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`The European Agency for the Evaluation of Medicinal Products
`Veterinary Medicines Evaluation Unit
`
`EMEA/MRL/6 14/99-FINAL
`June 1999
`
`COMMITTEE FOR VETERINARY MEDICINAL PRODUCTS
`
`POLYOXYL CASTOR OIL
`POLYOXYL HYDROGENATED CASTOR OIL
`
`SUMMARY REPORT
`
`Polyoxyl n castor oil (n=30 to 40) (synonyms: ethoxylated castor oil, polyethylene glycol castor
`oil) is a mixture of triricinoleate esters of ethoxylated glycerol with small amounts of
`polyethyleneglycol (macrogol) ricinoleate and the corresponding free glycols. The number (n)
`associated with the name of the substance represents the average number of oxyethylene units in
`the compound. Polyoxyl n hydrogenated castor oil (n40 to 60) is a mixture of trihydroxystearate
`esters of ethoxylated glycerol with small amounts of macrogol trihydroxystearate and the
`corresponding free glycols. The substances are generally highly dispersible in water.
`
`Polyoxyl castor oil and polyoxyl hydrogenated castor oil are nonionic surfactants, which are used
`as emulsifying and solubilising agents in pharmaceutical preparations and cosmetics. Examples
`are polyoxyl 35 castor oil (Cremophor EL; CAS 61791-12-6), polyoxyl 40 castor oil (Marlowet
`40, Emulgin RO 40), polyoxyl 40 hydrogenated castor oil (Cremophor RH 40) and polyoxyl
`60 hydrogenated castor oil (Cremophor RH 60). The substances are included as excipients in
`numerous preparations intended for use in all food producing species by parenteral, oral or topical
`administration. The concentration in products is usually between 0.1% and 20% with a maximum
`of 27.5%. The doses of concentrated substances to different species is in a range of 0.01 and
`2.5 ml/day (cattle and horses 0.75 to 2.5 ml, sheep and goats 0.2 to 0.5 ml, swine 0.25 to 1.20 ml,
`poultry 0.001 to 0.03 ml and salmon as a dip for 30 minutes in a 36% solution diluted 1/3 x 106
`before use).
`
`In rats, polyoxyl 35 castor oil, had some antidiuretic effect after oral administration of
`2.5 ml/kg bw. It was shown that polyoxyl 35 castor oil could bind to membrane transport
`P-glycoproteins in vitro, thereby inhibiting the elimination of drugs out of cells and increasing
`bioaccumulation of drugs within cells. It was concluded that polyoxyl 35 castor oil is a
`pharmacological active substance. However, polyoxyl castor oil and polyoxyl 40 hydrogenated
`castor oil are claimed to be devoid of pharmacological activity at the concentrations at which they
`are employed as excipients, i.e. a maximum of 2.5 ml/animal by the intramuscular, subcutaneous,
`topical or oral route. Studies showing possible pharmacological activity have not been performed
`in the target species.
`
`4. No data on metabolism and pharmacokinetics of polyoxyl castor oil and polyoxyl hydrogenated
`castor oil were provided. However, it is known that polyoxyethylene compounds are poorly
`absorbed from the gastrointestinal tract due to their high dispersibility in water and limited
`liposolubility.
`
`7 Westferry Circus, Canary Wharf, London, E14 4HB, UK
`Switchboard (44-20-7) 418 8400 Fax (44-20-7) 418 8447
`http://www.eudra.org/emea.html
`E-mail: mail'emea.eudra.org (cid:9)
`cFMFA 1999 Rpnrnrliintion nd1or dietrihiition of this rtoniiment is iithorised for non nommerriI niirnoses only nrovirted the FMFA is enknowledned
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`6.
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`7.
`
`For polyoxyl 35 castor oil oral LD 50 values of 640 mg/kg bw in the dog and 6500 mg/kg in the
`mouse have been reported in the published literature. The acute oral toxicity of polyoxyl 40 castor
`oil appears to be low, the LD 50 in rats being greater than 10000 mg/kg bw. According to
`summary information provided In another study the acute oral toxicity of polyoxyl 40 castor oil
`was investigated in male Wistar rats. The LD 50 was reported to be greater than 2000 mg/kg. The
`acute toxicity of polyoxyl 25 hydrogenated castor oil, polyoxyl 40 hydrogenated castor oil,
`polyoxyl 60 hydrogenated castor oil were reported to be very low with LD 50 values of more than
`5000 mg/kg body weight in rats.
`
`Polyoxyl 35 castor oil and polyoxyl hydrogenated castor oil were judged slightly irritating when
`applied to skin to both humans and rabbits and non-irritating to the eye. Polyoxyl 35 castor oil did
`not induce sensitisation in guinea pigs.
`
`In the published literature there are toxicology studies reported for polyoxyl-40 hydrogenated
`castor oil, polyoxyl 40 castor oil, polyoxyl 35 castor oil and polyoxyl castor oil (number of moles
`of ethyleneoxide was not specified).
`Studies with polyoxyl-40 hydrogenated castor oil were performed in rats for 6 months with doses
`up to 100 000 mg/kg/feed (theoretical calculated doses 5000 mg/kg bodyweight) and in dogs for
`6 months with doses up to 5% of the diet (theoretical calculated doses 3750 mg/kg bw). No
`treatment related effects were observed.
`Furthermore, polyoxyl castor oil 10% (number of moles of ethyleneoxide was not specified) was
`tested as a vehicle control in a study with mice for 90 days in the drinking water. The absolute
`and relative liver and kidney weights were significantly increased and the weight of the brain was
`significantly less than in the control group who received de-ionised water. Some statistically
`significant differences in the haematological and clinical chemistry values were also recorded.
`The same substance was tested for 3 weeks in Sprague Dawley rats in a dose of 0.5% in drinking
`water. The only change that was observed was reduced weight of the brains in the treated groups
`compared to the controls.
`Polyoxyl 40 castor oil was tested in rats and in dogs for 90 days with doses up to 5% in the feed.
`No treatment related effects were observed.
`
`Repeated dose studies after intramuscular injection were performed in dogs, after dosing with 11
`injections of 1 ml 50% polyoxyl 35 castor oil, in rabbits after dosing with 10 injections of 0.5 ml
`and in guinea pigs after dosing with 10 injections of 0.1 ml polyoxyl 35 castor oil, respectively.
`No significant effects were recorded.
`
`Only summaries of published studies concerning reproductive and teratogenic effects have been
`provided. Polyoxyl 40 hydrogenated castor oil was tested in rats fed up to 5 g/kg bw in the feed
`day 0 to 20 of gestation and to mice fed up to 1.5 g/kg bw in the feed during day 6 to 15 of
`gestation. No maternotoxic or teratogenic effects were recorded. Furthermore, a 3-generation
`study was performed with 1% polyoxyl 30 castor oil given to mice in the drinking water. No
`significant changes in reproductive performance were observed in any of the 3 generations. Mean
`litter size, postnatal body weights and survival indices were unaffected. The F Ic and F2b matings
`were produced to screen for dominant lethal and teratology effects. In this screening tests an
`increase in the ratio of dead foetuses to live foetuses was observed. In addition, polyoxyl-35
`castor oil was tested as a vehicle control in a teratogenicity study in mice. The mice were given
`oral doses of 0.005 mIll g bw of an 8% polyoxyl 5 castor oil in water at day 9, 10 or ii of
`gestation. No treatment related effects were observed.
`
`9. Only summaries of published studies of mutagenicity tests have been provided. Polyoxyl-35
`castor oil was tested in a dominant lethal test, micronucleus test in mice, spermatogonial test in
`Chinese hamsters. Polyoxyl-30 castor oil was tested in a chromosomal aberration assay using
`Chinese hamster ovary (CHO) cells, micronucleus and spermhead abnormality assays in mice.
`Furthermore, polyoxyl-60 hydrogenated castor oil was tested in Salmonella microsomal assay,
`with and without metabolic activation, in a chromosome aberration test in Chinese hamster V79
`cells, with and without metabolic activation, and in a micronucleus test in mice. None of the
`substances showed any mutagenic effect in any of the studies performed.
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`10. Polyoxyl castor oil, when used as a vehicle in parenteral preparations, has been associated with
`severe anaphylactic reactions in humans. No reports of sensitisation after oral treatment either in
`humans or in animals have been reported even though the polyoxyl castor oil derivatives have
`been used in several cosmetic products. In the toxicity studies provided, no allergic reactions have
`been observed after oral treatment.
`
`11. Polyethylene glycols with molecular weights 200 to 10000 are already included in Annex II of
`Council Regulation (EEC) No. 2377/90). The Joint FAO/WHO Expert Committee on Food
`Additives (JECFA) has evaluated castor oil as a food additive and established an ADI of
`0.7 mg/kg bw. Castor oil is approved by the FDA for use in e.g. hard candy.
`
`Conclusions and recommendation
`
`Having considered that:
`
`(cid:149) (cid:9)
`(cid:149) (cid:9)
`(cid:149) (cid:9)
`
`polyoxyl castor oil and polyoxyl hydrogenated castor oil are of low oral toxicity,
`only low doses administered to the target species,
`the incorporation of polyoxyl castor oil and polyoxyl hydrogenated castor oil in medicinal
`products intended for use in food producing species is unlikely to result in residues in food
`products of animal origin at concentrations of toxicological relevance to the consumer;
`
`the Committee for Veterinary Medicinal Products concludes that there is no need to establish an
`MRL for polyoxyl castor oil and polyoxyl 40 hydrogenated castor oil and recommends its
`inclusion in Annex II of Council Regulation (EEC) No 2377/90 in accordance with the following
`table.
`
`Animal species
`
`Pharmacologically active
`substance(s)
`Polyoxyl castor oil with 30 to All food producing species
`40 oxyethylene units
`Polyoxyl hydrogenated castor All food producing species
`oil with 40 to 60 oxyethylene
`units
`
`Other provisions
`
`
`
`For use as excipient
`
`For use as excipient
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