Nitrapyrin

Endpoint summary

Description of key information

Timchalk et al. (1987)

Absorbtion was from the GI tract. Excretion was via the urine (>80 %) and faecal (>11 %) routes. Two urinary metabolites were identified as 6-chloropicolinic acid (6-CPA) and the glycine conjugate of 6-CPA.

 

Domoradzki & Brzak (1998)

Over 98 % of the dose was excreted in 72 hours. The principal route of excretion was the urine, 76 and 82 % (low and high dose, respectively), which together with the faecal excretion, 22 and 16 % (low and high dose, respectively). The tissues contained less than 1 % radioactivity at 72 hours. Three urinary metabolites were identified: 6-chloropicolinic acid (6-CPA), the glycine conjugate of 6-CPA and the taurine conjugate of 6-CPA.

 

Domoradzki & Gibson (1997)

25 % of the dose was absorbed following a single dermal application to rats. Approximately 18 % remained in the skin after washing and could be available for further absorption. Of the 18 % of the dose remaining in the skin, approximately 14 % was absorbed in the animals that were sacrificed at 72 hours post-dosing.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

Timchalk et al. (1987)

This study was conducted to provide data on the pharmacokinetics of the test material in accordance with the standardised guideline EPA OPP 85-1 under GLP conditions. The study was awarded a reliability score of 1 in accordance with the criteria set forth by Klimisch et al. (1997).

14C-test material was administered orally to groups of 5 male and 5 female rats as a single dose at a low (1 mg/kg bw) and high (60 mg/kg body weight) dose level, and as a multiple 1 mg/kg non-radiolabelled dose for 14 days followed by a single oral dose of 1 mg 14C-test material/kg on day 15. Two additional groups of male rats were used to obtain 14C-plasma time-course and 14C-tissue distribution data.

The results indicate that although both doses were readily absorbed (>80 %), the low dose was absorbed at a faster rate than the high dose (t1/2 = 1.2 and 3.2 hours, respectively). The radioactivity was cleared from the plasma in a bi-exponential manner; half-lives for the rapid (initial) and slow (terminal) phases were 2.2 and 14.6 hours, respectively. Over 94 % of the dose was excreted in 72 hours. Although the absorption rates varied between doses, the AUCs were proportional to the dose (4.96 and 307.51 µg equivalent/g hour, at the low and high dose level, respectively) indicating that the amount of the test material absorbed was comparable at both doses, and the plasma clearance rates were identical (approx. 162 g/hour/kg).

The principle route of excretion was the urine (>80 %), which together with the faecal excretion (>11 %) accounted for approximately 99 % of the recovered dose. The tissues contained only a minor (<1 %) amount of 14C activity at 72 hours. HPLC and GC/MS analysis of urine samples identified two urinary metabolites as 6-chloropicolinic acid (6-CPA) and the glycine conjugate of 6-CPA (6-CPA-Gly), which accounted for 100 % of the urinary radioactivity, with approximately half of the 6-CPA conjugated with glycine. These data demonstrate that the test material was well absorbed from the GI tract. However, the 60 mg/kg dose was absorbed at a slower rate than the 1 mg/kg dose. After being absorbed the test material was rapidly metabolised and excreted principally in the urine by glomerular filtration as 6-CPA and 6-CPA-Gly. The elimination and final disposition of 14C-test material was unaffected by either dose level or prior exposure and comparable in males and females.

 

Domoradzki & Brzak (1998)

This study was conducted to obtain information on the absorption, distribution, metabolism and excretion of the test material in the mouse in accordance with the standardised guideline OPPTS 870.7485 under GLP conditions. The study was awarded a reliability score of 1 in accordance with the criteria set forth by Klimisch et al. (1997).

14C-test material was administered orally to groups of 10 male mice as a single oral gavage dose at 25 or 250 mg/kg body weight (low and high dose level, respectively). Both doses were readily absorbed with the low dose being absorbed at a faster rate than the high dose. Over 98 % of the dose was excreted in 72 hours for both the low and high dose groups. The principal route of excretion was the urine, 76 and 82 % (low and high dose, respectively), which together with the faecal excretion, 22 and 16 % (low and high dose, respectively), accounted for 98 % of the recovered dose. The half-life for urinary elimination for the low and high dose group was approximately 3 hours. The tissues contained less than 1 % radioactivity at 72 hours. Analysis of urine samples identified three urinary metabolites: 6-chloropicolinic acid (6-CPA), the glycine conjugate of 6-CPA and the taurine conjugate of 6-CPA which accounted for 100 % of the urinary activity.

No major differences were observed in the metabolic fate of the test material in the mouse at various dose levels or between the rat and mouse. Some quantitative differences in extent of conjugation of 6-CPA were seen between the two species.

 

Domoradzki & Gibson (1997)

This study was conducted under GLP conditions to provide data on the dermal absorption of the test material in male Fischer 344 rats. The study was awarded a reliability score of 1 in accordance with the criteria set forth by Klimisch et al. (1997).

Male Fischer 344 rats were exposed dermally for 24 hours to 10 mg 14C-test material/10 cm2 skin surface area (1 mg/cm2) in the vehicle dipropylene glycol monomethyl ether under occlusion conditions (Group I). Approximately 25 % of the administered dose was absorbed based on the radioactivity found in urine, faeces, carcass and tissues at the 24 hour sacrifice. The percentage of the administered dose detected in the dosed site, the bandage components and the skin washes was approximately 65 %. The percentage of the dose still remaining in the skin after the 24-hour wash and available for further absorption was approximately 18 %. The average total recovery of radioactivity was approximately 90 %.

An additional group of male rats was exposed in the same way for 24 hours, followed by a skin wash at 24 hours. The dermal dose site was then re-occluded until the animals were sacrificed at 72 hours post-dosing (Group II). The average percentage absorbed was approximately 35 % based on the radioactivity found in urine (31 %) and faeces (3 %) collected over the 72 hour period and in carcass/tissues (1 %) at sacrifice. The percentage of the administered dose detected at the dosed site, the bandage components and the skin washes was 49 % and that remaining in the skin decreased to approximately 4 %. The average total recovery of radioactivity was approximately 83 %.

In summary, following a single dermal exposure for 24 hours to 10 mg of 14C-test material/10 cm2 skin surface area (1 mg/cm2) an average of about 25 % of the dose was absorbed following a single dermal application to rats based on the amount of radioactivity recovered in the urine, faeces, tissues and carcass. Approximately 18 % remained in the skin after washing and could be available for further absorption. Of the 18 % of the dose remaining in the skin, approximately 14 % was absorbed in the animals that were sacrificed at 72 hours post-dosing. In total approximately 35 % of the applied dose was absorbed in the 72-hour period (Group II), with 25 % absorbed in the first 24 hours (Group I).