Ammonium hydrogendifluoride

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Published paper; investigative study

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

publication

Title:

Localized and systemic effects of environmental ammonia in rats

Author:

Schaerdel, A.D., White, W.J., Lang, C.M., Dvorchik, B.H. and Bohner, K.

Year:

1983

Bibliographic source:

Lab Anim Sci; 33 (1), 1983, 40-45.

Materials and methods

Objective of study:

absorption

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

Principles of method if other than guideline:

Rats with surgically implanted aortic cannulas were exposed to varying environmental ammonia concentrations (15-1157 ppm). Blood pH, pCO2 (partial pressure of CO2), PO2 (partial pressure of O2) and blood ammonia concentration were measured.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Ammonia, anhydrous

EC Number:

231-635-3

EC Name:

Ammonia, anhydrous

Cas Number:

7664-41-7

IUPAC Name:

ammonia

Constituent 2

Reference substance name:

ammonium, anhydrous

IUPAC Name:

ammonium, anhydrous

Details on test material:

No further information

Radiolabelling:

no

Test animals

Species:

rat

Strain:

other: Crl:COBS CD(SD)

Sex:

male

Details on test animals or test system and environmental conditions:

The animals were male Crl:COBS CD(SD) rats weighing 300 to 400 g, obtained from Charles River Laboratories (MA). The rats were quarantined for 5 days, in groups of 6 in stainless steel wire-bottom suspended cages. The quarantine cubicles had an environmental temperature of 21±0.5°C, 50±20% relative humidity, 29 fresh air changes per hour, and a 12-hour light/dark photoperiod.
The rats received a commercial rodent diet (RMH 3000) and water ad libitum. Urine and faeces were removed from the cages daily to reduce endogenous production of ammonia and other gaseous contaminants. No ammonia was detected in the quarantine cubicles throughout the course of the study.

Administration / exposure

Route of administration:

inhalation

Vehicle:

unchanged (no vehicle)

Details on exposure:

The ammonia exposure was conducted in a clear rigid plastic isolator fitted with two sets of rubber gloves. The atmosphere inside the chamber was produced by mixing compressed air and anhydrous ammonia. The total gas flow, measured at the outflow port of the chamber with a thermal anemometer, was set to 35 litres/minute (providing 3 complete air changes per hour).
The ammonia concentration within the chamber was measured for each exposure group by the gas impingement technique. Daily measurements of ammonia concentration, temperature and relative humidity inside the chamber were made during each exposure period.

Duration and frequency of treatment / exposure:

Phase 1: single exposure of 24 hours
Phase 2: 3 or 7 day continuous exposure

Doses / concentrations

Remarks:

Doses / Concentrations:
The rats were exposed to varying environmental ammonia concentrations (15-1157 ppm).

No. of animals per sex per dose / concentration:

Phase 1: 3 males/dose
Phase 2: 14 males/dose, divided into two subgroups of 7/dose

Control animals:

yes, concurrent vehicle

Positive control reference chemical:

A positive control was not included.

Details on study design:

The purpose of the study was to determine if environmental ammonia was absorbed through the lungs of the rats into the blood and exerted an effect on blood pH, blood gases and hepatic drug metabolizing enzyme activity. In phase 1 of the study, rats were exposed to varying environmental ammonia concentrations (15-1157 ppm). Blood pH, pCO2, pO2 and blood ammonia concentrations were measured at 0, 8, 12 and 24 h post exposure. In phase 2, hepatic microsomal enzyme activity (ethylmorphine-N-demethylase and cytochrome P-450) was determined after a 3 or 7 day exposure to varying environmental ammonia concentrations (4-714 ppm).

Details on dosing and sampling:

In phase 1 of the study, rats were exposed to varying environmental ammonia concentrations (15-1157 ppm). Blood pH, pCO2, pO2 and blood ammonia concentrations were measured at 0, 8, 12 and 24 h post exposure. In phase 2, hepatic microsomal enzyme activity (ethylmorphine-N-demethylase and cytochrome P-450) was determined after a 3 and 7 day exposure to varying environmental ammonia concentrations (4-714 ppm).
All arterial blood samples were collected through a permanently implanted aortic cannula (fitted under general anaesthesia). The animals were placed in individual metabolism cages within the chamber. Blood samples were collected by connecting a 3 ml heparinised syringe to the adaptor needle on the cannula and withdrawing 1 ml of blood. Blood gas and pH determinations were done on 0.6 ml samples of blood, using a pH/blood gas analyser. Blood ammonia concentrations were measured on 0.3 ml samples using the glutamate dehydrogenase procedure.
On the 3rd and 7th days of exposure in phase 2, one subgroup was removed from the isolator, and the animals decapitated. The liver microsomal fraction was isolated from the right lateral and left liver lobes, frozen in liquid nitrogen, and stored at -70°C. At the time of analysis, the final protein concentration of the microsomal fraction was adjusted to 0.75 mg of microsomal proten per ml of solution.
The trachea and lungs were also removed following phase 2 exposure and perfused with 10% neutral buffered formalin for 1 week. Sections were prepared, then embedded and stained with haematoxylin and eosin for histological examination.

Statistics:

Two way ANOVA with repeated measures of one factor was applied to phase 1 data. A three way factorial analysis was used to analyse phase 2 data. Comparisons were made using the Newman-Keul technique. In phase 2, significant differences between daily values were determined by the orthogonal components technique. A linear regression was done on each time period in phase 1.

Results and discussion

Preliminary studies:

No preliminary studies conducted.

Toxicokinetic / pharmacokinetic studies

Details on absorption:

No significant changes were found in the blood pH and pCO2. The pO2 and the microsomal enzymes had only minor changes. The blood ammonia concentration increased significantly in a linear fashion with increasing environmental ammonia concentrations indicating pulmonary absorption of ammonia.

Details on distribution in tissues:

No changes in the histologic appearance of the lungs or trachea.

Details on excretion:

No parameter measured.

Metabolite characterisation studies

Metabolites identified:

not measured

Details on metabolites:

No further information

Any other information on results incl. tables

No significant changes were found in the blood pH and pCO2. The pO2 and the microsomal enzymes had only minor changes. The blood ammonia concentration increased significantly in a linear fashion with increasing environmental ammonia concentrations indicating pulmonary absorption of ammonia. These levels also declined over time at higher concentrations suggesting that compensation occurred.There was no evidence of toxicity of ammonia during the exposure periods.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
No significant changes were found in the blood pH and pCO2. The pO2 and the microsomal enzymes had only minor changes. The blood ammonia concentration increased significantly in a linear fashion with increasing environmental ammonia concentrations indicating pulmonary absorption of ammonia.

Executive summary:

The purpose of the study was to determine if environmental ammonia was absorbed through the lungs of the rats into the blood and exerted an effect on blood pH, blood gases and hepatic drug metabolizing enzyme activity. In phase 1 of the study, rats were exposed to varying environmental ammonia concentrations (15-1157 ppm). Blood pH, pCO2, pO2 and blood ammonia concentrations were measured at 0, 8, 12 and 24 h post exposure. In phase 2, hepatic microsomal enzyme activity (ethylmorphine-N-demethylase and cytochrome P-450) was determined after a 3 and 7 day exposure to varying environmental ammonia concentrations (4-714 ppm). No significant changes were found in the blood pH and pCO2. The pO2 and the microsomal enzymes had only minor changes. The blood ammonia concentration increased significantly in a linear fashion with increasing environmental ammonia concentrations indicating pulmonary absorption of ammonia.