Carbamic acid ester

Repeated dose toxicity: oral

Administrative data

Endpoint:

chronic toxicity: oral

Remarks:

combined repeated dose and carcinogenicity

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Limited report, non-GLP, the information in the publication is limited to what is included in the summary. The results are indicative for low toxicity

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1971

Report date:

1971

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)

Principles of method if other than guideline:

study performed before OECD/EC guideline became available. limited report, limited number of animals included, no investigation of blood chemistry, limited urinary parameters checked

GLP compliance:

no

Limit test:

no

Test material

Reference

Name:

Unnamed

Type:

Constituent

Test material form:

not specified

Details on test material:

Fulfilling criteria British Pharmacopoeia

Colour (platinum-cobalt), max 10;
specific gravity (20/20°C), 1.038-1-040;
distillation range, min 185°C (initial boiling point) to max 189°C (dry point);
acidity (as acetic acid), max 0.005% w/w;
sulphates, nil;
chlorides, max 0"001% w/w;
arsenic, max 1 ppm;
heavy metals, max 5 ppm.

Test animals

Species:

rat

Strain:

CD-1

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River, France
- Age at study initiation: not indicated
- Weight at study initiation: males 120-150 g; females 120-140 g
- Housing: no data
- Diet: Spillers' Laboratory Small Animal Diet ad libitum
- Water: ad libitum
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± I°C
- Humidity (%): 50-60%
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data

Administration / exposure

Route of administration:

oral: feed

Details on oral exposure:

DIET PREPARATION: no data

VEHICLE: no data

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

2 years (additional group at 0 and 50000 ppm 15 weeks)

Frequency of treatment:

continuously in diet

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0, 6250, 12,500, 25,000 and 50,000 ppm
Basis:
nominal in diet

Doses / concentrations 2

Remarks:

Doses / Concentrations:
200, 400, 900 and 1700 mg/kg bw in males and 300, 500, 1000 and 2100 mg/kg bw in females
Basis:
actual ingested

No. of animals per sex per dose:

30/sex/dose

Control animals:

yes

Details on study design:

Earlier studies found some haematological effects (including haemolysis) and therefore 15 rats/sex were treated at 50000 ppm (1700-2100 mg/kg bw) for 15 weeks. These animals (including additional controls) were examined for renal concentration (gravity and volume) and activity of aspartate aminotransferase (AST) in urine samples collected over 6 hours. In addition haematological examination and assessment of blood-chemistry parameters (urea, AST and ALAT) was assessed. At autopsy brain, heart, liver, spleen, kidneys, adrenals, gonads and pituitary were weighed.

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: 2 weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Time schedule for examinations: 2 weekly
- Compound intake measured over a 24 period before weighing

WATER CONSUMPTION: No data

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes, collected from tail veins
- Time schedule for collection of blood: in week 13, 21, 52 and 80 on 8/sex from control, 25000 and 50000 ppm, in week 54 on 8/sex from control, 6250 and 12500 ppm, in week 104 on all survivors
- Anaesthetic used for blood collection: No
- Animals fasted: No
- Parameters checked:
in week 13 and 21: haemoglobin content, packed cell volume and counts of erythrocytes, total leucocytes and differential leucocytes.
in week 52, 54 and 80 haemoglobin content, packed cell volume and counts of erythrocytes, reticulocytes, total leucocytes and differential leucocytes.
in week 104: haemoglobin content and differential leucocytes count

CLINICAL CHEMISTRY: No (performed on additional group of 15 animals/sex)

URINALYSIS: Yes
- Time schedule for collection of urine: in week 13, 30 and 52 on selected rats from 0, 25,000 and 50,000 ppm.
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data; urine collection during water deprivation period of 6 hours; waterload of 25 mL/kg bw for two hours followed by urine collection over 4 hour period starting 16 hours thereafter
- Parameters checked:
deprivation: volume, gravity, cell count
waterload: volume, gravity

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes, full
HISTOPATHOLOGY: Yes , brain, heart, liver, spleen, kidneys, adrenals, gonads, stomach, small intestine, caecum, salivary gland, trachea, aorta,
thymus, lymph nodes, pituitary, urinary bladder, colon, rectum, pancreas, uterus, muscle and gross lesions
ORGAN WEIGHTS: Yes, brain, heart, liver, spleen, kidneys, adrenals, gonads, stomach, small intestine and caecum

Statistics:

Yes, but no details

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Description (incidence and severity):

limited parameters investigated in additional group

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

MORTALITY: males 18, 14, 16, 19 and 19 at 0, 6250, 12500. 25000 and 50000 ppm; females 15, 18, 11, 16 and 15 at 0, 6250, 12500. 25000 and 50000 ppm

CLINICAL SIGNS : no treatment related effects

BODY WEIGHT(gain): no treatment related effects

FOOD CONSUMPTION; no treatment related effects

HAEMATOLOGY: no treatment related effects

CLINICAL CHEMISTRY: no treatment related effects (in the additional control and 50000 ppm animals treated during 15 weeks)

URINALYSIS: no treatment related effects

ORGAN WEIGHTS (absolute and relative to body weight): no treatment related effects

GROSS PATHOLOGY: no treatment related findings
At all doses and controls
Kidney: yellow discoloration
Liver: fatty changes,

HISTOPATHOLOGY: NON-NEOPLASTIC: no treatment related effects
At all doses and controls
Kidney: nephropathy (no relationship with treatment)
Liver: portal lymphocyte infiltration, nodular hyperplasia, hepatocyte vacuolation , bile duct proliferation, cirrhosis and fibrosis (no relationship with treatment)
Lung: chronic infection (peribronchial and perivascular lymphocyte cuffing, thickening and collapse of the alveoli), pneumonia (polymorphonuclear leucocyte infiltration of the alveoli) (no relationship with treatment, but cause of most deaths during the study)

HISTOPATHOLOGY: NEOPLASTIC incidental findings within normal ranges for rats of this strain and age
females: mammary fibroadenomas, pituitary adenomas and subcutaneous fibrosarcomas
males: subcutaneous fibrosarcomas

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

1 700 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

2

Dose descriptor:

NOAEL

Effect level:

2 100 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

female

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

The NOAEL is 1700 mg/kg bw

Executive summary:

In a dietary study, the substance was fed to rats (30/sex/dose) for 104 weeks at 0, 6250, 12500, 25000 and 50000 ppm. Mortality was high and related to pulmonary disease, but showed no relationship with treatment. No treatment related effects were found on body weight(gain), food consumption, haematology, biochemistry (in additional group treated for 15 weeks at 50000 ppm) and urinalysis. Effects on kidney, liver and lungs were considered not related to treament. Some neoplasms were found but considered within normal ranges for rats of this age. Therefore it is concluded that the NOAEL is set at 50000 pp (1700 mg/kg bw for males and 2100 mg/kg bw for females). The substance is of low toxicity.