
b.w.), Dorough et al. (1978) found that 82 and 72 % of the dose was found in faeces, whereas
12 and 22 % was excreted in urine for males and females, respectively.

Biliary excretion of radio labelled compounds in male rats given 1.2 mg/kg b.w. as a single
dose was approximately 50 % for the α-isomer and 30 % for the ß-isomer over 48 hours.
There appeared to be little enterohepatic circulation.

In sheep receiving a single dose of 14C-endosulfan (Gorbach et al., 1968), radiolabelled
compounds were excreted mainly via the urine (41 %) and faeces (50 %). About half of the 50
% in faeces was unmetabolised endosulfan.

When treatment ceased after dietary administration of 14C-endosulfan for 14 days (Dorough et
al., 1978), the estimated residues half-lives were approximately one week for kidney and
three days in liver.

7. Carry over and tissue concentration

In pigs fed a diet containing 2 mg endosulfan/kg feed for up to 81 days, the compound was
detected in fat at concentrations of 70, 90 and 40 µg/kg after 27, 54 and 81 days of treatment,
respectively, suggesting that endosulfan does not bioaccumulate. 27 days after the exposure
ceased concentrations in fat were below the limit of detection (Maier-Bode, 1966).

Groups of three lactating Holstein cows were given diets containing 0, 0.3, 3, or 30 mg/kg
14
C-endosulfan for 30 days. Between days 7 and 29, the average concentrations in milk were



3.4, 40, and 462 µg/kg endosulfan in the three dose groups (Bowman, 1959). The
concentrations of tissue residues found at the three doses were: liver, 0.35, 2.45, and 25.3
mg/kg; kidney, 0.05, 0.35, and 6.29 mg/kg; and omental fat, 0.07, 0.71, and 7.08 mg/kg
(Keller, 1959).

After feeding 0.5 to 2 g technical endosulfan per day to dairy cows for 11 days, the parent
compound endosulfan was not found in milk, but merely the oxidation product endosulfan
sulfate (McCaskey and Liska, 1967). Braun and Lobb (1976) determined endosulfan
concentrations in different tissues of a dairy herd acutely intoxicated by endosulfan. In post
mortem samples from the carcass 1270 mg/kg was found in rumen content, whereas the
concentrations in liver (4.2 mg/kg), kidneys (1.1 mg/kg) and muscle (0.6 mg/kg) were much
lower. In animals which survived the concentrations in the milk decreased rapidly, with a
biological half life of about 3.9 days.

Two lactating sheep were given a single oral dose of 0.3 mg/kg b.w. 14C-endosulfan and were
killed after 40 days (Gorbach et al., 1968). The elimination of radio labelled compounds via
milk during 17 days was 0.37 % and 1.82 % of the dose in the two sheep. Fat, kidney, and
liver of the sheep contained 0.02 - 0.03 µg/g endosulfan; all of the remaining tissues had
considerably lower concentrations. The total amount of radio labelled compounds found in
organs and tissues accounted for less than 1 % of the administered dose.

In lactating goats receiving endosulfan in gelatine capsules at a dose of 1 mg/kg b.w. per day
for 28 days, the levels of total residues (α- and β-endosulfan and endosulfan sulfate) were
generally low, the highest being detected on the first day after cessation of treatment, with
0.29 mg/kg in kidney, 0.2 mg/kg in the gastrointestinal tract, 0.12 mg/kg in liver and 0.02
mg/kg in milk (Indraningsih et al., 1993). The concentration in the kidney was increased to
0.49 mg/kg one week after the treatment ceased, but no residues were detected 21 days after
end of treatment. Endosulfan residues did not accumulate in the fat; the concentrations
reached 0.06 mg/kg on day 1 after the end of treatment, but no residues were detected one
week 8 after treatment.

Naqvi and Vaishnavi (1993) reviewed bioaccumulation factors for aquatic animals. For
different organisms the reported bioconcentration factors were between 10 and 600. In an
ATSDR review (ATSDR, 2000) maximum bioconcentration factors in aquatic systems are
usually less than 3,000 and residues are eliminated within 2 weeks after transfer of fish to
endosulfan-free water. The tests with 14C-labelled endosulfan revealed that fish are capable of
forming water-soluble endosulfan metabolites in the liver. Analyses suggest that endosulfan
diol is formed, which conjugated with glucuronic acid and is passed via bile to the faeces and
excreted (Goebel et al., 1982).

Bargar et al. (2001a,b) studied the transfer of endosulfan injected in laying hens to the eggs.
About 0.04 to 0.12 % of the dose injected was transferred to the eggs (Bargar et al., 2001b).
During incubation of the fertilized eggs most of the endosulfan could be found in yolk and
albumin. There seemed an excretion and reabsorption of endosulfan and metabolites into/from
the allantoic fluid during the development of the embryo.



Endosulfan has been detected in breast milk of women environmentally exposed to a number
of contaminants in rural Kazakhstan (Lutter et al., 1998) and in Spain (Cerillo et al., 2005),
indicating that transfer to children can occur during lactation. No data on levels were reported
in the Kazakhstan study, but in the Spanish study a mean endosulfan (α plus β) concentration
of 11.38 ng/mL milk was found.

8. Human dietary exposure and comparison with ADI

The most important routes of exposure to endosulfan for the general population are ingestion
of food and the use of tobacco products with endosulfan residues remaining after treatment
(ATSDR, 2000). A total diet study performed between 1993 and 1996 in Canada revealed an
average daily dietary intake for total endosulfan 23.8 ng/kg b.w. (Health Canada, 2003). In a
recent Canadian study (Rawn et al., 2004) on a single location maximum intake of endosulfan
could be observed in 5 - 11 year old children (0.03 µg/kg b.w./day). These values correspond
with the results of an US study (0.05 µg/kg b.w./day) (Gunderson, 1995). In Hsinchu, Taiwan,
the dietary intake of α- and β-endosulfan was studied from June 1996 to April 1997 (Doong et
al., 1999). β-Endosulfan was not detected in any of the 14 different foods studied, including
fruits, meats, seafood, and cereal, and α-endosulfan, by contrast, was found in 78 of 149
samples at an average concentration of 2.8 ng/g wet weight. Data on endosulfan sulfate were
not reported in this study. Based on the average Taiwanese diet, the estimated daily intake of
α-endosulfan was 0.62 µg/person. Converted to body weight this results at approximately 0.01
µg/kg b.w. (Doong et al., 1999). In Europe, the Czech Republic reported results of dietary
intake for the sum of α-, β-endosulfan and endosulfan sulphate. Median of summary exposure
to endosulfan in 1994 was 0.015 µg/kg b.w./day (Ruprich et al., 1995). Mean intake 0.003
µg/kg b.w./day has been reported in 2002 (Ruprich et al., 2003). 4136 samples representing
all major food groups after processing were analysed during the period 1994 - 2002. Most
frequently contaminated foods were offal (30 %) and fish and fish products (28 %) but
concentrations were low (up to 15 µg/kg of sample).

CONCLUSIONS
Chemistry and environmental fate
• Once released into the environment, α- and β-endosulfan, which are the major
constituents of the technical-grade pesticide endosulfan, can be broken down by
hydrolysis, biodegradation. β-endosulfan is more persistent than the α- isomer.
Endosulfan sulfate is the main degradation product of both isomers. It is equally toxic
and more persistent in vivo than its parent compounds. Therefore, it is mandatory that
analysis of endosulfan residues in feed and food includes the parent compounds α-
and β-endosulfan as well as their major degradation product endosulfan sulfate.

Adverse effect in animals
• Fish show high sensitivity to endosulfan exposure via water. Oral exposure studies
have shown effects on thyroxin level and thyroid hormone metabolism at dietary



concentration of 100 µg/kg (Nile tilapia), and ultrastructural alterations of the liver
and intestinal tract at dietary concentration of 0.5 µg/kg (common carp). These effects
were subtle, possibly adaptive, and not considered to represent adverse effects.

• The dominant toxic effect in mammals is stimulation and disturbance of the nervous
system.

• A NOAEL for clinical toxicity of 1.1 mg/kg b.w. was found in young steers, fed
endosulfan for 60 days, corresponding to a concentration in the diet of 40 mg/kg dry
matter. This concentration in feed is 400 times higher than the current ML for the
corresponding feed product.

• For chicken fed endosulfan for eight weeks a lowest observed adverse effect level of
30 mg/kg feed (LOAEL of 3 mg/kg b.w.) was found. This concentration in feed is 300
times higher than the current ML for the corresponding feed product.

• In dogs, orally dosed endosulfan for one year, a no observed adverse effect level of 10
mg/kg feed (NOAEL of 0.8 mg/kg b.w.) was found. This concentration in feed is 100
times higher than the current ML for the corresponding feed product.
Occurrence in feed and carry over
• Residues of endosulfan in feed are mostly reported by the Member States to the
Commission as condensed overall summaries just giving the number of compliant and
non compliant samples. Thus, primary data are not accessible, and as a consequence,
detailed occurrence levels of endosulfan in feed are scarce.
• The limited data available on the occurrence of endosulfan and endosulfan sulfate in
various feed categories, including fish feed, show only a limited number of samples
containing residues (usually below 1 µg/kg product).
• Endosulfan does not significantly bioaccumulate in mammals.

• In living organisms, β-endosulfan is more persistent than α-endosulfan.
• Depending on species and duration of exposure, residues (parent compounds and
endosulfan sulfate) are predominantly found in kidney, fat and liver. Transfer of
residues to milk and eggs occurs to a limited extent.
• Based on the limited data on animal exposure via feed produced according to good
agricultural practice, it is not likely that terrestrial animals will be exposed to levels
that could cause toxic effects.

Human exposure
• Limited exposure data collected in the 1990s in Canada, United States and Taiwan
show a mean daily dietary intake between 0.01 and 0.05 µg total endosulfan/kg body
weight. Recent data on human endosulfan exposure in European adults are reported
from the Czech Republic for the years 1994 - 2002. These show a mean daily dietary



intake between 0.003 and 0.015 µg total endosulfan/kg body weight. A similar dietary
exposure can be assumed for other EU Member States based on the occurrence data of
endosulfan in various food commodities measured in co-ordinated European
monitoring programmes since 1997.
• Endosulfan does not significantly bioaccumulate in humans. During the latest WHO
field study 27 human milk pools from 16 European and non-European countries were
analysed for pesticides and showed no endosulfan contamination at a limit of detection
of 1 µg/kg milk fat.
• The limited data available indicate that human dietary exposure to endosulfan is well
below the ADI at 6 µg/kg b.w. set by JMPR in 1998.
Important gaps in the database
• Detailed data on residues of endosulfan and its metabolites in feedingstuffs and food
of animal origin are scarce.
• Only limited information on oral toxicity of endosulfan exposure in fish and no data
on laying hens are available.

RECOMMENDATION
• Most of the surveillance data from Member States are required by the European
Commission to be reported as compliant or non-compliant. To allow for a better intake
assessment it is necessary that the actual levels as well as the contaminant are
reported.

• Studies on carry-over, accumulation and oral toxicity of endosulfan, especially in
farmed fish and laying hens, should be performed.



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SCIENTIFIC PANEL MEMBERS

Jan Alexander, Herman Autrup, Denis Bard, Angelo Carere, Lucio Guido Costa, Jean-Pierre
Cravedi, Alessandro Di Domenico, Roberto Fanelli, Johanna Fink-Gremmels, John Gilbert,
Philippe Grandjean, Niklas Johansson, Agneta Oskarsson, Andrew Renwick, Jirí Ruprich,
Josef Schlatter, Greet Schoeters, Dieter Schrenk, Rolaf van Leeuwen, Philippe Verger.

ACKNOWLEDGEMENT

The Scientific Panel on Contaminants in the Food Chain wishes to thank Jan Alexander,
Aksel Bernhoft, George Bories, Jean-Pierre Cravedi, Peter Fürst, Niklas Johansson and Hans
Schenkel for the contributions to the draft opinion.

DOCUMENTATION PROVIDED TO EFSA
Submission of occurrence data
Belgium, The Federal Agency for the Safety of the Food Chain, 2000-2004.
Czech Republic, Central Institute for Testing and Supervising in Agriculture, 2004, and
National Institute of Public Health, 1994 - 2004.
Germany, Chemisches Landes- und Staatliches, Veterinäruntersuchungsamt Münster, 2003
and 2004.
European Feed Manufacturers' Federation.


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