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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Non-guideline non-GLP study, published in peer-reviewed literature, with adequate and well described methods and detailed results.

Data source

Reference
Reference Type:
publication
Title:
Long-term toxicity of propylene glycol in rats.
Author:
Gaunt IF, Carpanini FMB, Grasso P, Lansdown ABG
Year:
1972
Bibliographic source:
Fd Cosmet Toxicol, 10, 151-162.

Materials and methods

Principles of method if other than guideline:
Groups of 30 male and 30 female weanling rats were fed for 2 years on diets containing 0, 6250, 12500, 25000 and 50000 ppm propylene glycol. Next to histopathological examinations and gross necropsy haematological examination and urinalysis were performed.
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): monopropylene glycol, propylene glycol
- Impurities (identity and concentrations): sulphates, 0%; chlorides, max. 0.001%; arsenic, max. 1 ppm; heavy metals, max. 5 ppm
- Supplier: Shell Company Ltd.

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: SPF-breeding colony, Charles River, France
- Age at study initiation: weanlings
- Weight at study initiation: males 120-150 g, females 120-140 g
- Diet: Spillers' Laboratory Small Animal Diet, ad libitum
- Water: ad libitum:

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21± 1
- Humidity (%): 50-60

Administration / exposure

Route of administration:
oral: feed
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
2 years
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0, 6250, 12500, 25000 and 50000 ppm
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
0, 200, 400, 900 and 1700 mg/kg bw/day (males); 0, 300, 500, 1000 and 2100 mg/kg bw/day (females)
Basis:
actual ingested
No. of animals per sex per dose:
30/sex/dose
Control animals:
yes, plain diet

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least once daily

BODY WEIGHT: Yes
- Time schedule for examinations: at 2 weeks intervals


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): yes
The food intake was measured over the preceding 24 hr

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at weeks 13, 21, 52 and 80 of the study, blood was collected from the tail veins of eight males and eight females from each of the groups that had een fed on diets containing 0, 25000 and 5000 ppm propylene glycol. An additional bleed of eight rats from the control, 6250 and 12500 ppm was made at week 54.
- How many animals: groups of 8 males and 8 females
- Parameters examined: haemoglobin content, packed cell volume and counts of erythrocytes, total leucocytes and the individual types of leucocytes. Counts of reticulocytes were also carried out on the samples obtained after 52, 54 and 80 weeks. At week 104 the haematological investigations were limited to measurements of haemoglobin concentration and examination of a stained blood smear from all surviving rats.

URINALYSIS: Yes
- Time schedule for collection of urine: at weeks 13, 30 and 52, an urinary concentratio test was conducted on selected rats from the control and two highest treatment levels (25000 and 50000 ppm).
- Parameters examined: specific gravity and volume of urine produced during a 6-hr period of water deprivation, during a 2-hr period following a water load of 25 ml/kg and during a 4-hr period commencing 16 hr after the water load. Urinary cell counts were carried out on the 6-hr samples.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes; brain, heart, liver, spleen, kidneys, adrenals, gonads, stomach, small intestine and caecum were weighed.
HISTOPATHOLOGY: Yes; next to the organs named above, salivary gland, trachea, aorta, thymus, lymph nodes, pituitary, urinary bladder, colon, rectum, pancreas, uterus, muscle and any tissue that appeared to be abnormal were examined.

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:
no effects observed
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
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not specified
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:
CLINICAL SIGNS AND MORTALITY
No abnormalities were seen in the appearance or behavior of the rats. There were no statistically significant differences between treated and control rats in cumulative death rate.

BODY WEIGHT AND WEIGHT GAIN
There were no statistically significant differences between treated and control rats in cumulative body-weight gain.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
There were no statistically significant differences between treated and control rats in cumulative food consumption.

HAEMATOLOGY
There were no significant differences between treated and control rats in the results of the haematological examination.

URINALYSIS
There were no significant differences between treated and control rats in the results of the urinary cell excretion or renal concentration tests.

ORGAN WEIGHTS
Values of absolute organ weights and weights of organs relative to the terminal body weight were similar in all treated and control groups.

HISTOPATHOLOGY: NON-NEOPLASTIC
There was a wide range of histological abnormalities, particularly in kidney, liver and lung, though the incidence was similar in both test and control groups of rats. The kidney changes varied in severity and consisted of tubular degeneration, stromal and periglomerular fibrosis and inflammatory-cell infiltration mainly with lymphocytes. Occasional foci of calcification were also seen. The pigment in the kidneys of treated and control animals was found within the cells of the proximal tubule and resembled lipofuscin. The chronic changes found in the lungs were, generally, peribronchial and perivascualr lymphocyte cuffing and, in som cases, thickening and collapse of the alveili. The animals with pneumonia showed definite polymorphonuclear leucocyte infiltration of the alveoli. Most (86%) of the cases of pneumonia were found in animals which died due to ill health during the course of the study.

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
there was a high incidence of mammary fibroadenomas and pituitary adenomas mainly affecting female rats, but the incidence was similar in test and control groups. Only a few of the neoplasms were malignant. The most numerous were subcutaneous fibrosarcomas but these occurred in both treated and control rats. The abdominal fibrosarcoma found in a control male rat was large and occupied the upper part of the abdomen involving the pancreas and liver but not the stomach or bile duct. Numerous small nodules (1-3 mm in diameter) were scattered in the remainder of the pancreatic tissue and mesentery. Larger masses (2 cm in diameter) were found in the lower abdominal cavity on the right vas deferens. The lung contained one metastasis.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
1 700 mg/kg bw/day (actual dose received)
Sex:
male
Basis for effect level:
other: No adverse effects noted at the highest dose tested.
Dose descriptor:
NOAEL
Effect level:
2 100 mg/kg bw/day (actual dose received)
Sex:
female
Basis for effect level:
other: No adverse effects noted at the highest dose tested.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion