Cadmium, dross

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

No information

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: reliable without restriction. Well documented and scientifically acceptable. Method comparable to OECD Guideline.

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

reference to same study

Cross-reference 2

Reason / purpose for cross-reference:

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

Guideline:

OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)

Deviations:

yes

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 respiratory system and Cd distribution in F344 rats. The test material was administered 6 h and 20 min/d and 5 d/wk for 13 wk at 0, 0.025, 0.05, 0.1, 0.25 or 1 mg CdO/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.

GLP compliance:

yes

Remarks:

in compliance with United States FDA GLP regulations (21 CFR, Part 58)

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Cadmium oxide

EC Number:

215-146-2

EC Name:

Cadmium oxide

Cas Number:

1306-19-0

IUPAC Name:

oxocadmium

Details on test material:

-Name of the test material: CdO
SOURCE: Lot 110383 from Johnson Matthey Aesar Group (Seabrook, NH).
PURITY: Purity : 99.4 % ( 0.6 % )
Impurities : 400 ppm chlorine, all other impurities detected totaled less than 263 ppm

Test animals

Species:

rat

Strain:

Fischer 344

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 old
- Weight at study initiation: M: 101-104 g (mean body weight per group); F: 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:

whole body

Vehicle:

other: unchanged (no vehicle)

Remarks on MMAD:

MMAD / GSD: MMAD = 1.1 - 1.6 µm

Details on inhalation exposure:

Particle size: MMAD = 1.1 - 1.6 µm

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:

6 h and 20 min/d; 5 d/wk

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 0.025, 0.05, 0.1, 0.25 or 1 mg CdO/m3
Basis:
nominal conc.

No. of animals per sex per dose:

 10 M and 10 F per dose and control

Control animals:

yes

Details on study design:

Sacrificed after 13 weeks of exposure

Positive control:

None

Examinations

Observations and examinations performed and frequency:

Clinical observations performed and frequency: 
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.

Sacrifice and pathology:

Autopsy: Organs examined at necropsy (macroscopic and microscopic): complete necropsies were performed.
Following organs were weighed: heart, right kidney, liver, lungs, spleen, right testis and thymus.

Other examinations:

Additional analyses: Cd distribution studies and Influence on blood pressure

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.

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

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

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Details on results:

TOXIC RESPONSE/EFFECTS BY DOSE LEVEL:
Body weight: the final mean body weights and mean body weight gains of male and female rats in the highest exposure groups were notably lower than those of the control group (final weight relative to controls (%): 93).

Food/water consumption: no information

Description, severity, time of onset and duration of clinical signs: rats: nasal discharge in males and females. In females, the frequency of this sign increased with increasing exposure concentration.

Ophtalmologic findings incidence and severity: no information

Hematological findings incidence and severity: reticulocyte numbers were greater in exposed females (0.025 mg/m3 and higher groups) than in the controls at day 24, indicating a bone marrow response. However, there were no consistent changes indicating anaemia.

Clinical biochemistry findings incidence and severity: changes in rats were minor, sporadic and not considered significant Mortality and time to death:all rats survived until the end of the study.

Gross pathology incidence and severity: rats: enlargement and paleness of the tracheobronchial and mediastinal lymph nodes

Organ weight changes: rats: significant differences in organ weights from control values occurred in the three highest exposure groups: 0.1, 0.25 or 1 mg/m3

Histopathology incidence and severity:

Selected histopathologic lesions for male and female F344/N rats in the 13-week inhalation study of CdO (NTP Report, 1995) (See table 1)

MEASUREMENTS OF BLOOD PRESSURE:
There were no biologically significant effects of cadmium oxide exposure on blood pressure measurements at any time point. There were statistically significant differences in females in the 0.25 and 1 mg/m3 groups at Week 13. However, these differences were considered to be anomalies for the following reasons: the 0.25 and 1 mg/m3 group means (120 to 130 mm) were within the normal range, the control value (102 mm) was on the low end of the normal range, a dose-response relationship was not present, and the data for females at the initial time point varied considerably from one group to another. Using a one-way analysis of variance test (Weter et aL, 1985), a significant difference among female rats was found at the initial time point. When the data were standardized by the initial time point data, there were no significant differences in dose-response or time-response for blood pressure measurements.

CADMIUM DISTRIBUTION STUDY:
Cadmium accumulation increased with exposure concentration at all time points, but the increases were not proportional to the increases in exposure concentration. Cadmium lung concentration did not achieve steady state over the course of the study. Cadmium concentrations increased with increasing exposure concentration in the kidney at all time points and in the blood at Day 9, Day 30, and Week 13. Concentrations of cadmium in the lung and kidney were significantly greater than those of the controls for all exposure groups at every time point. Cadmium concentrations in the blood of rats exposed to 1 mg/m3 cadmium oxide were significantly greater than the controls after just three days of exposure and remained so throughout the study. For rats in the 0.25 mg/m3group, cadmium concentrations in the blood were significantly greater than in the controls after 9 days of exposure and throughout the study. Further details on tissue levels of cadmium are reported by Dill et al (1994).

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

0.025 mg/m³ air

Sex:

male/female

2

Dose descriptor:

LOAEL

Effect level:

0.05 mg/m³ air

Sex:

male/female

Basis for effect level:

other: lung effects

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

None

Applicant's summary and conclusion

Conclusions:

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.

Executive summary:

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

The test material was administered 6 h and 20 min/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.

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.