Avilamycin

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of >1X10+5(SRC), determined from a structure estimation method(2), indicates that avilamycin is expected to be immobile in soil(SRC). Volatilization of avilamycin from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of <1X10-10 atm-cu m/mole(SRC), using a fragment constant estimation method(2). Avilamycin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of <1X10-10 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2015).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of >1X10+5(SRC), determined from a structure estimation method(2), indicates that avilamycin is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of <1X10-10 atm-cu m/mole(SRC), developed using a fragment constant estimation method(2). Estimated hydrolysis half-lives were 5.6 years and 200 days at pH 7 and 8, respectively(2). According to a classification scheme(4), an estimated BCF of 20(SRC), from an estimated log Kow of 2.49(2) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data in water were not available(SRC, 2015).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), avilamycin, which has an estimated vapor pressure of <1X10-10 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase avilamycin may be removed from the air by wet and dry deposition(SRC). Avilamycin contains chromophores that absorb at wavelengths >290 nm(3) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

IDENTIFICATION AND USE: Avilamycin is an antibiotic mainly active against Gram-positive bacteria, including Bacillus spp., Clostridium spp., Corynebacterium bovis, Enterococcus spp., Lactobacillus spp., Listeria monocytogenes, Micrococcus luteus, Staphylococcus aureus and Streptococcus spp. Avilamycin is intended for use as a veterinary medicine in chickens, turkeys, pigs and rabbits to control bacterial enteric infections. HUMAN EXPOSURE AND TOXICITY: Avilamycin may be irritating to the eyes and may cause allergic reactions in those hypersensitive to avilamycin. ANIMAL STUDIES: The acute toxicity of avilamycin has been evaluated using various routes of administration in mice, rats and rabbits. The acute intraperitoneal toxicity of avilamycin was more severe than its oral or dermal toxicity. However, the deaths observed after intraperitoneal administration were mainly due to the inflammatory reactions to the unabsorbed avilamycin in the abdominal cavity rather than to the toxicity of avilamycin itself. Mice were fed avilamycin incorporated into the pelleted diet at levels of 0, 30, 300 or 3000 mg avilamycin activity/kg diet continuously for 28 days. There was a slight increase in feed intake and body weight of the males given 450 mg avilamycin activity/kg bw per day. In another study, rats received dietary doses of 0, 4, 6 or 10% dried fermentation product of avilamycin (14.9% avilamycin activity) for 2 weeks. The only treatment-associated finding was brown to black discoloration of the waste trays by urine, although urine was yellow in the bladder or when freshly voided. Avilamycin (mycelial cake form, activity 7.83%) was fed to pigs at levels of 0, 30, 300 and 3000 mg avilamycin activity/kg in the diet for 21 weeks, followed by a 4-week withdrawal period. Some blood biochemistry parameters, such as gamma glutamyl transferase (GGT), aspartate aminotransferase (AST), sodium and inorganic phosphorus, were changed from control values, but those changes were weak and in the normal range In a 2-year experiment, male and female rat litters were fed avilamycin (derived from mycelial cake of 7% activity) at doses of 0, 30, 300 or 3000 mg avilamycin activity/kg in the diet and pure avilamycin at 3000 mg avilamycin activity/kg in the diet during the whole period of the study. The litters were from parent rats fed avilamycin at the same doses of 0, 30, 300 or 3000 mg avilamycin activity/kg in the diet for 1 week and then mated and maintained on their treatments during gestation and lactation. The mortality was 58-78%, with no difference between treatments. Clotting times were significantly decreased, with dose dependency in males at 15 and 150 mg avilamycin activity/kg bw per day, where avilamycin was derived from mycelial cake, on weeks 13, 26, 52 and 78. However, they recovered at the last two sampling times (weeks 104 and 112). There was a non-statistically significant increase in pancreatic exocrine adenomas in male rats that were fed avilamycin derived from mycelial cake at 15 and 150 mg avilamycin activity/kg bw per day. A higher incidence of thyroid parafollicular cell carcinoma was also observed in male rats treated with avilamycin derived from mycelial cake at 15 and 150 mg avilamycin activity/kg bw per day, without statistical significance. No thyroid parafollicular cell carcinoma was found at 1.5 mg avilamycin activity/kg bw per day for the mycelial cake and 150 mg avilamycin activity/kg bw per day for the pure form of avilamycin. Pregnant rabbits were administered a dried fermentation product of avilamycin (17.8% activity) by oral gavage in daily doses of 0, 250, 716 and 2000 mg/kg bw. Abortions occurred in two rabbits from the low dose group and one rabbit from both middle and high dose groups. All except one of these rabbits had diarrhea or were anorectic prior to abortion. The low incidence of abortions that occurred in all treatment groups was regarded as a secondary consequence of maternal toxicity. Avilamycin was not mutagenic in the reverse mutation assay with Salmonella typhimurium strains TA98, TA100, TA1535, TA1537, TA1538, G46, C3076 and D3052 and Escherichia coli strains WP2 and WP2uvrA both with and without S9 activation. Also, avilamycin did not present any genotoxicity in a deoxyribonucleic acid (DNA) repair assay using primary cultures of adult rat hepatocytes, in a forward mutation assay using L5178Y mouse lymphoma cells and in a chromosomal aberration assay using Chinese hamster ovary cells both with and without S9 activation. Avilamycin was not mutagenic in sister chromatid exchange assays in bone marrow of Chinese hamsters that were orally administered avilamycin and in micronucleus tests with bone marrow of mice treated with avilamycin..

Using a structure estimation method based on molecular connectivity indices(1), the Koc of avilamycin can be estimated to be >1X10+5(SRC). According to a classification scheme(2), this estimated Koc value suggests that avilamycin is expected to be immobile in soil.

An estimated BCF of 20 was calculated in fish for avilamycin(SRC), using an estimated log Kow of 2.49(1) and a regression-derived equation(1). According to a classification scheme(2), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

The Henry's Law constant for avilamycin is estimated as <1X10-10 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that avilamycin is expected to be essentially nonvolatile from water and moist soil surfaces(2). Avilamycin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of <1X10-10 mm Hg(SRC), determined from a fragment constant method(1).

/LABORATORY ANIMALS: Acute Exposure/ Acute ocular irritation effects of avilamycin were examined in three female and three male rabbits (New Zealand White) approximately 12-18 weeks old and weighing 2.7-3.2 kg. One eye of each of six animals was treated once with 69 mg (equivalent in volume to 0.1 mL and in activity to 10.3 mg) of avilamycin dried fermentation product, and irritation signs were observed for 7 days. Corneal dullness, slight iritis and slight conjunctivitis developed in all treated eyes within 1 hr after treatment, but the symptoms cleared within 7 days post-treatment. All treated eyes gave a negative response to sodium fluorescein dye 24 hr after treatment, which indicates that there were no corneal lesions.

/LABORATORY ANIMALS: Acute Exposure/ The acute toxicity of avilamycin has been evaluated using various routes of administration in mice, rats and rabbits. ... The acute intraperitoneal toxicity of avilamycin was more severe than its oral or dermal toxicity. However, the deaths observed after intraperitoneal administration were mainly due to the inflammatory reactions to the unabsorbed avilamycin in the abdominal cavity rather than to the toxicity of avilamycin itself. ... Deaths induced by the intraperitoneal dosing were preceded by lethargy, with hunchback position, distended abdomen, piloerection and decreased locomotor activity.

/LABORATORY ANIMALS: Acute Exposure/ Avilamycin was evaluated for allergic contact sensitization in 18 female albino guinea-pigs 8-12 weeks of age and weighing approximately 430 g ... . Avilamycin, a 14.9% dried fermentation product, was applied at a concentration of 5% by weight (w/w) in petrolatum to the skin and held under occlusion for 6 hr. During the induction phase, applications (0.2 ml) were given to 12 animals 3 times weekly for 2 weeks. A challenge application was performed 8 days after the final induction exposure. Six additional animals remained untreated during induction and received the avilamycin dose only at challenge. Dinitrochlorobenzene, 0.1% (w/v) dissolved in 70% ethanol, and undiluted petrolatum were tested as positive and vehicle controls, respectively. In the positive and vehicle control groups, 18 guinea-pigs each were allocated for challenge with or without induction. There was no evidence of sensitization or dermal irritation in any of the animals treated with 5% (w/w) avilamycin in petrolatum. Irritation and sensitization were observed only with the positive control, dinitrochlorobenzene. Avilamycin did not elicit a contact sensitization response in guinea-pigs.

/LABORATORY ANIMALS: Acute Exposure/ The local lymph node assay was performed ... to investigate the skin sensitization potential of avilamycin. Twenty-eight female CBA/J mice approximately 9 weeks old and weighing 20 g were allocated to seven groups of four animals each: five treated groups, one positive control group and one negative control group. The treatment groups received 5, 10, 25, 50 or 100% of avilamycin dissolved in an acetone/olive oil (4:1 by volume [v/v]) mixture. As avilamycin is not soluble in the usual vehicles, an extract of granular avilamycin (purity 26.4%) at a concentration of 10% (weight by volume (w/v)) in acetone was used for treatment, and the concentrations of avilamycin tested were expressed as a percentage (by volume) of the extract in the vehicle. The negative control group received the acetone/olive oil (4:1, v/v) mixture only, and the positive control group received I-hexylcinnamaldehyde, a moderate sensitizer, dissolved in a mixture of acetone/olive oil (4:1, v/v) at a concentration of 25%. The test materials (25 uL) were applied over the ears for 3 consecutive days. Following 2 days of resting, ear thickness and the proliferation of lymph node cells in the lymph node draining the application site were measured. Clinical signs, morbidity, mortality and body weight were also examined during the study. No mortality and no clinical signs were observed during the study. No cutaneous reactions and no increase in ear thickness were observed in the animals of the treated groups. There was no lympho proliferation seen at any concentration, whereas significant lympho proliferation was observed with the positive control. Avilamycin did not induce delayed contact hypersensitivity in the murine local lymph node assay.

A base-catalyzed second-order hydrolysis rate constant of 0.039 L/mole-sec(SRC) was estimated for avilamycin using a structure estimation method(1); this corresponds to half-lives of 5.6 years and 200 days at pH values of 7 and 8, respectively(1). Avilamycin contains chromophores that absorb at wavelengths >290 nm(2) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

Avilamycin's production and use as an antibiotic may result in its release to the environment through various waste streams. If released to air, an estimated vapor pressure of <1X10-10 mm Hg at 25 °C indicates avilamycin will exist solely in the particulate phase in the atmosphere. Particulate-phase avilamycin will be removed from the atmosphere by wet and dry deposition. Avilamycin contains chromophores that absorb at wavelengths >290 nm and, therefore, may be susceptible to direct photolysis by sunlight. If released to soil, avilamycin is expected to have no mobility based upon an estimated Koc of >1X10+5. Volatilization from moist soil surfaces is not expected to be an important fate process based upon an estimated Henry's Law constant of <1X10-10 atm-cu m/mole. Avilamycin is not expected to volatilize from dry soil surfaces based upon its vapor pressure. Biodegradation data in soil or water were not available. If released into water, avilamycin is expected to adsorb to suspended solids and sediment based upon the estimated Koc. Volatilization from water surfaces is not expected to be an important fate process based upon this compound's estimated Henry's Law constant. An estimated BCF of 20 suggests the potential for bioconcentration in aquatic organisms is low. Estimated hydrolysis half-lives were 5.6 years and 200 days at pH 7 and 8, respectively. Occupational exposure to avilamycin may occur through inhalation and dermal contact with this compound at workplaces where avilamycin is produced or used. (SRC)

Oligosaccharide antibiotic

Veterinary growth promotant

MEDICATION (VET)

Anti-Bacterial Agents