Ammonium hydrogencarbonate

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

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

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable publication which meets basic scientific principles; Data taken from EU risk assessment/SIDS

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Tributyl Phosphate Effects on Urine and Bladder Epithelium in Male Sprague-Dawley Rats

Author:

Arnold L.L. et al.

Year:

1997

Bibliographic source:

Fund. Appl. Toxicol. 40, 1997

Reference 2

Reference Type:

publication

Title:

OECD SIDS Ammonium Chloride, Final 8/2006

Author:

OECD

Year:

2006

Bibliographic source:

OECD SIDS AMMONIUM CHLORIDE

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

In this subchronic feeding study, ten male Sprague-Dawley received 12300 ppm ammonium chloride (equivalent to 684 mg/kg bw/day) continuously via diet for 70 days.

GLP compliance:

no

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Ammonium chloride

EC Number:

235-186-4

EC Name:

Ammonium chloride

Cas Number:

12125-02-9

IUPAC Name:

ammonium chloride

Details on test material:

- Name of test material (as cited in study report): Ammonium chloride
- Supplier: Sigma Chemical
- Analytical purity: > 98.7%

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories Inc. (Kingston NY)
- Age at study initiation: 4 - 5 weeks
- Weight at study initiation: mean 175 g
- Housing: individually in suspended stainless steel wire-mesh cages
- Diet (e.g. ad libitum): Purina Mills Certified Rodent Lab Chow, St. Louis, MO); ad libitum
- Water (e.g. ad libitum): water; ad libitum
- Acclimation period: 12 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/-4
- Humidity (%): 55 +/- 15
- Photoperiod (hrs dark / hrs light): 12 / 12

Administration / exposure

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The ammonium chloride content in the diet was determined by photometric analysis following extraction of chloride from feed using boiling water. The water/chloride extract was analyzed with a COBAS MIRA Plus Chemistry System (Roche Diagnostic System, Inc.)

Duration of treatment / exposure:

70 days

Frequency of treatment:

continously by feed

Doses / concentrations

Remarks:

Doses / Concentrations:
12300 ppm in the diet (equivalent to 684 mg/kg bw/day)
Basis:
nominal in diet

No. of animals per sex per dose:

10

Control animals:

yes, concurrent no treatment

Details on study design:

- Post-exposure recovery period: 7 days

Positive control:

Tributyl phosphate (TBP): 0, 3000 ppm (including 10 week recovery period)

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: Yes
- Time schedule for collection of urine: after each week
- Metabolism cages used for collection of urine: No
- Animals fasted: No data
- Parameters examined: pH, osmolality, Magnesium, Calcium, Creatinine, Phosphate, Protein

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes: bladder, kidney
HISTOPATHOLOGY: Yes: bladder, kidney

Results and discussion

Results of examinations

Details on results:

BODY WEIGHT
No significant difference between ammonium chloride treatment and control. Significantly decreased in the TBP treatment group.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
No significant difference among any of the groups (ammonium chloride, TBP and control); mean 110 g/kg b.w./day (initial) to 55.6 g/kg b.w./day (final)

URINALYSIS
- pH: ammonium chloride treatment reduced urinary pH to 6.04 (control: 7.56)
-Calcium: significantly increased in the ammonium chloride treatment. However the crystals from urine were not found.

ORGAN WEIGHTS
No significant difference compared to control


HISTOPATHOLOGY:
No abnormalities found.

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

12 300 ppm

Sex:

male

Basis for effect level:

other: no adverse effects noted

2

Dose descriptor:

NOAEL

Effect level:

684 mg/kg bw/day (nominal)

Sex:

male

Basis for effect level:

other: no adverse effects noted

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Effects on urinary chemistry:

	pH	Magnesium (mEq/l)	Osmolality (mOs/kg bw)	Calcium (mg/dl)	Creatinine (mg/dl)	Phosphate (mg/dl)	Protein (mg/dl)
NH4Cl	6.04 ± 0.10*	42.8 ± 11.3	1305 ± 156	11.0 ± 1.4*	52 ± 5+	51 ± 9	108 ± 24
3000 ppm TBP	7.61 ± 0.05	37.6 ± 3.1	1034 ± 58*	4.5 ± 0.5	60 ± 4*	37 ± 11	119 ± 12
Control	7.56 ± 0.07	48.9 ± 5.1	1395 ± 87	5.9 ± 0.6	80 ± 5	41 ± 6	117 ± 11

* p<0.05

Histopathological effects on the bladder:

	Bladder weight		Bladder histology
	g	g/kg bw	normal	simple hyperplasia	papillary/nodular hyperplasia	BrdU labeling index
NH4Cl	0.138 ± 0.008	0.260 ± 0.014	10	0	0	0.17 ± 0.03
3000 ppm TBP	0.218 ± 0.027*	0.446 ± 0.052*	0	10*	6*	1.81 ± 0.30
Control	0.124 ± 0.010	0.227 ± 0.016	10	0	0	0.20 ± 0.03

* p<0.05