Registration Dossier

Toxicological information

Repeated dose toxicity: oral

Currently viewing:

Administrative data

Endpoint:
chronic toxicity: oral
Remarks:
combined repeated dose and carcinogenicity
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: Publication in a peer-reviewed journal, adequate for assessment. Substance tested is a major hepatic metabolite of allyl alcohol.

Data source

Reference
Reference Type:
publication
Title:
Two-year toxicity and carcinogenicity study of acrolein in rats.
Author:
Parent, R.A., Caravello, H.E., Long, J.E.
Year:
1992
Bibliographic source:
Journal of Applied Toxicology 12: 131-139

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Reference substance name:
Acrolein
IUPAC Name:
Acrolein
Constituent 2
Reference substance name:
Acrylaldehyde
EC Number:
203-453-4
EC Name:
Acrylaldehyde
Cas Number:
107-02-8
IUPAC Name:
acrylaldehyde
Details on test material:
Two samples were supplied by Baker Performance Chemicals, Houston, Texas.
Purity: 94.9 - 98.5% (stabilised with 0.25 - 0.31% hydroquinone).
Acrolein is a known, major liver metabolite of allyl alcohol

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Portage, Michigan
- Age at study initiation: approximately 6 weeks old
- Housing: Stainless steel cages
- Diet (e.g. ad libitum): Agway R-M-H 3200 certified meal ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Air changes (per hr): 160
- Photoperiod (hrs dark / hrs light): 12 hour light/12 hour dark

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
Oral gavage was carried out using a stainless-steel ball-tipped needle. The dosing volume used was 10 ml/kg, and the daily dosing was carried out under a hood.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Dosing solutions were analysed weekly using gas chromatography or (late in the study period) by UV absorption chromatography
Duration of treatment / exposure:
12 months (chronic toxicity study performed concurrently with Year 1 of a 2-year carcinogenicity study)
Frequency of treatment:
Daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 0.05, 0.5 and 2.5 mg/kg/day
Basis:
actual ingested
No. of animals per sex per dose:
For the chronic toxicity study 10 rats of each sex group were used (+ extra satellite animals, 10/sex/group).
Control animals:
yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: performed daily for first 4 weeks and weekly thereafter

BODY WEIGHT: Yes
- Time schedule for examinations: Recorded weekly for the first 14 weeks and then every 4 weeks after.

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

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Prior to initiation of the study and prior to scheduled sacrifice

HAEMATOLOGY: Yes
- Time schedule for collection of blood: prior to initiation of study (15 sentinel rats/sex), then at 3, 6 and 12 months (10/sex/group satellite animals)
- Parameters checked: haemoglobin, haemocrit, red blood cell count, white blood cell count, white blood cell differential count, platelet count, mean corpuscular volume, mean corpuscular haemoglobin and mean corpuscular haemoglobin concentration.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: prior to initiation of study (15 sentinel rats/sex), then at 3, 6 and 12 months (10/sex/group satellite animals)
- Parameters checked: total protein, albumin, globulin, A/G ratio, serum glutamic pyruvic transaminase, serum glutamic oxaloacetic acid transanimase, serum alkaline phosphatase, gamma glutamyl transpeptidase, creatine phosphokinase, blood urea nitrogen, fasting blood sugar, bilirubin, creatine, phosphorous, calcium, sodium, potassium, chloride and cholesterol.

URINALYSIS: Yes
- Time schedule for collection of urine: Collected from satellite groups (10/sex/group) at 3, 6, and 12 months
- Parameters checked: colour, appearance, specific gravity, pH, protein, glucose, ketones, urobilinogen, bilirubin, occult blood and volume.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Statistics:
Body weights, feed consumption, haematological parameters, clinical chemistry and organ weights were analysed using one-way analysis of various. If this analysis suggested a difference, then Dunnett's t-test was used to determine which of the means in the treated groups were significantly different to the control group.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Significant reduction of survival in the highest-dose group (a marginal significant reduction in survival in the mid-dose group was also observed).
Mortality:
mortality observed, treatment-related
Description (incidence):
Significant reduction of survival in the highest-dose group (a marginal significant reduction in survival in the mid-dose group was also 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:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Significant reduction in serum creatinine phosphokinase levels in all dosed groups.
Urinalysis findings:
no effects observed
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
- Statistical analysis of the survival curves reveal that survival was significantly reduced in the high-dose group. In addition, the mid-dose group also displayed a moderately significant reduction in survival.

BODY WEIGHT AND WEIGHT GAIN
- No test substance related effects

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
- No test substance related effects

OPHTHALMOSCOPIC EXAMINATION
- No test substance relate effects

HAEMATOLOGY
- No test substance related effects

CLINICAL CHEMISTRY
- Serum creatinine phosphokinase levels were significantly reduced in all treated groups, except males at 12 months

URINALYSIS
- No test substance related effects

ORGAN WEIGHTS
- No test substance related effects

GROSS PATHOLOGY
- No test substance related effects

HISTOPATHOLOGY: NON-NEOPLASTIC
- No test substance related effects

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
- No test substance related effects

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
0.05 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
mortality
Dose descriptor:
LOAEL
Effect level:
0.5 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
mortality

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Under the conditions of this study the NOAEL was determined to be 0.05 mg/kg/day and the LOAEL was determined as 0.5 mg/kg/day (both based on survival rates).
Executive summary:

In a 1-year repeat-dose rat study, acrolein was administered to 10 rats (Sprague-Dawley)/sex/dose by gavage at dose levels of 0, 0.05, 0.5 and 2.5 mg/kg/day for 12 months. Analysis of the survival curves reveal that survival was significantly reduced in the high-dose group. In addition, the mid-dose group also displayed a moderately significant reduction in survival. Clinical chemistry revealed a significant reduction in serum creatinine phosphokinase levels in all treated groups, but the significance of this is unclear.

 

In this study the NOAEL was determined to be 0.05 mg/kg/day and the LOAEL was determined as 0.5 mg/kg/day (both based on survival rates).