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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Justification for type of information:
The extrapolation from sorbic acid to potassium sorbate or vice versa is considered not to be restricted in any way, since the determinant of potential toxicity is on the "sorbate" anion.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2003
Report Date:
2003

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
Version / remarks:
adopted 1995-07-27
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
Version / remarks:
adopted 1996
Deviations:
no
Principles of method if other than guideline:
The conduct of the study was consistent in all important aspects with method B.7 (96/54/EEC), OECD guideline 407 and OPPTS 870.3050 (U.S. EPA).
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material: Sorbic acid
- Physical state: White crystalline powder


Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Winkelmann GmbH, Borchen, Germany
- Age: Approx. 6 weeks
- Weight at study initiation: Males: 127-155 g (mean: 141 g); females: 117-134 g (mean: 126 g)

Administration / exposure

Route of administration:
oral: feed
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
- Stability and homogeneity of the test compound in the diet was confirmed by HPLC analysis for 7 days.
Duration of treatment / exposure:
28 days
Frequency of treatment:
continuous
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 25 000, 50 000 and 100 000 ppm
Basis:
nominal in diet
No. of animals per sex per dose:
Number of animals per group:
- Group 1: 10 males and 10 females (recovery: 5 males and 5 females)
- Group 2: 5 males and 5 females
- Group 3: 5 males and 5 females
- Group 4: 10  males and 10 females (recovery: 5 males and 5 females)
- Control animals: 10 males and 10 females
Control animals:
yes, plain diet
Details on study design:
Post-exposure period: 15 days recovery

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: clinical signs once daily and mortality twice daily

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

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption: Yes (twice weekly)
- Intake of test substance: Yes (twice weekly)

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule: End of study and after recovery period (only group 1 and  group 4)
- How many animals: All animals
- Parameters: Erythrocyte count, haemoglobin concentration, haematocrit, MCV, MCH,  MCHC, reticulocytes, Heinz Bodies, white blood cell count, neutrophils,  eosinophils, basophils, lymphocytes, monocytes, platelets, coagulation time

CLINICAL CHEMISTRY: Yes
- Time schedule: End of study and after recovery periode (only group 1 and  group 4)
- How many animals: All animals
- Parameters: Sodium, potassium, calcium, chloride, phosphorus, bilirubin total, bilirubin direct, glucose, uric acid, creatinine, urea nitrogen, cholesterol, triglycerides, protein total, albumin, aspartate aminotransferase, alanine aminotransferase, γ-glutamyltranspeptidase, alkaline phosphatase, albumin/globulin ratio, globulin

URINALYSIS: Yes
- Number of animals: All animals
- Time schedule: End of study
- Parameters: Volume, pH value, specific weight, bilirubin, urobilinogen, ketone bodies, glucose, protein, blood

NEUROBEHAVIOURAL EXAMINATION: Yes
- Number of animals: All animals 
- Time schedule for examinations: Day 25
- Parameters:  "Open field" observations, assessment of sensory function, forelimb and hindlimb grip strength.
Sacrifice and pathology:
GROSS PATHOLOGY AND HISTOPATHOLOGY: Yes
- Number of animals: All animals
- Time points: End of study and after recovery period
- Organs: Heart, kidneys, liver, lungs, spleen, thymus, iliac lymph node, mandibular lymph node, trachea, forestomach, glandular stomach, jejunum, colon, cerebrum, cerebellum, medulla oblongata, spinal cord, sciatic nerve, adrenal cortex, adrenal medulla, thyroid gland, parathyroid glands, urinary bladder, ovaries, uterus, prostate, seminal vesicles, testes, epididymides, bone marrow

ORGAN WEIGHTS: Yes
- Number of animals: All animals
- Time points: End of study and after recovery period (only group 1 and group 4)
- Organs: Heart, liver, kidney, spleen, testes, epididymes, adrenals, brain, thymus
Statistics:
Statistics: None

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
Urinalysis findings:
no effects observed
Behaviour (functional 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:
not specified
Description (incidence and severity):
not applicable
Details on results:
- Clinical signs: No effects. An incidental finding: One mid dose group male exhibited slight alopecia between study days 15 and 24. This incident appears not to be treatment related.

- Mortality: No unscheduled deaths throughout the study.

- Body weight gain: Throughout the study the mean body weight increased in all 4 groups. Compared to the control group the overall body weight gain was slightly reduced for high dose males. On study day 4 and 11 the mean body weight of high dose males was also slightly but statistically significantly decreased. This difference was marginal, and was considered the result of massive test compound intake and loss of calories through dietary  reduction. The same happened on study day 36 in high dose recovery  females: The mean body weight was also statistically significantly decreased. This finding was considered as incidental. 

- Food consumption and compound intake: No effects. 

- Ophtalmoscopic examination: Not examined

- Neurotoxicological examinations: "Open field" observations, assessment of sensory function and forelimb and hindlimb grip strength showed no effects. The number of movements was statistically significantly reduced for low dose females. This finding  was considered as incidental. 

- Blood analysis:        
- Haematology: No haematological effects in the final and recovery group occurred throughout the study. For high-, mid-, and low dose group males the mean haemoglobin was statistically significantly decreased compared to the control. This finding was considered as incidental. White cell count picture and the blood coagulation time in all groups at final and after recovery showed no effects. 
- Clinical chemistry: No clinical chemistry effects in the final and recovery group occurred throughout the study. In several serum parameters (chloride, cholesterol, alkaline phosphatase, albumin, albumin/globulin ratio) slight but statistically significant increases could be observed for females compared to the control group. Except for albumin the values were all within the physiological range of the control data and therefore considered not to be toxicologically significant. The high dose males showed a slight but statistically significant increase of alanine aminotransferase; in addition, 1-glutamyltranspeptidase was statistically significantly decreased for high dose males when compared to the control group. This finding was considered not to be toxicologically significant. Slight statistically significant increases of calcium, phosphorus, total protein and alkaline phosphatase activity in high dose males compared to the control. No toxicological significance was shown. 

- Urinalysis: No effects. 

- Sacrifice and pathology:   
- Organ weights: No effects on mean absolute organ weights in the final and recovery group throughout the study. The kidney of the high dose males showed a  statistically significant decrease when compared to the control and the liver of the low dose, middle dose and high dose females and the thymus of the high dose females showed a statistically significant increase when compared to the control. However, as they were all within the physiological  range no functional, clinical and histopathological correlation are shown. The adrenal weight of the high dose males showed statistically significant increases when compared to the control. Although the values  were slightly outside the upper physiological range a histopathological  correlate was not identified for this organ.
- Relative organ weights: At the end of the treatment period, the livers of the low, mid dose and high dose females, and the thymus of the mid and high dose females showed a statistically significant increase when compared to the control. These relative organ weight changes were all within the physiological range of the control data for this rat strain, gender and age. This finding was considered as incidental and not toxicologically significant.
- Gross pathology: No effects at final and recovery necropsy that could be related to administration. Only incidental findings were stated.
- Microscopic pathology: No effects at final and recovery necropsy that could be related to administration. Only incidental findings were stated.

- Other: None

Effect levels

Dose descriptor:
NOAEL
Effect level:
100 000 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality
food consumption and compound intake
haematology
clinical biochemistry
urinalysis
gross pathology

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
No overt clinical signs of toxicity, no mortalities, no-treatment related effects on food consumption and no changes in neurotoxicological measurements were observed during the study. The high dose group showed a reversible trend of slightly lower overall mean body weight gains. This was considered due to palatability problems of feeding a high test compound concentration in the diet (10%). No treatment related changes in haematological, blood serum parameters and urine analysis were seen. No treatment related macroscopic or microscopic changes were identified upon necropsy.
Conclusion:
LO(A)EL: Not applicable
NO(A)EL: 100 000 ppm males and females (male: 9200 mg/kg bw/d and female: 8600 mg/kg bw/d)