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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:
experimental study
Adequacy of study:
key study
Study period:
1981
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Rationale: GLP Guideline study

Data source

Reference
Reference Type:
other: Unpublished data
Title:
Unnamed
Year:
1981
Report date:
1981

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
GLP compliance:
yes
Type of assay:
micronucleus assay

Test material

Constituent 1
Chemical structure
Reference substance name:
Phosphorous acid, diphenyl isodecyl ester
Molecular formula:
C22H31O3P
IUPAC Name:
Phosphorous acid, diphenyl isodecyl ester
Constituent 2
Chemical structure
Reference substance name:
Triphenyl phosphite
EC Number:
202-908-4
EC Name:
Triphenyl phosphite
Cas Number:
101-02-0
Molecular formula:
C18H15O3P
IUPAC Name:
triphenyl phosphite
Constituent 3
Chemical structure
Reference substance name:
Diisodecyl phenyl phosphite
EC Number:
247-098-3
EC Name:
Diisodecyl phenyl phosphite
Cas Number:
25550-98-5
Molecular formula:
C26H47O3P
IUPAC Name:
Reaction products of triphenyl phosphite and isodecanol (1:2)
Constituent 4
Reference substance name:
Grouped, low level constituents (1) - see description
Molecular formula:
C21H29O3P and C23H33O3P
IUPAC Name:
Grouped, low level constituents (1) - see description
Constituent 5
Reference substance name:
Grouped, low level constituents (2) - see description
Molecular formula:
N/A
IUPAC Name:
Grouped, low level constituents (2) - see description
Constituent 6
Chemical structure
Reference substance name:
Triisodecyl phosphite
EC Number:
246-998-3
EC Name:
Triisodecyl phosphite
Cas Number:
25448-25-3
Molecular formula:
C30H63O3P
IUPAC Name:
Phosphorus acid, triisodecyl ester
Constituent 7
Reference substance name:
Grouped, low level constituents (3) - see description
Molecular formula:
N/A
IUPAC Name:
Grouped, low level constituents (3) - see description
Test material form:
liquid

Test animals

Species:
mouse
Strain:
CD-1
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 18 and 21 grams
- Fasting period before study: The animals were fasted overnight prior to dosing.
- Housing: group-housed in plastic caging maintained in a controlled environment
- Diet: ad libitum
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22oC
- Air changes (per hr): 30 air changes/hour
- Photoperiod (hrs dark / hrs light): 12-hour light/dark cycle

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
- Vehicle(s)/solvent(s) used: corn oil;
Duration of treatment / exposure:
24 hours
Frequency of treatment:
Two oral gavage doses administered over 24 hours
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 2250, 4500, and 9000 mg/kg (total dose)
Basis:
actual ingested
No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle
Positive control(s):
The concurrent positive control group was given an intraperitoneal injection of mitomycin C at a concentration of 0.4 mg/mL.

Examinations

Tissues and cell types examined:
A direct bone marrow smear from each femur was placed onto a slide and prepared for microscopic analysis to determine the incidence of micronucleated cells per 1000 polychromatic erythrocytes per animal and the ratio of normochromatic to polychromatic erythrocytes (PCE/NCE ratio).
Evaluation criteria:
A material was considered to show evidence of mutagenic activity if it produced a statistically significant increase (p>0.05) using Wilcoxin’s ‘sum or ranks test’) in micronucleated cells compared to the concurrent negative control group values. If the erythrocyte ratios at the top dose were not significantly different from the concurrent negative control values, then the ratios of the two lower doses were not scored.

Results and discussion

Test results
Sex:
male/female
Genotoxicity:
negative
Toxicity:
yes
Positive controls validity:
valid
Additional information on results:
After administration of DPDP at 9000 mg/kg, signs of toxicity (hypopnea and lethargy) were observed 30 minutes after dosing in both sexes. The symptoms decreased over the next few hours and were not observed 3 hours after administration. A single female died within 7 hours after this highest dose. Macroscopic examination at post mortem did not reveal abnormalities in any animal. No toxic reactions were observed in the corn oil negative control group or the 2250 and 4500 mg/kg group. After administration of mitomycin C, no toxic reactions or mortality were observed.

Any other information on results incl. tables

DPDP Mouse Micronucleus Results

 

Test Group

Micronucleated Cells per 1000 PCEs/animal

mean (range)

PCE/NCE Ratiomean (range)

Negative Control

0.4 (0–2)

2.69 (1.19–5.29)

Mitomycin C

32.2 (9-96)

9.09 (14.73)

2250 g/kg DPDP

0.4 (0–1)

*

4500 g/kg DPDP

1.1 (0-3)

*

9000 g/kg DPDP

0.8 (0–2)

2.32 (1.36–3.27)

Historical Control

0.79 (0.1-1.8)

0 - 5

 

*Criteria for evaluating results: A material was considered to show evidence of mutagenic activity if it produced a statistically significant increase (p>0.05 using Wilcoxin’s ‘sum or ranks test’) in micronucleated cells compared to the concurrent negative control group values. If the erythrocyte ratios at the top dose were not significantly different from the concurrent negative control values then the ratios of the two lower doses were not scored.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): negative
Based on the conditions of this study, it was concluded that the test article, DPDP, was considered to be negative in both sexes for mutagenic potential and bone marrow toxicity when administered orally.
Executive summary:

Based on the conditions of this study, it was concluded that the test article, DPDP, was considered to be negative in both sexes for mutagenic potential and bone marrow toxicity when administered orally.