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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
fertility, other
Remarks:
other: 13-wk inhalation toxicity study
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
no information
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: reliable without restrictions. Generally in compliance with OECD TG 413 and EC TM B26 Dir. 87/302/EEC 30/05/88.
Cross-reference
Reason / purpose for cross-reference:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1995

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
other: OECD TG 413 and EC TM B26 Dir. 87/302/EEC 30/05/88
Deviations:
not specified
GLP compliance:
yes
Remarks:
in compliance with United States FDA GLP regulations (21 CFR, Part 58)
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Cadmium oxide
EC Number:
215-146-2
EC Name:
Cadmium oxide
Cas Number:
1306-19-0
Molecular formula:
CdO
IUPAC Name:
oxocadmium
Details on test material:
Name of test material: CdO
Source: Lot 110383 from Johnson Matthey Aesar Group (Seabrook, NH).
Purity: 99.4 %
Impurities : 400 ppm chlorine, all other impurities detected totaled less than 263 ppm

Test animals

Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Simonsen Laboratories (Gilroy, CA)
- Age at study initiation: 6 wk
- Weight at study initiation: no information
- Housing: in individual cages within the exposure chambers
- Diet : NIH-07 Open Formula Diet (Zeigler Brothers, Inc., Gardners, PA) in pellet form
- Water : City water (Richland, WA), ad libitum
- Acclimation period: 12-15 d


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

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure (if applicable):
whole body
Mass median aerodynamic diameter (MMAD):
>= 1.1 - <= 1.6 µm
Vehicle:
unchanged (no vehicle)
Details on exposure:
Particle size: MMAD = 1.1 - 1.6 µm, GSD : 1.7-1.8
Details on mating procedure:
None
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Concentrations  were monitored automatically (measured concentrations within 85% of nominal conc)
Duration of treatment / exposure:
13 wk
Frequency of treatment:
6h/d; 5 d/w
Details on study schedule:
None
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/m³ air
Dose / conc.:
0.025 mg/m³ air
Dose / conc.:
0.05 mg/m³ air
Dose / conc.:
0.1 mg/m³ air
Dose / conc.:
0.25 mg/m³ air
Dose / conc.:
1 mg/m³ air
No. of animals per sex per dose:
10 males and 10 females per dose and control
Control animals:
yes
Details on study design:
Post exposure period: no

Satellite groups and reasons they were added : additional 10 males & 10 female mice used for hematology and clinical chemistry evaluations and additional 20 males rats (0, 0.1, 0.25 and 1 mg/m3) used for Cd tissue distribution
Positive control:
None

Examinations

Parental animals: Observations and examinations:
- Clinical observations performed and frequency: animals were observed twice daily for mortality and signs of toxicity and were weighed on Day 1, weekly thereafter and on the day of necropsy.

Supplemental evaluations :
- clinical pathology (hematology, clinical chemistry, urine analysis),
- Cd tissue distribution (blood, lung and kidney samples collected on Days 3, 9, 30, end of study), for details rep dose tox
Oestrous cyclicity (parental animals):
Females were evaluated for necropsy body weight, estrous cycle length and the percent of cycle spent in the various stages.
Sperm parameters (parental animals):
Male mice were evaluated for necropsy body and reproductive tissue weights, spermatozoal data and spermatogenesis. Sperm motility evaluations were performed on base study animals in the 0, 0.025, 0.1 and 1 mg/m3 groups at the end of study.
Litter observations:
Not examined
Postmortem examinations (parental animals):
- Autopsy: complete necropsies were performed on all base-study animals. The following organs were weighed : heart, right kidney, liver, lungs, spleen, right testis and thymus. Histopathologic evaluations were performed on all animals in the 0 and 1 mg/m3 groups. The following organs
were examined in the lower exposure groups : larynx, lungs, lymph nodes and nasal cavity.
Postmortem examinations (offspring):
Not examined
Statistics:
Organ and body weight data, which have approximately normal distributions, were analyzed with the parametric multiple comparison procedures of
Williams (1971, 1972) and Dunnett (1955). Clinical pathology, spermatid, epididymal spermatozoa data and Cd tissue concentrations were analyzed
with the nonparametric multiple comparisosn methods of Shirley (1977) and Dunn (1964). Jonckheere's test (Jonckheere 1954) was used to assess
the significance of dose-response trends and to determine whether a trend-sensitive test (Williams' or Shirleys' test) was more appropriate for
pairwise comparisons than a test that does not assume a monotonic dose-response (Dunnett's or Dunn's test). Trend-sensitive tests were used when Jonckheere's test was significant at a P-value less than 0.1. For indirect systolic blood pressure measurements, a one-way analysis of variance test
(Weter et al, 1985) was used to assess dose-response and time-response trends. For analysis of vaginal cytology data, because the data are
proportions (the proportion of the observation period that an animal was in a given estrous stage), an arcsine transformation was used to bring the
data into closer conformance with normality assumptions. Treatment effects were investigated by applying a multivariate analysis of variance
(Morrison, 1976) to the transformed data to test for simultaneous equality of measurements across dose levels.
Reproductive indices:
No information
Offspring viability indices:
Not examined

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
One male mouse died during week 13 of the study.
Mortality:
mortality observed, non-treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food efficiency:
not specified
Ophthalmological findings:
not specified
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Other effects:
not specified

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
not specified

Details on results (P0)

TOXIC RESPONSE/EFFECTS BY DOSE LEVEL: 

For detailed data on toxicity : see 7.5.2. Repeated dose toxicity: inhalation

Reproductive toxicity : 
sperm motility and vaginal evaluations were performed on base-study mice exposed to 0, 0.025, 0.1 or 1 mg/m3 CdO for 13 wk. No significant differences occurred in males or females.

Effect levels (P0)

Dose descriptor:
NOAEL
Remarks:
reproductive toxicity
Effect level:
1 mg/m³ air
Sex:
male/female
Basis for effect level:
other: No treatment related effects on reproductive system

Results: F1 generation

General toxicity (F1)

Clinical signs:
not examined
Mortality / viability:
not examined
Body weight and weight changes:
not examined
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Histopathological findings:
not examined

Details on results (F1)

Not applicable

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Sex:
male/female
Remarks on result:
not measured/tested

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

None

Applicant's summary and conclusion

Conclusions:
Reproductive system toxicity was not observed at any exposure level in mice.
Executive summary:

A study was conducted to determine the effects of sub-chronic exposure in lungs and reproductive system of B6C3F1 mice.

Groups of mice were exposed to the test material at 0, 0.025, 0.05, 0.1, 0.25 or 1 mg/m3 for 6 h/d, 5 d/wk for 13 wk. Animals were observed twice daily for mortality and signs of toxicity and were weighted on day 1, weekly thereafter and on the day of necropsy. Clinical observations were recorded daily. Following organs were weighed at necropsy: heart, right kidney, liver, lungs, spleen, right testis and thymus.

Available data shows treatment-related respiratory tract lesions in the lungs, nose and larynx of B6C3F1 mice exposed by inhalation to CdO for 13 wk. However, reproductive toxicity was not observed at any exposure level.