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

75     Animal toxicity

75.1     Single dose toxicity

75.1.1     Inhalation

Rabbits were exposed to of 10% PG aerosol for 20 or 120 minutes. No deaths were reported. In the tracheal epithelium, the goblet cells were degenerated at both observation times, whereas ciliated cells were slightly affected at 20 min., and seriously at 120 minutes. No details of the aerosol particle size or other exposure conditions were given. (Konrádová et al. 1978 - quoted from ATSDR and LaKind et al. 1999).

Dogs were exposed for 15 minutes to a 10 or a 20% PG aerosol and haemolysis or haemodynamic effects were investigated. No effects on the blood were seen. No details of the aerosol particle size or other exposure conditions were given. (Konrádová et al. 1978 - quoted from ATSDR and LaKind et al. 1999).

75.1.2     Oral intake

Reported LD₅₀-values in rats for PG range from 21 to 33.5 g/kg b.w., and minimum lethal doses of 19.8 and 20.9 g/kg were reported for the substance. (IUCLID 2000, LaKind et al. 1999).

Rats were administered single doses of 10 ml of 10, 20, 50 or 100 % PG solutions/kg (equivalent to 1.04, 2.08, 5.2 and 10.4 g PG/kg b.w.). No deaths were reported. At the two highest doses, PG produced decreased respiration and marked CNS depression, including ataxia, ptosis (hanging eye lid), decrease of spontaneous motor activity and of body/limb tone, and of respiration. (Singh et al. 1982 - quoted from LaKind 1999).

Rats administered a single dose of 23.5 g/kg PG developed acute haemorrhagic enteritis and extensive adrenocortical haemorrhage. Widespread lymphocyte depletion was also evident. (Clark et al. 1979 - quoted from LaKind 1999).

Single oral doses of 730 or 2940 mg PG/kg b.w. were administered to adult female albino Wistar rats to examine haematological effects. PG was found to decrease packed cell volume for up to 2 days. Red blood cell count was reversibly decreased. (Saini et al. 1996 - quoted from LaKind et al. 1999).

LD₅₀-values of 22, 23.9, 24.8 and 31.9 g/kg b.w. were reported in mice for PG (LaKind et al. 1999 and IUCLID 2000). The study of Singh et al. reported above also included mice, in which similar effects as for the rats were described. (Singh et al. 1982 - quoted from LaKind 1999).

Single doses of 23310 mg PG/kg b.w. administered to mice by stomach tube caused slight microscopic changes in the kidney with nuclear pyknosis and vacuolar degeneration of the cytoplasm. A few cortical tubules contained protein debris. (Laug et al. 1939 - quoted from LaKind et al. 1999).

In rabbits, the LD₅₀-values for PG were reported to range from 18 to 19.3 g/kg b.w. (IUCLID 2000). Dosing by stomach tube with 13.73 to 21 g/kg b.w. PG resulted in increased respiratory rate, loss of equilibrium, depression, analgesia and coma. Deaths occurred in 18 to 36 hours. (Braun & Cartland 1936 - quoted from LaKind et al. 1999).

LD₅₀-values in guinea pigs of 18.35, 18.9 and 19.6 g/kg b.w. were reported (LaKind et al. 1999).

An LD₅₀-value in dogs of 22 g/kg b.w. has been cited (IUCLID 2000).

75.1.3     Dermal contact

A LD₅₀-value in rabbits of 20800 mg/kg b.w. is reported without any details (Raw Material Data Handbook 1974 – quoted from IUCLID 2000).

75.1.4     Irritation and sensitisation

Several dermal irritation studies with PG in rabbits were conducted. Very few details were reported. The results ranged from none to mild irritation. (IUCLID 2000).

PG was reported to be not irritating to mildly irritating to rabbits eyes in a number of eye irritation tests in rabbits reported with very few details (IUCLID 2000).

No studies on sensitisation were found.

75.2     Repeated dose toxicity

75.2.1     Inhalation

Nineteen Sprague-Dawley rats/sex/dose were exposed nose-only to an aerosol containing 0, 160, 1000 or 2200 mg PG/m³ (0, 51, 321 or 707 ppm), 6 hours/day, 5 days/week over 90 days. Treatment related nose bleeding occurred from week 2 through the study. The authors attributed the effect to dehydration of the tissues. At the two highest dose levels, the number, size and mucous content of the goblet cells in the nasal epithelium were significantly increased. Slight dose related body weight reduction was reported females. Significant but not dose-related changes in haematological parameters were seen. No toxicological effects were seen on liver, kidney, spleen or lung. (Suber et al. 1989).

Twenty-nine monkeys (Macacus Rhesus) were continuously exposed over 13 months to levels of 32-112 ppm PG (not further specified. equivalent to 101-354 mg/m³). Thirteen animals died or were killed because of illness due to infection. No effects were seen on body weights, respiratory system, gastrointestinal tract, liver, kidney or spleen. The haemoglobin count was elevated at 112 ppm compared to controls. However, as many of the monkeys suffered from parasite infection and lung mites, the authors concluded that the haematological effects were not related to PG. (Robertson et al. 1947 - quoted from ATSDR 1997).

75.2.2     Oral intake

Inbred albino rats were administrated 2.45 % or 4.9 % PG (approximately 1225 or 2450 mg/kg b.w./day). The duration of exposure was not given in the reference. No effects of PG were reported on growth rate, food and water consumption, survival, gross and microscopic lesions in lung, heart, liver, spleen, kidney, adrenal or testis. (Morris et al. 1942 – quoted from LaKind et al. 1999).

Six male Wistar rats/group were dosed with 0 or 2942 mg PG/kg/day in the water for 10, 20 or 30 days. No death was observed. Body weights were reduced 41% at 10 days, but were then increased at 20 and 30 days. Enzyme activity in the gastrointestinal tract was increased, but no effects on the jejunal surface were seen.  (Morshed et al. 1991 – quoted from ATSDR 1997).

Rats were given drinking water containing 1, 2, 5, 10, 25 or 50 % PG v/v (corresponding to approximately 1320, 2640, 6600, 13200 or 26400 mg PG/kg b.w./day) for 140 days (20 weeks). Animals of the two highest exposure groups died within 10 weeks. No adverse effects were seen up to 10%  PG (13200 mg). (Clayton & Clayton 1982 – quoted from LaKind et al. 1999 and IUCLID 2000).

In a two-year feeding study in CD-1 rats, levels of 0, 6250, 12500, 25000 or 50000 ppm PG (corresponding to approximately 0, 200, 400, 900 or 1700 mg/kg b.w./day in males and 300, 500, 1000 or 2100 mg/kg b.w./day in females) were used. No significant compound-related effects were observed in any treated group when compared to controls with respect to behaviour, body weights, organ weights, haematology, or microscopic examination of the heart, lung, liver, kidney and adrenal. (Gaunt et al. 1972 - quoted from ATSDR 1997, LaKind et al. 1999 and IUCLID 2000).

Rats administered up to 1834 mg/kg b.w./day for 2 years showed very slight liver damage, but no renal pathology (Clayton & Clayton 1982 – quoted from LaKind et al. 1999).

Cats fed 1200 ppm PG in the diet for 2 weeks showed increased haptoglobin concentration (Weiss et al. 1992 – quoted from ATSDR 1997).

Cats were fed 1600 or 8000 mg PG/kg b.w./day for 3 or 5 weeks. At the high dose, the animals developed decreased activity, mental depression and slight to moderate ataxia. The high dose cats also had polyuria and polydipsia, and showed decreased erythrocyte counts Heinz body formation and hypercellularity of the bone marrow, while the level of D-lactate was 44 fold higher than controls. No effects were reported at the low dose. (Christopher et al. 1989 and 1990 – quoted from LaKind et al. 1999 and ATSDR 1997).

In a 12-week study, kittens administered 5 or 10 % PG in the diet (corresponding approximately to 1100 and 2400 mg/kg b.w./day, respectively) showed increased Heinz body formation. (Hickman et al. 1990 – quoted from LaKind et al. 1999).

Cats administered 0, 80, 443, 675, 1763 or 4239 ppm PG/kg feed for 13 weeks showed increased Heinz-body formation from 443 ppm. This effect was dose related as the haemosiderin content in the liver and the spleen from 673 ppm PG. (DOW 1979 – quoted from IUCLID 2000).

Male and female cats were treated in their diet with 0, 6, or 12 % PG (corresponding to 0, 2100 or 3560 mg/kg b.w./day) for 13 weeks. Haematological parameters were examined with 2 weeks interval in the treatment period. Haemoglobin was significantly decreased in the low, but not the high dose group. Erythrocyte count was significantly decreased in both treated groups, but not in controls. Reticulocyte aggregate numbers were significantly increased in the 12 % group and Heinz bodies significantly increased in both treated groups. (Bauer et al. 1992 – quoted from LaKind et al. 1999).

Cats exposed in the diet to 2400 mg PG /kg b.w./day for 17 weeks showed Heinz body formation (Weiss et al. 1990 - quoted from ATSDR 1997).

Dogs were exposed to PG in the drinking water at levels of 5% PG twice a day for females and 600 ml of 10 % PG for males daily over 9 months. No functional deficits in the kidney or liver were reported and no pathological changes were found in these organs. (VanWinkle & Neuman 1941– quoted from LaKind et al. 1999).

Groups of 5 male and 5 female dogs were given 2000 or 5000 mg/kg b.w./day for 2 years. An additional “control” group were given 63500 mg dextrose/kg/day. At 2000 mg/kg b.w./day, no effects were seen on body weights or on any organs. At 5000 mg/kg b.w./day slight decrease in erythrocyte count, haemoglobin and haematocrit, which was reversible, was noted, but no effects on the bone marrow could be shown. Increased urinary output and decreased water intake were noted. The relevance of these findings was not discussed in any of the references. (Weil et al. 1971 – quoted from ATSDR 1997, LaKind et al. 1999 and IUCLID 2000).

75.2.3     Dermal contact

No effects on the kidney were seen from PG doses of 0.16 to 5.0 ml/kg b.w. applied to the shaved abdominal skin or rabbits for 30 days (Hanzlik et al. 1947 - quoted from LaKind et al. 1999).

75.3     Toxicity to reproduction

75.3.1     Inhalation

75.3.1.1     Fertility

White rats exposed continuously to a concentration of 55-112 ppm PG for 18 months showed no adverse effects on the ability to produce live young, or on survival of the offspring (Roberson et al. 1947).

No data were found on developmental effects of PG after inhalation.

75.3.2     Oral intake

75.3.2.1     Fertility

No effects on reproductive parameters were reported from administration to CD-1 mice of 5 % PG in the drinking water (equivalent to 10100 mg/kg b.w./day over 14 weeks in a continuous breeding study. The offspring were examined for reproductive parameters, but did not show any effect of PG either. (Gulati et al. - quoted from LaKind et al. 1999).

A multigeneration, continuous breeding feeding study in Swiss albino mice was performed, using concentrations of 1, 2.5 or 5% in the drinking water (corresponding to 1820, 4800 or 10100 mg/kg b.w./day) over 98 days from day 1 before mating in the parent generation (F₀). No significant effects were seen on the fertility of this generation. No effects were noted in the offspring (F₁) or the following generation (F₂) for mating or fertility indices, mean number of liver pups per litter, proportion of pups born live, or gender of pups born live. (Morrissey 1989 - quoted from LaKind et al. 1999).

No significant differences were seen on fertility rate, numbers of resorptions, average litter size or birth weight in CD1-mice treated by gavage with 10000 mg PG/kg b.w./day on gestation days 8-12. (Kavlok et al. 1987 - quoted from LaKind et al. 1999).

75.3.2.2     Developmental toxicity

Testing for developmental effects in several mammalian species using a 10-day exposure identified no effects at the highest dose tested, e.g. respectively 1600 mg/kg b.w./day for Wistar rats and CD-1 mice; 1550 mg/kg b.w./day for golden hamsters and 1230 mg/kg b.w./day for Dutch-belted rabbits. No differences in numbers of soft tissue changes or skeletal abnormalities between treated groups and control groups, and no effects on maternal or fetal survival were noted. (Food and Drug Research Laboratories Report No 1573j-1574j 1973 – quoted from LaKind et al. 1999).

In a developmental screening test, mice were administered 10000 ppm PG via gavage on days 8 to 12 of gestation. No significant differences were reported for maternal deaths, numerous reproductive endpoints, postnatal pup weight gain or abnormalities in the pups. No further details were found. (Kavlok et al. 1987 – quoted from LaKind et al. 1999).

75.3.3     Dermal exposure

No data were found.

75.4     Mutagenic and genotoxic effects

75.4.1     In vitro studies

PG was negative in an Ames test conducted without metabolic activation in Salmonella typhimurium strains TA98, TA 100, TA 1535 and TA 1537. (Pfieffer & Dunkelberg 1980 – quoted from IUCLID 2000).

PG was also negative in another Ames test in strains TA 92, TA 94, TA 98, TA 100, TA 1535 and TA 1537 conducted with metabolic activation. (Ishidate et al. 1984 – quoted from IUCLID 2000).

A third Ames test was conducted in Salmonella typhimurium strains TA 98, TA 100, TA 1535, TA 1537 and TA 1538 at concentrations of 20-5000 mg PG/plate with and without metabolic activation. The result of this study was also negative. (BASF 1981 – quoted from IUCLID).

A chromosome aberration assay was conducted twice in human lymphocytes, using concentrations of 476, 1910 and 3810 mg PG/l, according to OECD guideline 473. PG did not cause a statistically significant increase in the proportion of metaphases containing chromosome aberrations. (EC GmbH 1990 – quoted from IUCLID 2000).

A chromosome aberration test conducted in human embryonic lung cells (WI-38) with 0.001, 0.01 and 0.1 mg PG/ml was negative (Litton Bionetics Inc. 1974 - quoted from IUCLID).

In another chromosome aberration test, Chinese hamster lung fibroblast (CHL) cells were exposed to 32 mg PG/ml without metabolic activation. The test was positive. However, when the concentration was doubled and metabolic activation added, no increase in chromosome aberrations was found (Ishidate et al. 1984, 1988 - quoted from Mortensen 1993).

A DNA damage and repair assay conducted with PG in Chinese hamster V79-cells with and without activation was negative (Swenberg et al. 1976 - quoted from IUCLID).

A cell transformation assay conducted with PG in Syrian hamster embryo cells was negative (Mutat Res 1983 - quoted from IUCLID).

75.4.2     In vivo studies

No chromosome aberrations in the bone marrow were seen in a cytogenetic assay in rats following administration by gavage of a single dose or 5 doses of 30, 2500 and 5000 mg PG /kg b.w. The same dosing regime was used in a dominant lethal assay which was negative. (Litton Bionetics 1974 – quoted from IUCLID 2000).

A dominant lethal assay in mice treated intraperitoneally with a single dose of 10 mg PG/kg b.w was negative (Kennedy Jr. et al. 1975 – quoted from IUCLID 2000 and A&H 1983).

75.5     Carcinogenic effects

75.5.1     Inhalation

No data were found.

75.5.2     Oral intake

No treatment-related increase in neoplasms was seen in a two-year study in rats treated with up to 2500 mg/kg b.w./day in the diet. Other effects seen in this study are reported under section 4.2.2. (Gaunt et al. 1972 – quoted from ATSDR 1997).

75.5.3     Dermal contact

No increase in tumours was observed after twice weekly application of PG to the skin of Swiss mice for 120 weeks, at doses up to 2 mg. No further details were given. (Stenbak & Shubik 1974 - quoted from ATSDR 1997).

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