4-hydroxymethyl-1,3-dioxolan-2-one

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

Study period:

Not stated

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The study was conducted prior to test guidelines and GLP.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1962

Report date:

1962

Materials and methods

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

Test material was administered in the diet at 5 and 20% for 90 days. Body weights and feed consumption were measured at selected intervals. At necropsy, lung, heart, liver, kidney, spleen and testes absolute and relative weights were obtained. Basic hematologic and clinical chemistry measurements were made.

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Glycerol

EC Number:

200-289-5

EC Name:

Glycerol

Cas Number:

56-81-5

Molecular formula:

C3H8O3

IUPAC Name:

propan-1,2,3-triol

Details on test material:

Test material obtained from Dow Chemical, Shell and Proctor and Gamble was used. This study was conducted to determine whether there was a difference in the toxicologic profile of the three products. No additional information provided.

Test animals

Species:

rat

Strain:

not specified

Sex:

male/female

Details on test animals or test system and environmental conditions:

After weaning at 21 days, the rats were maintained on Purina Laboratory Chow pellets until the age of 52 days, when they were divided according to body weight into well matched groups of each sex and started on the experimental diets. The stock diet for this experiment was ground Purina Laboratory Chow. Two rats were housed together in a wire bottom cage. Food and water were available at all times

Administration / exposure

Route of administration:

oral: feed

Vehicle:

not specified

Analytical verification of doses or concentrations:

no

Details on analytical verification of doses or concentrations:

No analytical verification of concentration provided.

Duration of treatment / exposure:

90 days

Frequency of treatment:

Daily

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 5 and 20 %
Basis:
nominal in diet

No. of animals per sex per dose:

10 males + 10 females per dose level

Control animals:

yes, concurrent no treatment

Details on study design:

Groups of male and female rats (ten of each sex per group) were maintained for :90 days on diets containing 0.0 (Control), 20 percent and 5 percent Proctor and Gamble glycerine 20 percent and 5 percent Shell glycerine, and 20 percent and 5 percent Dow glycerine.

During the course of the experiment, the animals were weighed twice weekly for the first 28 days, and once a week thereafter. They were observed frequently for gross changes in appearance or behavior. Whenever possible, failing animals were autopsied when moribund in an effort to ascertain the cause of impending death. In addition, records were kept of mortality, and food consumption was. recorded for the first month.

Terminal hematological values were obtained from five female rats at the 0.0 (Control), 20, and 5 percent level of each of the three brands. At autopsy the animals were fasted overnight, weighed, and killed by decapitation. The lungs, heart, liver, kidneys, spleen, brain and testes were removed and weighed. Portions of these organs, as well as pancreas and adrenals, were preserved and hematoxylin/eosin stained sections were prepared for histological examination.

Samples of blood serum were obtained for the determination of urea nitrogen content and alkaline-phosphatase activity.

Positive control:

No data.

Examinations

Observations and examinations performed and frequency:

During the course of the experiment, the animals were weighed twice weekly for the first 28 days, and once a week thereafter. They were observed frequently for gross changes in appearance or behavior. Whenever possible, failing animals were autopsied when moribund in an effort to ascertain the cause of impending death. In addition, records were kept of mortality, and food consumption was. recorded for the first month.

Sacrifice and pathology:

Terminal hematological values were obtained from five female rats at the 0.0 (Control), 20, and 5 percent level of each of the three brands. At autopsy the animals were fasted overnight, weighed, and killed by decapitation. The lungs, heart, liver, kidneys, spleen, brain and testes were removed and weighed. Portions of these organs, as well as pancreas and adrenals, were preserved and hematoxylin/eosin stained sections were prepared for histological examination.

Samples of blood serum were obtained for the determination of urea nitrogen content and alkaline-phosphatase activity.

Other examinations:

No additional information available.

Statistics:

When appropriate, the Fisher "t" t e s t was used in comparing the mean values obtained on the experimental groups with those of the controls; in general, probability values (p) of less than 0.05 were interpreted as indicating a significant difference.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

gained weight faster than controls

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

not specified

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

increased liver/body weight ratio

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

liver histopathology

Histopathological findings: neoplastic:

not specified

Details on results:

5 percent level
No evidence of adverse effect was noted in male or female rats when maintained for 90 days on diets containing 5 percent glycerine, whether produced by Proctor and Gamble, Shell, or Dow. Judgment was based on gross appearance and behavior, mortality, growth, food consumption records, final average body and organ weights, terminal hematological values, blood urea nitrogen and alkaline phosphatase determinations, and gross and microscopic examination of the tissues.

20 .percent level
In the male rats which received 20 percent Proctor and Gamble, Shell, or Dow glycerine, there was an increase in the final liver/body weight ratio, and upon microscopic examination generalized cloudy swelling and hypertrophy of the parenchymal cells was observed. The only effect in the female rats on this level was some generalized cloudy swelling upon microscopic examination of the liver. There was no significant variation of the extent of liver changes in the rats fed the three brands of glycerine as a part of the diet.

The statistically significant decrease in the final heart/body weight ratio in the female rats fed 20 percent Shell glycerine, and the increase in the final kidney/body weight ratio in the female rats fed 20 percent Dow glycerine, were not accompanied by any cellular changes, nor is significance indicated by examination of the absolute weights in grams. Therefore, these may be attributed to chance.

In general, all the groups of rats that received the experimental diets containing glycerine grew faster and bigger than the controls.

Effect levels

1

Dose descriptor:

NOEL

Effect level:

50 000 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No treatment related effects noted.

2

Dose descriptor:

LOEL

Effect level:

200 000 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Average body weight for male and female rats after 4 weeks was approximately 240 and 155 g, respectively. Average feed consumption for the first 30 days for male and female rats was 22 and 20 g/day, respectively. Using these values, a 5% glycerol in the diet corresponds to 4580 and 6450 mg/kg/day for male and female rats, respectively. At 20% glycerol in the diet, male and female rats ingested 18,750 and 25,800 mg/kg/day, respectively. Obviously younger animals ingested more glycerol in the diet while older animals would ingest less glycerol in the diet. But this gives an approximation of the dose these animals received.

Applicant's summary and conclusion

Conclusions:

Under the conditions of the study, the dietary level of 5 percent was tolerated without any evidence of adverse effect, while in the dose level of 20 percent, the only signs of adverse effects were slight pathological changes in the liver.

Executive summary:

The effect of glycerine following administration for 90 days in a subchronic toxicity study was examined.

Rats fed 5 or 20% glycerine in the diet for 90 days gained weight at a faster rate than control animals. There were no adverse treatment related effects noted in male or female rats fed 5% glycerine in the diet.

In the male rats which received 20 percent glycerine, there was an increase in the final liver/body weight ratio and upon microscopic examination generalized cloudy swelling and hypertrophy of the parenchymal cells was observed. The only effect in the female rats on this level was some generalized cloudy selling upon microscopic examination of the liver.

A 5% glycerol in the diet corresponded to 4580 and 6450 mg/kg/day for male and female rats, respectively, after 4 weeks and a 20% glycerol in the diet corresponded to 18,750 and 25,800 mg/kg/day for male and female rats, respectively, after 4 weeks.