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Toxicological information

Genetic toxicity: in vivo

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Administrative data

Endpoint:
in vivo mammalian somatic cell study: cytogenicity / bone marrow chromosome aberration
Remarks:
Type of genotoxicity: chromosome aberration
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: see 'Remark'
Remarks:
The study was conducted according to a protocol that is similar to an appropriate OECD test guideline, with acceptable restrictions. The restrictions were that only 50 cells per animal were scored for aberrations. It was not compliant with GLP. Read across to the registered substance is considered scientifically justified.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1975
Report Date:
1975

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 475 (Mammalian Bone Marrow Chromosome Aberration Test)
Deviations:
yes
Remarks:
only 50 cells analysed per animal
GLP compliance:
no
Type of assay:
chromosome aberration assay

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Compound FDA 71-54, citric acid, granular
- Substance type: monoconstituent substance
- Physical state: solid

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Flow Laboratories random-bred, closed colony
- Age at study initiation: 10-12 weeks
- Weight at study initiation: 325-375 g
- Assigned to test groups randomly: yes
- Fasting period before study:
- Housing: 1-5 per cage
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 4-11 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): no information
- Humidity (%): no information
- Air changes (per hr): no information
- Photoperiod (hrs dark / hrs light): no information

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
- Vehicle(s)/solvent(s) used: physiol. saline
- Justification for choice of solvent/vehicle: none given
- Concentration of test material in vehicle: no information
- Amount of vehicle (if gavage or dermal): no information
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: no information
Duration of treatment / exposure:
1 and 5 days
Frequency of treatment:
single dose and daily for 5 days
Post exposure period:
Subacute study (five doses): 4 hours after final compound administration, 4 mg/kg Colcemid was given intraperitoneally. Animals were sacrificed 2 hours later.
Acute study (single dose): Animals were sacrificed 6, 24 and 48 hours after administration
Doses / concentrations
Remarks:
Doses / Concentrations:
test 1: 1.2, 12.0, 120 mg/kg bw; test 2; 300, 500, 3000, 3500 mg/kg bw
Basis:

No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle
Positive control(s):
- triethylenemelamine
- Justification for choice of positive control(s): none given in report
- Route of administration: ip injection
- Doses / concentrations: 0.3 mg/kg bw

Examinations

Tissues and cell types examined:
Bone marrow
Details of tissue and slide preparation:
CRITERIA FOR DOSE SELECTION: based on toxicity test data

DETAILS OF SLIDE PREPARATION: duplicate slides were prepared with fixed bone marrow cells, and stained with Giesma

METHOD OF ANALYSIS: The slides were examined using optical microscopes and the chromosomes were counted. Diploid cells were analysed for chromatid and chromosome gaps and breaks; reunions, > 10 aberrations, polyploidy, pulverisation and any other aberrations.

50 cells were scored per animal. Mitotic indices were determined from 500 cells per animal.

Results and discussion

Test results
Sex:
male
Genotoxicity:
negative
Toxicity:
not examined
Vehicle controls validity:
valid
Negative controls validity:
not applicable
Positive controls validity:
valid
Additional information on results:
RESULTS OF RANGE-FINDING STUDY
- Dose range: 100, 250, 500, 1000, 2000, 3000 mg/kg
- Solubility: not reported
- Clinical signs of toxicity in test animals: none reported
- Evidence of cytotoxicity in tissue analyzed: not reported
- Rationale for exposure: based on LD 50

RESULTS OF DEFINITIVE STUDY
- Types of structural aberrations for significant dose levels (for Cytogenetic or SCE assay): none
- Appropriateness of dose levels and route: appropriate dose and route
- Statistical evaluation: no statistically significant effects

Any other information on results incl. tables

Table 2 Test 1 Acute study

Compound

Dose (mg/kg bw)

Time

Mitotic index

% cells with aberrations

Negative control

saline

6

6

0

24

12

0

48

12

0

Low level

1.20

6

5

0.4

24

9

0

78

7

0

Intermediate level

12.0

6

6

0.4

24

10

0

48

6

0

LD5

120

6

4

0

24

8

0.9

48

7

0

Positive control

0.3

48

5

30

 

Table 3 Test 1 Subacute study

Compound

Dose (mg/kg bw)

Mitotic index

% cells with aberrations

Negative control

saline

5

0

Low level

1.20

4

0

Intermediate level

12.0

5

0

LD5

120

4

0

 

Table 4 Test 2 Acute study

Compound

Dose (mg/kg bw)

Time

Mitotic index

% cells with aberrations

Negative control

saline

6

3.67

0

24

2.86

3

48

5.16

5

Intermediate level

500

6

3.45

0

24

3.20

1

48

3.90

1

High level

3500

6

4.47

29

24

3.47

0

48

5.73

0

Positive control

0.3

48

1.06

101

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): negative
Citric acid has been tested according to a protocol that is similar to OECD 475. No treatment-related increase in the number of cells with aberrations was observed. Vehicle and positive controls gave expected results. It is concluded that the test substance is negative for the induction of chromosome aberrations in vivo under the conditions of the test.