MGK-264 (Hexyl-1-(14)C) (99.0% purity, s.a.:18.4 mCi/mmol). 2 Charles River CD rats/sex were treated with single dose (100 mg/kg) of radiolabeled [Hexyl-1-(14)C] MGK-264 by oral gavage. After dosing, animals were placed in Roth metabolism cages and expired (14)CO was collected in a gas trap containing ethanolamine/cellusolve (2/1;V/V). Samples were 2 collected at 2, 4, 8, 24 and 48 hours after dosing and the (14)C radioactivity was measured. After 48 hours the 14C radioactivity recovered from the male/female rats averaged 0.02% of the total dose. These results demonstrate that (Hexyl-1-(14)C) MGK-264 undergoes very little metabolic degradation to (14)CO2 in these rats.
MGK-264([Hexyl-1-(14)C), (unlabeled MGK 264; 93.1% purity) s.a.:18.4 mCi/mmol, 98.4% radiopurity. 5 Sprague-Dawley rats/sex were treated with single (100 or 1000 mg/kg) or multiple doses (pretreated daily with 100 mg/kg unlabeled MGK-264 for 14 days followed by a single dose of radiolabeled (Hexyl-1-14C) MGK-264). Metabolic profile of the (14)C residues in the urine and extracts of fecal samples (extracted with water and methanol) ... were determined using HPLC. Additional male and female rats (8/sex) were orally dosed with (Hexyl-1-(14)C) MGK-264 at 859 mg/kg and 697 mg/kg to generate urinary and fecal (14)C residues for qualitative analysis. Major metabolites from 0-24 hour urine samples collected from males and had similar retention times as the four metabolites previously observed in rats dosed with (Norbornene 2,3-(14)C) MGK 264. The percentage of polar metabolites resulting from the beta-oxidation was higher in males (53.6% - 62.41%) than females (34.79% - 42.75%), while less polar metabolites in urine or feces resulting from T-oxidation was higher in females (44.72% - 59.34) than males (30.93% - 37.03%) indicating a sex difference in the quantitative metabolism of MGK-264.
The rat metabolism studies identified 2 major MGK-264 metabolites (approximately 20% of the applied dose each) in urine and feces samples. These metabolites apparently were formed by oxidation of the norbornene double bond to form an epoxide and either beta-oxidation or omega-1 oxidation of the nitrogen side chain to form a carboxylic acid.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
致癌性证据
癌症分类：C组可能的人类致癌物
Cancer Classification: Group C Possible Human Carcinogen
IDENTIFICATION AND USE: MGK 264 is a very light, yellow colored liquid. It is used as a synergist for pyrethroids in aerosol sprays for household and veterinary use. HUMAN STUDIES: In vitro, MGK 264 treatment did not result in statistically significant and reproducible alterations in testosterone or estradiol production. MGK 264 was negative for estrogen receptor transcriptional activation in the test system. MGK 264 inhibited aromatase activity. ANIMAL STUDIES: MGK 264 caused acute eye irritation in rabbits. A 90-day rat inhalation toxicity study demonstrated that at the lowest dose tested, there were indications of metaplasia/hyperplasia and changes in the larynx. At higher doses, histopathology of the larynx revealed additional changes and more intense changes in the epithelium and throat. The liver is the target organ of MGK 264. Liver effects were noted in the adults in a rat chronic/oncogenicity study, a mouse chronic/oncogenicity study, a rat multi-generation reproduction study, and subchronic and chronic dog studies. The dog appeared to be the most sensitive species for liver alterations but these alterations were limited to slight to moderate brown pigment and circulating enzyme changes. In the mouse, liver changes include bile duct histological changes including liver tumors, as well as kidney weight effects and brown pigment. MGK-264 was administered to rats, 25/dose by gavage at 0, 100, 300 or 1000 mg/kg/day from days 6 through 15 of gestation. There was no evidence of developmental toxicity observed even at the highest dose tested (and limit dose) of 1000 mg/kg/day. MGK 264 was negative in the uterotrophic assay. MGK 264 was not interactive in the estrogen receptor binding assay. MGK 264 was used in a Salmonella typhimurium mutagenicity assay with tester strains TA100, TA98, TA1535, TA1537 and TA1538 at 0, 10, 33, 100, 333, 1000, 3333 and 10,000 ug/plate with and without activation. There were no effects observed at any dose with any of the tester strains. MGK 264 was negative in the uterotrophic assay. In a female pubertal assay serum T4 and TSH levels were not affected, and there were no treatment-related effects on thyroid weight. MGK 264 was negative for androgenicity and anti-androgenicity in the Hershberger assay. MGK 264 was not active in the estrogen receptor binding and in the androgen receptor binding assays. ECOTOXICITY STUDIES: The survival of tadpoles exposed to MGK 264 was not significantly affected as survival was 100% in the control and low and mid treatment groups with one mortality occurring in the high treatment group. There were no clinical signs of toxicity or observations of abnormal behavior at any concentration. MGK 264 caused no significant acceleration or delay of median developmental stage at Day 7 or 21 at any treatment level relative to the negative control. Further, no asynchronous development was observed.
Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/
Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/
MGK-264 (Norbornene-2,3 - (14)C), s.a.:26.0 mCi/mmol, (99.8% radiopurity). 5 Sprague-Dawley rats/sex were treated with single (100 or 1000 mg/kg) or multiple doses (pretreated daily with 100 mg/kg unlabeled MGK- 264 for 14 days followed by a single dose of radiolabeled (Norbornene-2,3 -(14)C) MGK-264). Blood levels of radioactivity for male rats peaked approximately 4 hours after dosing for males and approximately 6 hours after dosing for females. The blood half-life was calculated to be approximately 4.2 hours for males and approximately 3.5 hours for females. Most of the radioactivity recovered was excreted during the first 24 hours in the urine and during the first 36 hours for the feces following administration. Following single and multiple dose administration at 100 mg/kg, 41.84- 68.25% of the radiolabel was eliminated in the urine and 25.28-51.90% in feces. The total mean recovered radioactivity of the administered dose in the three groups ranged between 93.53%-99.88%. Radioactivity appeared to be more rapidly absorbed from the male gastrointestinal tract than that of females, however the blood radioactivity half-lives suggest that radioactivity was more rapidly eliminated by the females than the males. The pattern of excretion of radioactivity in urine and feces within females was similar with the female rats in the low dose groups excreting approximately 22-24% more of the total radioactivity in the urine than the males. However, the male rats in single oral high dose group were similar to the females. Additionally males in all groups excreted approximately 10-20% more of the total radioactivity in the feces than the females and retained more radioactivity in the liver and intestines than females. Thus (Norbornene-2,3 -(14)C) MGK-264 appears to undergo entero-hepatic circulation at different rates in the males and females, with females excreting it more rapidly in the urine than males.
MGK-264 (Hexyl-1-14C) (unlabeled MGK 264, s.a.:18.4 mCi/mmol, 98.3% radiopurity). 5 Sprague-Dawley rats/sex were treated with single (100 or 1000 mg/kg) or multiple doses (pretreated daily with 100 mg/kg unlabeled MGK-264 for 14 days followed by a single dose of radiolabeled (Hexyl-1-14C) MGK-264). Blood levels of radioactivity for male rats peaked approximately 4 hours after dosing and for females approximately 6 hours after dosing. The blood half-life was calculated to be approximately 6 hours for females and approximately 8 hours for males. Following single and multiple dose administration at 100 mg/kg, 49.49-73.05% and 20.87-46.67% of the radiolabel was eliminated in the urine and feces, respectively. The total mean recovered radioactivity of the administered dose in the three groups ranged between 93.13%-97.43%. The pattern of excretion of radioactivity in urine and feces within each sex was similar. However, the female rats in each dose group excreted approximately 10-20% more of the total radioactivity in the urine than the males while the male rats in each dose group excreted approximately 10-20% more of the total radioactivity in the feces than the females. Tissue residues of (14)C were negligible (less than 0.43% of the administered dose) in all groups.
Four healthy male volunteers were dermally administered 5.3 mg (approximately 50 uCi) of (14)C labelled MGK-264 with 17.0 mg DEET and 1.0 mg MGK 326, to a 4 x 6 cm area on the volar aspect of the forearm. The area had a non-occlusive cover and 8 hours after application the /remaining/ dose was removed by wiping dosed area with isopropyl alcohol swabs. Blood samples were collected from both forearms (ipsilateral and contralateral) over 120 hours at regular intervals to determine levels of radioactivity in plasma. Urine and fecal samples were collected for 5 consecutive days and the skin was stripped (tape stripping) with ... tape at 1, 23 and 45 hours after removal of the dosage. A mean of 0.39% of the administered radioactivity was excreted in the urine, most remained in the outer layer of the skin with no measurable amount in the feces. A total mean of 89.96% was recovered. The tape stripping revealed that radioactivity did not accumulate in the skin.
MGK-264 (Hexyl-1-(14)C) (93.1% purity), s.a.:18.4 mCi/mmol, 98.3% radiopurity) was administered dermally to 5 male rats as a 5% (w/w) solution in isopropanol. A mean single dose of 13.64 mg/kg was achieved. Blood samples were collected over 120 hours at regular intervals to determine levels of radioactivity. Blood levels of radioactivity for male rats peaked at approximately 6 and 12 hours after dosing and the halflife was 31.17 hours. Additionally, 5 male rats/group were administered the (14)C MGK-264 as a 5% solution and euthanized at peak blood level (12 hours), blood half-life (hour 43), second half-life (hour 74) and at 168 hours post -dose. Necropsies were conducted and tissues, urine and feces were examined for levels of radioactivity. The treated skin and enclosures glued on to the treated skin area were also removed and rinsed and the rinses were measured for radioactivity. The mean amounts of radioactivity in the skin rinse at the four time points were 81.07%, 53.06 %, 29.96% and 0.62% respectively. The radioactivity from the carcass decreased at the 168 hour euthanasia interval suggesting a lack of accumulation in tissues examined. The occurrence of two peaks and the presence of radioactivity in the intestines, liver and feces indicate involvement of the enterohepatic circulation in the elimination of MGK 264.
A study with human volunteers indicated that the dermal absorption factor for MGK-264 is approximately 10% based on the combination of radiolabelled material in the urine (about 1%) and unaccounted for radioactivity (about 9%, assumed to be retained in the body).
