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Toxicological information

Genetic toxicity: in vivo

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Administrative data

Endpoint:
in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus
Remarks:
Type of genotoxicity: chromosome aberration
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Guideline study (GLP)
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:
1989
Report Date:
1989

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
Version / remarks:
1983
Deviations:
no
GLP compliance:
yes
Type of assay:
micronucleus assay

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material: Sorbic acid
- Physical state: solid, white powder
- Analytical purity: 99 %
- Stability under test conditions: The test substance was considered to be stable for the duration of the study.
- Storage condition of test material: dark at 4 °C

Test animals

Species:
mouse
Strain:
NMRI
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Hoechst AG, Frankfurt, Germany
- Strain: NMRKf (SPF71)
- Age at study initiation: 7 weeks
- Weight at study initiation: males: 27–36 g, females: 21–29 g
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2 °C
- Humidity (%): 55 ± 10 %
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
- Vehicle(s)/solvent(s) used: sesame oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Rate of preparation of diet (frequency): freshly prepared every day
Duration of treatment / exposure:
72 hours
Frequency of treatment:
single application
Post exposure period:
24, 48 or 72 hours
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 500, 1500, 5000 mg/kg bw
Basis:
actual ingested
Criteria for selection of MTD: a preliminary study reported 5000 mg/kg bw as the highest tolerable dose
No. of animals per sex per dose:
5 males and 5 females
Control animals:
yes, concurrent vehicle
Positive control(s):
Positive control: 50 mg/kg bw Cyclophosphamide (Endoxan ®), concentration: 50 mg/kg bw.

Examinations

Tissues and cell types examined:
Bone marrow:
- Number of animals: 5 per sex at each of 3 time points
- Number of cells: 1000
- Time points: 24, 48 and 72 hours after treatment
- Type of cells: Erythrocytes in bone marrow
- Parameters: Polychromatic/normo-chromatic erythrocyte ratio, occurrence of micronuclei
Evaluation criteria:
Criteria for evaluating results: number of cells with micronuclei, PCE:NCE ratio
Statistics:
Statistical methods: Wilcoxon

Results and discussion

Test results
Sex:
male/female
Genotoxicity:
negative
Toxicity:
not specified
Vehicle controls validity:
not specified
Negative controls validity:
not specified
Positive controls validity:
not specified
Additional information on results:
RESULTS OF DEFINITIVE STUDY
- No mortalities were observed, and the only clinical sign was uncoordinated gait, which had recided 24 hours after application. 
- There were no substance-related findings upon necropsy, or effects on body weight.
- Ratio of PCE/NCE (for Micronucleus assay): The PCE/NCE ratio was unaffected.
- Statistical evaluation: The test yielded no statistically significant increase of micronucleated polychromatic erythrocytes and normochromatic erythrocytes with micronuclei.

Any other information on results incl. tables

Table1: In-vivomicronucleus test of bone marrow cells from male mice receiving Sorbic acid, sesame oil (vehicle control) or Cyclophosphamide (positive control).

 

Positive control

Vehicle control

Low dose (500 mg/kg)

Mid dose (1500 mg/kg)

High dose (5000 mg/kg)

Number of cells evaluated

5000

5000

5000

5000

5000

Sampling time [h]

24

24

48

72

24

48

72

24

48

72

24

48

72

No. of erythrocytes

 

 

 

 

 

 

 

 

 

 

 

 

 

Normo-chromatic with micronuclei

2

1

1

1

2

1

2

1

1

1

1

1

1

Polychromatic with micronuclei

32*

2

1

0

2

2

2

2

2

1

1

1

2

Ratio of erythrocytes

 

 

 

 

 

 

 

 

 

 

 

 

 

Polychromatic/ normo-chromatic

0.97

0.93

0.90

0.94

0.98

0.89

1.02

0.98

0.90

1.12

1.05

0.95

0.99

*) significantly different from control (p < 0.05)

 

 

Table2: In-vivomicronucleus test of bone marrow cells from female mice receiving Sorbic acid, sesame oil (vehicle control) or Cyclophosphamide (positive control).

 

Positive control

Vehicle control

Low dose (500 mg/kg)

Mid dose (1500 mg/kg)

High dose (5000 mg/kg)

Number of cells evaluated

5000

5000

5000

5000

5000

Sampling time [h]

24

24

48

72

24

48

72

24

48

72

24

48

72

No. of erythrocytes

 

 

 

 

 

 

 

 

 

 

 

 

 

Normo-chromatic with micronuclei

1

1

0

1

0

1

1

0

1

0

1

0

0

Polychromatic with micronuclei

21*

1

2

1

1

1

3

1

1

1

2

2

1

Ratio of erythrocytes

 

 

 

 

 

 

 

 

 

 

 

 

 

Polychromatic/ normo-chromatic

0.89

0.99

1.17

1.00

0.94

1.12

1.14

0.94

1.22

1.24

1.13

1.05

1.15

*) significantly different from control (p < 0.05)

 

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): negative
Treatment with Sorbic acid did not cause any increase in the number of micro-nucleated polychromatic erythrocytes and micro-nucleated normo-chromatic erythrocytes at any of the three sampling times at either dose level. Statistically significant increases in the number of polychromatic cells with micronuclei were observed in positive control animals treated with 50 mg/kg bw Cyclophosphamide. Sorbic acid was not genotoxic under the conditions of this test.