Lead Carbonate Intermediate

Genetic toxicity: in vivo

Administrative data

Endpoint:

in vivo mammalian germ cell study: cytogenicity / chromosome aberration

Remarks:

Type of genotoxicity: chromosome aberration

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Hypothesis for read-across: Lead (Pb) is the main component of the target substance, and considered the major driver for adverse effects based on its properties and relative quantity in the substance. For toxicity assessment the bioavailable part is relevant. From the target substance itself, Pb is poorly soluble. For read-across purpose, however, data from more soluble compounds was used. Therefore, it is considered that the used read-across data gives worst-case estimate on the adverse effects.

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Male mice (n=12) were exposed to lead chloride in drinking water (1.33 g/L) for six weeks. Half of the mice were injected with cyclophosphamide (120 mg/kg) one week prior to mating with untreated females. On day 14 of gestation, the uteri of dams were examined for evidence of dominant lethal mutations by counting live fetuses, early implantation losses (resporption sites), and late implantation losses.

GLP compliance:

not specified

Type of assay:

rodent dominant lethal assay

Test animals

Species:

mouse

Strain:

NMRI

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Bomholt Gaard Breeding and Research Centre Ltd. (Ry, Denmark).
- Age at study initiation: 9 weeks.
- Assigned to test groups randomly: yes.
- Fasting period before study: none.
- Housing: males housed invdividually, females housed in groups of four.
- Diet: ad libitum, laboratory chow (EWOS, R34).
- Water: ad libitum, tap water.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23-25
- Humidity (%): >55
- Photoperiod: 12 hours light/12 hours dark

Administration / exposure

Route of administration:

oral: drinking water

Vehicle:

Tap water.

Details on exposure:

1.33 g/L lead chloride was provided in the drinking water for six weeks. Controls received untreated tap water.

Duration of treatment / exposure:

6 weeks.

Frequency of treatment:

Animals drank treated water ad libitum.

Doses / concentrations

Remarks:

Doses / Concentrations:
1.33 g/L
Basis:
nominal conc.

No. of animals per sex per dose:

6 males per group (lead-treated or lead + cyclophosphamide)

Control animals:

yes, concurrent vehicle

Positive control(s):

Cyclophosphamide.

Examinations

Tissues and cell types examined:

Blood from male rats was analyzed for lead concentration. Ovaries and uteri were excised and uteri were scored for evidence of dominant lethal mutations.

Statistics:

Treatment effects on dominant lethal mutations were evaluated by nonparametric tests (Wilcoxon rank sum test, Kruskall-Wallis test). Dichotomous outcomes were analyzed for treatment effects by table analysis and unconditional logistic regression analysis with exact tests for significance and computation of estimated odds ratios and 95% confidence limits. A significance level of less than 0.05 (two-tailed) was taken as criterion of a positive result.

Results and discussion

Test results

Sex:

male

Genotoxicity:

negative

Toxicity:

not examined

Vehicle controls validity:

valid

Negative controls validity:

not examined

Positive controls validity:

valid

Any other information on results incl. tables

There was no effect on the number of implantations or resorptions reported for the lead chloride treatment group compared to the vehicle control group. In the lead chloride + cyclophosphamide treatment group, as well as the cyclophosphamide-treated positive controls, the number of implantations decreased and the number of readsorptions and mean mortality both increased compared to the vehicle control group. Although signs of fetotoxicity were evident, the significance of the negative response is equivocal due to the relatively low blood lead level (25 mcg/dL) achieved by the single administered dose of lead.

Applicant's summary and conclusion

Conclusions:

Interpretation of results: negative.
The authors concluded that lead chloride did not influence the mutagenicity of cyclophosphamide in the dominant lethal test.

Executive summary:

Male mice (n=12) were exposed to lead chloride in drinking water (1.33 g/L) for six weeks. Half of the mice were injected with cyclophosphamide (120 mg/kg) one week prior to mating with untreated females. On day 14 of gestation, the uteri of dams were examined for evidence of dominant lethal mutations by counting live fetuses, early implantation losses (resporption sites), and late implantation losses. There was no effect on the number of implantations or resorptions reported for the lead chloride treatment group compared to the vehicle control group. In the lead chloride + cyclophosphamide treatment group, as well as the cyclophosphamide-treated positive controls, the number of implantations decreased and the number of readsorptions and mean mortality both increased compared to the vehicle control group. The authors concluded that lead chloride did not influence the mutagenicity of cyclophosphamide in the dominant lethal test.