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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:
experimental study
Adequacy of study:
key study
Study period:
29 Apr 1986 - 05 Aug 1986
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study conducted in compliance with GLP regulations

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1986
Report Date:
1986
Reference Type:
publication
Title:
Genetic Toxicology of Acrylic Acid.
Author:
McCarthy KL et al.
Year:
1992
Bibliographic source:
Fd. Chem. Toxic. 30: 505-515
Reference Type:
publication
Title:
COMPARISON OF IN VIVO AND IN VITRO CYTOGENETIC ASSAY RESULTS ON ACRYLIC ACID.
Author:
McCarthy KL et al.
Year:
1988
Bibliographic source:
Abstr. of the 10th Annual Meeting of the Environmental Mutagen Society, Env. Mol. Mutag. 11 (Suppl. 11), Abstr. No. 163, 67
Reference Type:
study report
Title:
Unnamed
Year:
1986
Report Date:
1986

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 475 (Mammalian Bone Marrow Chromosome Aberration Test)
Principles of method if other than guideline:
An in vivo bone marrow chromosomal aberration assay was conducted with rats. Chromosome aberrations were analyzed (5 animals per sex, 50 metaphases per animal) at 6, 12, and 24 h after oral gavage doses of 100, 333 or 1000 mg/kg bw.
GLP compliance:
yes
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): CJP-60
- Source: Hoechst Celanese Company (according to McCarthy et al., 1992)
- Analytical purity: >99.8 %

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Raleigh, North Carolina
- Age at study initiation: 6-7 weeks of age
- Weight at study initiation: 142-177 g (males), 132-164 g (females)
- Housing: singly
- Diet: ad libitum
- Water: ad libitum
- Assigned to test groups randomly: yes
- Acclimation period: at least 7 days


ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12 hrs/12 hrs

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
- Vehicle(s)/solvent(s) used: water
- Concentration of test material in vehicle:
- Amount of vehicle (if gavage or dermal):
Duration of treatment / exposure:
one treatment by gavage
Frequency of treatment:
once
Post exposure period:
At the time specified following dosing in the acute dosing regime, the rats received an intraperitoneal injection of colchicine (1.0 mg/kg bw) based on terminal weight to arrest mitosis. 2-4 hrs later the animals were sacrificed.
Doses / concentrations
Remarks:
Doses / Concentrations:
100, 333, and 1000 mg/kg bw (in a total volume of 3 mL/kg bw)
Basis:
actual ingested
No. of animals per sex per dose:
5 animals/sex/dose/sacrifice time
Control animals:
yes, concurrent vehicle
Positive control(s):
cyclophosphamide
- Route of administration: gavage
- Doses / concentrations: 10 mg/mL

Examinations

Tissues and cell types examined:
bone marrow cells from the femur
Details of tissue and slide preparation:
CRITERIA FOR DOSE SELECTION:
Dose levels for the in vivo cytogenetic assay were selected on the basis of body weight changes, gross observations, and mortality in a preliminary toxicity test. The results of the preliminary toxicity test led to the selection of 1000 mg/kg body weight as the maximum dose for the acute assay. Also a preliminary assessment of bone marrow cell cycle kinetics at 900 mg/kg bw indicated no significant cell cycle delay at 21 hr after dosing.

TREATMENT AND SAMPLING TIMES ( in addition to information in specific fields): at 6, 12, and 24 hours after dose administration


DETAILS OF SLIDE PREPARATION: At least three slides from each animal were prepared. Stain: Giemsa


METHOD OF ANALYSIS: 50 metaphase spreads for each animal were scored. The mitotic index for each animal was determined.
Each metaphase figure was scored for the following items:
1. Number of chromosomes in each metaphase figure.
2. Gaps - Achromatic region in chromatid no greater than the width of the chromatid.
3. Chromatid breaks - Achromatic region in the chromatid greater than the wigth of the chromatid or where the broken piece is misaligned with the rest of the arm.
4. Chromosome breaks - Achromatic region in both chromatids at the same locus with marked displacement of both distal fragments.
5. Fragments - Chromatid(s) not containing a centromere. May be seen in association or not in association with a parent chromatid.
6. Exchange figure - Chromatid interchange involving two or more chromosomes, with either symmetrical or asymmetrical distortion of the usual chromatid pattern.
7. Dicentric - Chromosome with two centromeres.
8. Ring - Chromosome whose ends have joined to form a double or single circle, with or without a centromere.
9. Polyploid - Increase in chromosome number in excess of the diploid and in multiple of the haploid number.
10. Pulverization - Extreme fragmentation of the chromatid material.
11. Severely damaged cell - Cell with ten or more abberations of any type or with pulverization.
Evaluation criteria:
The test article is considered to induce a positive response when the number of aberrations per cell is significantly increased (p <= 0.05, Student's t-test) relative to the vehicle control. A significant increase at the high dose only with no dose-response also is considered positive. A significant increase at one dose other than the high dose with no dose-response is considered equivocal.
Statistics:
The t-test was used to compare pairwise the number of aberrations per cell of each treated group with that of the vehicle control. Each comparison was considered to be between two independent, random samples of unequal variance and a significant increase in the treatment mean relative to the vehicle control (one-sided) was sought.

Results and discussion

Test results
Sex:
male/female
Genotoxicity:
negative
Toxicity:
yes
Vehicle controls validity:
valid
Negative controls validity:
not applicable
Positive controls validity:
valid
Additional information on results:
RESULTS OF RANGE-FINDING STUDY
- Dose range: 0, 700, 900, 1100, and 1300 mg/kg bw (male); 0, 600, 800, 1000, and 1200 mg/kg bw (female)
- Solubility: completely soluble
- Clinical signs of toxicity in test animals:
One female rat in the 1200 mg/kg bw dose group and one male rat in the 900 mg/kg bw group were found dead approximately 72 hours following dose administration. A reduction in body weight gain was observed in all test article treated rats 24 hours after dose administration and persisted up to 72 hours in male rats that received 1200 and 1000 mg/kg bw. Clinical signs of toxicity observed included lethargy, irregular breathing (including wheezing and sneezing), lacrimation, crusty eyes, excessive salivation, and nasal discharge. Based on these results and previous LD50 data, 1000 mg/kg bw was selected as high dose.
- Harvest times: 6, 12, and 24 hours


Any other information on results incl. tables

Mortality and Clinical signs:

A moderate reduction in weight gain was observed on day 1 after dose administration in male and female rats that received 1000 mg/kg bw of test substance. Two female animals, one that received 1000 mg/kg bw and one that received 333 mg/kg bw, were found dead prior to their scheduled sacrifice. Irregular breathing and wheezing were noted in three females from the 1000 mg/kg bw group. All other animals appeared normal over the course of the study period.

Chromosomal damage in bone marrow of male rats following acute exposure to acrylic acid:

 

 

Treatment

[mg/kg bw]

Time [hr]

Total no. of cells

Incidence of aberrations1[%]

Total no. of aberrations

Aberrations from severely damaged cells3

Aberrations/cell1

 

evaluated

with aberrations1

 

gaps

breaks2

rearrangements

 

 

Water

6

250

0

0.0

3

0

0

0

0.000±0.000

(3 mL/kg)

12

250

1

0.4

0

1

0

0

0.004±0.009

 

24

250

0

0.0

0

0

0

0

0.000±0.000

 

 

 

 

 

 

 

 

 

 

TS 1000

6

250

1

0.4

1

1

0

0

0.004±0.009

 

12

250

0

0.0

0

0

0

0

0.000±0.000

 

24

250

1

0.4

1

1

0

0

0.004±0.009

 

 

 

 

 

 

 

 

 

 

TS 333

6

250

2

0.8

2

2

0

0

0.008±0.011

 

12

250

1

0.4

1

1

0

0

0.004±0.009

 

24

250

0

0.0

1

0

0

0

0.000±0.000

 

 

 

 

 

 

 

 

 

 

TS 100

6

250

1

0.4

0

1

0

0

0.004±0.009

 

12

250

1

0.4

0

1

0

0

0.004±0.009

 

24

250

0

0.0

0

0

0

0

0.000±0.000

 

 

 

 

 

 

 

 

 

 

CP 30

24

250

98

39.2**

0

172

67

390

2.516±0.599**

1: Excluding gaps.

2: Includes chromatid and chromosome breaks and fragments.

3: Cells having more than 10 aberrations were counted as 10.

* p<0.05; ** p<0.01

CP: cyclophosphamide

Chromosomal damage in bone marrow of female rats following acute exposure to acrylic acid:

 

 

Treatment

[mg/kg bw]

Time [hr]

Total no. of cells

Incidence of aberrations1[%]

Total no. of aberrations

Aberrations from severely damaged cells3

Aberrations/cell1

 

evaluated

with aberrations1

 

gaps

breaks2

rearrangements

 

 

Water

6

250

1

0.4

0

1

0

0

0.004±0.009

(3 mL/kg)

12

250

1

0.4

2

1

0

0

0.004±0.009

 

24

250

0

0.0

0

0

0

0

0.000±0.000

 

 

 

 

 

 

 

 

 

 

TS 1000

6

250

0

0.0

1

0

0

0

0.000±0.000

 

12

250

0

0.0

1

0

0

0

0.000±0.000

 

24

250

0

0.0

0

0

0

0

0.000±0.000

 

 

 

 

 

 

 

 

 

 

TS 333

6

250

1

0.4

1

1

0

0

0.004±0.009

 

12

250

0

0.0

0

0

0

0

0.000±0.000

 

24

250

0

0.0

0

0

0

0

0.000±0.000

 

 

 

 

 

 

 

 

 

 

TS 100

6

250

1

0.4

1

1

0

0

0.004±0.009

 

12

250

1

0.4

0

1

0

0

0.004±0.009

 

24

250

1

0.4

0

1

0

0

0.004±0.009

 

 

 

 

 

 

 

 

 

 

CP 30

24

250

83

32.2**

1

105

72

3104

1.948±0.854**

1: Excluding gaps.

2: Includes chromatid and chromosome breaks and fragments.

3: Cells having pulverization or > 10 aberrations of any type.

4: Includes 10 aberrations contributed by 1 pulverized cell.

* p<0.05; ** p<0.01

CP: cyclophosphamide


 

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): negative