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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
toxicity to reproduction
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-referenceopen allclose all
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study

Data source

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

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
other: OECD TG 413 and EC TM B26 Dir. 87/302/EEC 30/05/88
Deviations:
not specified
Principles of method if other than guideline:
A study was conducted to determine the effects of sub-chronic exposure of the test material on the reproductive system in F344 rats.

The test material was administered 6 h/d and 5 d/wk for 13 wk at 0, 0.025, 0.05, 0.1, 0.25 or 1 mg/m3 to groups of 10 rats/sex/dose. 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 with clinical signs being observed daily. Following organs were weighed at necropsy: heart, right kidney, liver, lungs, spleen, right testis and thymus. Additionally, Cd distribution study and influence on blood pressure was evaluated. Additionally, sperm motility and vaginal cytology evaluations were performed on base study animals in the 0, 0.025, 0.1 and 1 mg/m3 groups at the end of study. Male rats were evaluated for necropsy body and reproductive tissue weights, spermatozoal data and spermatogenesis. Females were evaluated for necropsy body weight, estrous cycle length and the percent of cycle spent in the various stages.
GLP compliance:
yes
Remarks:
in compliance with United States FDA GLP regulations (21 CFR, Part 58)
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
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 totalled less than 263 ppm

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Simonsen Laboratories (Gilroy, CA)
- Age at study initiation: 6 wk
- Weight at study initiation: rat: Male: 101-104 g (mean body weight per group); Female: 92-94 g (mean body weight per group)
- 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
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/wk
Details on study schedule:
No information
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 0.025, 0.05, 0.1, 0.25 and 1 mg CdO/m3
Basis:
nominal conc.
No. of animals per sex per dose:
10 males and 10 females per dose
Control animals:
yes
Details on study design:
Post exposure period:no

Satellite groups and reasons they were added : additional 10 male & 10 female rats 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:
PARAMETERS ASSESSED DURING THE STUDY:
- 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. Clinical observations were recorded weekly.

Supplemental evaluations : 
- clinical pathology (hematology, clinical chemistry, urine analysis), 
- blood pressure measurements, 
- Cd tissue distribution (blood, lung and kidney samples collected on Days 3, 9, 30, end of study), see rep dose tox study
Estrous 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):
Sperm motility and vaginal cytology : evaluations were performed on base study animals in the 0, 0.025, 0.1 and 1 mg/m3 groups at the end of study. Male rats were evaluated for necropsy body and reproductive tissue weights, spermatozoal data and spermatogenesis. 
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 comparison 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:
Not examined
Offspring viability indices:
Not examined

Results and discussion

Results: P0 (first parental animals)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Other effects:
not specified

Reproductive function / performance (P0)

Reproductive function: estrous cycle:
effects observed, treatment-related
Reproductive function: sperm measures:
effects observed, treatment-related
Reproductive performance:
not examined

Details on results (P0)

TOXIC RESPONSE/EFFECTS BY DOSE LEVEL: 
For detailed data on toxicity : see 7.5.3 Repeated dose toxicity: inhalation

Reproductive toxicity : in males in the 1 mg/m3 group, spermatid heads per gram of testis, spermatid heads per testis and spermatid count were significantly lower than those of control males. There were no treatment-related microscopic changes in the testis or epididymis. In females, there was a significantly greater estrous cycle length than the controls at the 1 mg/m3 exposure level, but no treatment-related histologic changes in the reproductive organs.

Effect levels (P0)

open allclose all
Dose descriptor:
LOAEL
Effect level:
1 mg/m³ air
Sex:
male/female
Basis for effect level:
other: Decrease in spermatid head count and spermatid count in testes; increase in estrous cycle length
Dose descriptor:
NOAEL
Effect level:
0.1 mg/m³ air
Sex:
male/female
Basis for effect level:
other: Decrease in spermatid head count and spermatid count in testes; increase in estrous cycle length

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

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

none


Applicant's summary and conclusion

Conclusions:
In rats at the highest exposure level (1 mg/m3), there was a reduced number of spermatids per testis and an increase in the length of the estrous
cycle. However, there were no histopathologic lesions indicative of toxicity to the reproductive system, suggesting that the changes may be related to other effects of cadmium, such as hormonal modifications.
Executive summary:

A study was conducted to determine the effects of sub-chronic exposure of the test material on the reproductive system in F344 rats.

The test material was administered 6 h/d and 5 d/wk for 13 wk at 0, 0.025, 0.05, 0.1, 0.25 or 1 mg/m3 to groups of 10 rats/sex/dose. 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 with clinical signs being observed daily. Following organs were weighed at necropsy: heart, right kidney, liver, lungs, spleen, right testis and thymus. Cd distribution and influence on blood pressure was evaluated. Additionally, sperm motility and vaginal cytology evaluations were performed on base study animals in the 0, 0.025, 0.1 and 1 mg/m3 groups at the end of study. At necropsy, body and reproductive tissue weights, spermatozoal data and spermatogenesis were recoirded for males. Females were evaluated at necropsy for bodyweight, estrous cycle length and the percent of cycle spent in the various stages.

Available results indicate enlargement and paleness of the tracheobronchial and mediastinal lymph nodes in the treated groups. Overall, treatment-related respiratory tract lesions were found in the lungs, nose and larynx of FN344/N rats exposed by inhalation to CdO for 13 wk.

Reproductive toxicity was observed in the 1mg/m3 groups of rats and was evidenced by a reduced number of spermatids per testis and an increase in the length of the estrous cycle.