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Appendices 1-18 to: Report on the Health Effects of Selected Pesticide Coformulants

115     Animal toxicity

115.1     Single dose toxicity

115.1.1     Inhalation

Intratracheal instillation to each of 12 male Sprague-Dawley rats of 100 ml of a solution containing 1% polyEGDE (9 ethylene oxide molecules), 1% ethyl alcohol and saline caused irritation of the lungs one day after administration. Histopathology revealed desquamation of bronchial and alveolar epithelium with inflammatory cell infiltration, oedema and haemorrhage. At days 3 and 7 after administration, hyperplasia and squamous metaplasia of bronchial and bronchiolar epithelium and proliferation of fibroblast-like interstitial cells were observed in the alveoli, indicate regenerative process, was reported. No pathological changes were seen in the group of 12 rats treated with saline only. (Suzuki et al. 2000).

Groups of 3 male Wistar rats were dosed with 20, 50 or 100 ml 1% w/v polyEGDE (with 9 ethylene oxides) in saline in one nostril. The epithelium showed cell loss and reduction in epithelium height in the treated side in all groups at 5, 20 and 60 minutes after application, the effect being more pronounced and widespread with dose and time of contact. Thus, 20 ml of the polyEGDE solution only affected a part of the epithelium on the same side of the septum, 50 ml also affected a small area of the untreated side at 5 min. which extended at 20 min. and at 60 min., and 100 ml caused depletion of the epithelium in the whole nasal epithelium including the untreated nostril. (Chandler et al. 1991).

Twenty-five µl of 1% polyEDGE (9 ethylene oxide molecules) in saline were placed into the nostril of Sprague-Dawley rats. Controls only treated with saline were also used. Samples of the nasal epithelium from 2-4 rats were taken at 4, 24 hours, 2, 3, 4, 5, 7 and 10 days after exposure. At 4 hours after exposure, the mucosa was swollen, but no histopathological changes were apparent. Samples, taken 24 and 48 hours after administration, showed necrosis of the epithelium. Regeneration of the epithelium was observed from day 3 including basal cell re-growth and presence of immature cells in a loose and irregular cuboidal to columnar epithelium. Differentiation occurred from day 4. Regeneration, including complete columnar epithelium cells and ciliae, was observed from day 7. (Zhou & Donovan 1995).

115.1.2     Oral intake

An oral LD50-value in rats of 8600 mg/kg was reported for a 4 ethylene-oxides containing polyEGDE. For the mouse, the LD₅₀ is reported to be 4940 mg/kg. (RTECS 2001).

A polyEGDE with 7 ethylene oxides was tested in rats and mice for acute oral toxicity. The LD₅₀-values calculated from the results were 4150 mg/kg b.w. in rats and 1170 mg/kg in mice (RTECS 2001).

For polyEGDE with 23 moles ethylene oxide, LD₅₀-values of 8600 mg/kg b.w. in the rat and 3500 mg/kg b.w. in the mouse were reported. (RTECS 2001).

Single oral doses polyEGDE given to dogs (above 2 g/kg b.w.) and monkeys (5 g/kg b.w.) were reported to exert emetic action and central nervous system depression (e.g. ataxia, weakness and sedation) (Gosselin et al. 1984).

115.1.3     Dermal contact

No data on systemic toxicity by skin contact were found.

115.1.4     Irritation

PolyEGDE containing 7 ethylene oxides in the molecule was reported to be irritating to the skin of rabbits following application of 100 mg/kg b.w. No further details were available in RTECS. (RTECS 2001).

Application to rabbit skin of 75 mg/kg b.w. for 24 hours of an unspecified polyEGDE caused mild irritation, while 500 mg/kg b.w. caused moderate irritation. No further details were available in RTECS. (RTECS 2001).

An interlaboratory comparative skin irritation test was conducted with 12 chemicals among which polyEGDE. Each laboratory used eight male albino rabbits for 4 chemicals. The animals were clipped and 0.5 g polyEGDE was applied under non-occlusive 1 square inch patch for 24 hours. Scoring was performed 30 minutes after patch removal and 48 hours later based on a maximum of 8 scoring points for erythema, 8 for oedema and 30 for necrosis. The results ranged from 0 to 28 with a mean of 8.0. Necrosis was reported in 38 out of 183 animals. (Weil & Scala 1971).

A Czech reference is quoted in RTECS to have reported mild irritation in rabbits from a 24-hour skin application of 500 mg polyEGDE of unspecified chain-length (Marhold 1972 – quoted from RTECS 2001).

Ten milligrams polyEGDE (chain of 7 ethylene oxides) instilled in rabbits eye were reported to be irritating. No details are provided in RTECS. (RTECS 2001).

An interlaboratory comparison eye irritation test conducted in 12 laboratories according to the method of Draize with minimum 6 male albino rabbits/laboratory. The maximum possible score was 110 points and consisted of elements: Scoring for effects on cornea, including opacity degree and area affected, contributed to the maximum score with 80 points, effects on iris with a maximum of 10 points and effects on conjuctiva, including redness, chemosis and discharge contributed with a maximum of 20 points. PolyEGDE scored average scores of 28.2 at 24 hours, 29.5 at 72 hours, and 16.0 at 7 days post instillation of 0.1 ml polyEGDE.  (Weil & Scala 1971).

Quoting from a Czech reference, RTECS reports that 750 mg polyEGDE applied to rabbits eyes was severely irritating at 24 hours following instillation. (Marhold 1972 – quoted from RTECS 2001).

PolyEGDE was not eye irritating in a Draize test in rabbits. No further details were available. (Conduzorgues et al. 1989 – quoted from Toxline 2001).

Three animals were subject to a low volume eye test (LVET) with polyEGDE’s of different chain lengths. Irritation was scored following the Draize scale (0-110) at 1, 24, 48, 72 and 96 hours. Scores varied from 0 to 7.0 for the polyEGDE’s, with reversibility within 4 days. The eye irritating potential of the substances was evaluated to be none or low. (Heinze et al. 1999).

115.2     Repeated dose toxicity

No data were found.

115.3     Toxicity to reproduction

No data were found.

115.4     Mutagenic and genotoxic effects

115.4.1     In vitro studies

PolyEGDE was negative in a Salmonella/microsome assay using 0, 3, 10, 33, 100 and 333 mg/plate in strains TA 98, TA 100, TA 1535 and TA 1537 with and without liver S9 activation (Zeiger 1987, Zeiger et al. 1987 – the latter quoted from HSDB 2001).

PolyEGDE was reported to be negative in a reverse mutation test in Escherichia coli WP2uvrA with and without metabolic activation with S9 mix (Suzuki et al. 1989 – quoted from Toxline 2001).

PolyEGDE was reported to induce polyploidy in Chinese hamster lung fibroblast cells without metabolic activation. However, no structural chromosomal aberrations were seen. (Suzuki et al. 1989 – quoted from Toxline).

A sister chromatid exchange (SCE) test was conducted in Chinese Hamster Ovary-cells (CHO) with and without metabolic activation using 5 test concentrations from 0.3 up to 30 mg polyEGDE /ml. The result was negative.

A chromosomal aberration test was performed with polyEGDE in CHO cells with and without metabolic activation using 3 test concentrations of 0, 5, 15 and 50 mg/ml. PolyEGDE was also negative in this test.

(Loveday et al. 1990).

An L5178Y mouse lymphoma mutation assay was conducted with 6-7 concentrations from 0.005 to 0.050 ml polyEGDE/l, with and without S9 mix. The assay was conducted in duplicate and included positive and negative controls. The assay was negative, except for one trial without activation where some cultures at 0.020-0.0030 ml/l showed an almost two-fold increase in mutant frequency. Concentrations of 0.030-0.050 ml/l were lethal. (Myhr & Caspary 1991).

115.4.2     In vivo studies

A sex linked recessive lethal mutation test was conducted in male Drosophila melanogaster. PolyEGDE did not induce mutations in meiotic or post-meitotic germ cells by feeding of 12500 mg/kg food or by injection of 2000 mg/kg food. (Foureman et al. 1994).

Mice were exposed to 3 daily intraperitoneal doses of 0, 31.25, 62.5 or 125 mg/kg b.w. polyEGDE. Bone marrow samples were obtained 24 hours following the final exposure. There was no significant increase in number of micronuclei. (Shelby et al. 1993).

115.5     Carcinogenic effects

The National Toxicology Program (NTP) informs that a carcinogenicity study conducted with polyEGDE in rats and in mice, referred in several references to be negative, was inadequate and that no report would be issued (NTP 2002).

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