Reaction mass of glycerol, glycerol 1-formate, glycerol 2-formate, glycerol 1,2-diformate, glycerol 1,3-diformate and glycerol triformate

Repeated dose toxicity: oral

Administrative data

Endpoint:

chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Justification for type of information:

This endpoint study record is part of a Weight of Evidence approach comprising of read-across from four analogue source substance studies. The results of the read-across studies agree as to the repeated dose toxicity potential and are sufficient to fulfil the information requirements as further explained in the provided repeated dose toxicity endpoint summary.

Data source

Reference

Reference Type:

publication

Title:

Comparative toxicity of synthetic and natural glycerin

Author:

Hine CH, Anderson HH, Moon HD, Dunlap MK, Morse MS

Year:

1953

Bibliographic source:

Arch Ind Hyg Occup Med 7:282-291

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 452 (Chronic Toxicity Studies)

Version / remarks:

Test material was administered in the diet for up to 2 years. Study design followed intent of OECD 452. The number of animals/dose level used was less than required and minimal histopathology was conducted.

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:

Propane-1,2,3-triol

Details on test material:

GLYCERINE USP grade

Specific details on test material used for the study:

Reported as: glycerin

Test animals

Species:

rat

Strain:

Long-Evans

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ORGANISMS
- Age: not indicated
- Weight at study initiation: 96-109 g (males), 92-108 g (females)
- Number of animals: 22/sex/treatment, 26/sex for controls
- Source: Institute of Experimental Biology of University of California

Upon arrival at the laboratory, each rat was assigned to an individual numbered cage. Distribution among the experimental groups was accomplished by reference to a standard random number table.

Administration / exposure

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

ADMINISTRATION / EXPOSURE
- Exposure period: 2 year (1 year for the high dose group)
- Route of administration: oral in diet. Diet consisted of a standard dog-food meal with which the glycerin was thoroughly mixed. Feed was prepared once a week and stored in stoneware crocks. The crocks were weighed and refilled weekly, and the unconsumed feed was discarded.
- Doses: 5, 10 and 20% in diet; males 2000, 4000 and 8000 mg/kg bw, females 2500, 5000 and 10000 mg/kg bw
- Water was allowed freely.

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Continuous

Frequency of treatment:

Daily for up to two years

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

2 000 mg/kg bw/day (nominal)

Remarks:

males: 5% nominal in diet

Doses / concentrations 2

Dose / conc.:

2 500 mg/kg bw/day (nominal)

Remarks:

females: 5% nominal in diet

Doses / concentrations 3

Dose / conc.:

4 000 mg/kg bw/day (nominal)

Remarks:

males: 10% nominal in diet

Doses / concentrations 4

Dose / conc.:

5 000 mg/kg bw/day (nominal)

Remarks:

females: 10% nominal in diet

Doses / concentrations 5

Dose / conc.:

8 000 mg/kg bw/day (nominal)

Remarks:

males: 20% nominal in diet

Doses / concentrations 6

Dose / conc.:

10 000 mg/kg bw/day (nominal)

Remarks:

females: 20% nominal in diet

No. of animals per sex per dose:

22/sex/treatment
26/sex for controls

Control animals:

yes, concurrent no treatment

Details on study design:

No additional information available

Positive control:

No Data

Examinations

Observations and examinations performed and frequency:

CLINICAL OBSERVATIONS AND FREQUENCY:
- Clinical signs: daily in cage and weekly examination outside the home cage
- Mortality: daily
- Body weight: weekly
- Food consumption: weekly
- Haematology: erythrocyte and leucocyte count and haemoglobin after 3, 6, 12, 18 and 24 months
- Urinalysis: albumin, glucose, casts and red and white blood cells after 3, 6, 12, 18 and 24 months (24-48 hr urine collection)

Sacrifice and pathology:

ORGANS EXAMINED AT NECROPSY (MACROSCOPIC AND MICROSCOPIC):
- Organ weights: liver, kidneys, heart, spleen and lungs
- Macroscopic: no details provided
- Microscopic: liver, spleen, adrenals, kidney, small intestine, gonads and urinary bladder

Other examinations:

glycogen and lipid content of the liver of surviving rats at 0 and 20% glycerol

Statistics:

Chi-square test, student t-test, ANOVA (Fisher) were used as appropriate

Results and discussion

Results of examinations

Clinical signs:

not specified

Mortality:

not specified

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

slightly increased (significant) in males at 5 and 10% natural glycerin

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

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:

not specified

Details on results:

TOXIC RESPONSE/EFFECTS BY DOSE LEVEL:
- Mortality and time to death: not indicated
- Clinical signs: not reported
- Body weight gain: no statistically significant differences between treated and control animals
- Food consumption: slightly increased (significant) in males at 5 and 10% natural glycerin
- Haematology: no treatment related effects
- Urinalysis: albumin: no significant treatment related effects (92% incidence in females at 20% natural glycerin compared to 54-64% in controls); glucose, casts, red and white blood cells: no treatment related effects
- Organ weights: incidental increases and decreases were reported without apparent relationship to treatment
- Gross pathology: no lesions related to treatment.
- Histopathology: Incidental bronchiectasis, pneumonia, pulmonary abscesses, taenia infestation of the liver, hydronephosis and pyelonephritis (total 27 rats were affected).
- Other: liver glycogen and lipid did not significantly differ between 0 and 20% glycerin (liver glycogen natural glycerin 4.2-4.3% and synthetic glycerin 3.7-4.2%)

Effect levels

1

Dose descriptor:

NOEL

Remarks:

1 Year

Effect level:

10 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Remarks on result:

other: 20% in diet for 1 year

2

Dose descriptor:

NOEL

Remarks:

2 year

Effect level:

5 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Remarks on result:

other: 10% in diet for 2 years

Target system / organ toxicity

Critical effects observed:

no

Applicant's summary and conclusion

Conclusions:

The study authors concluded that the administration of 10% (equivalent to 5,000 mg/kg bw/day) of SS1 via the diet for two years did not induce any adverse effects in rats. Based on the results, a no observed effect level (NOEL) was determined to be 10,000 mg/kg bw/day (20% in diet) for 1 year.