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Toxicological information

Repeated dose toxicity: inhalation

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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:
comparable to guideline study
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Reference
Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
Principles of method if other than guideline:
A study was conducted to determine the effects of sub-chronic exposure in lungs 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 and 20 min/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.
GLP compliance:
yes
Remarks:
in compliance with United States FDA GLP regulations (21 CFR, Part 58)
Limit test:
no
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 old
- 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

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Mass median aerodynamic diameter (MMAD):
>= 1.1 - <= 1.6 µm
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
Dose / conc.:
0.025 mg/m³ air
Remarks:
mgCdO/m3
Dose / conc.:
0.05 mg/m³ air
Remarks:
mgCdO/m3
Dose / conc.:
0.1 mg/m³ air
Remarks:
mgCdO/m3
Dose / conc.:
0.25 mg/m³ air
Remarks:
mgCdO/m3
Dose / conc.:
1 mg/m³ air
Remarks:
mgCdO/m3
No. of animals per sex per dose:
 10 M and 10 F per dose and control
Control animals:
yes
Details on study design:
Post-exposure period: sacrifice after 13 weeks of exposure
Positive control:
None
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:
None
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.
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, non-treatment-related
Description (incidence):
One male mouse died during week 13 of the study.
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
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not specified
Details on results:
TOXIC RESPONSE/EFFECTS BY DOSE LEVEL:

Body weight: final mean body weights and mean body weight gains of exposed mice were similar to or slightly greater than those of the control mice

Food/water consumption: no information

Description, severity, time of onset and duration of clinical signs: no clinical signs of toxicity considered to be related to CdO exposure were observed

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.

Gross pathology incidence and severity: enlargement of the tracheobronchial lymph nodes and pale grey mottled lungs (0.25 and 1 mg/m3 groups)

Organ weight changes:  significant differences in lung weights occured from 0.05 mg/m3

Histopathology incidence and severity:
Selected histopathologic lesions for male and female B6C3F1 mice in the 13-week inhalation study of CdO (NTP Report, 1995) (See table 2)
Dose descriptor:
NOAEL
Sex:
male/female
Basis for effect level:
other: could not be determined
Remarks on result:
not measured/tested
Dose descriptor:
LOAEL
Effect level:
0.025 mg/m³ air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: lung effects
Critical effects observed:
not specified

None              

Conclusions:
Treatment-related respiratory tract lesions were found in the lungs, nose and larynx of FN344/N rats and B6C3F1 mice exposed by inhalation to CdOfor 13 weeks.
Executive summary:

A study was conducted to determine the effects of sub-chronic exposure in lungs 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 and 20 min/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.

Reason / purpose for cross-reference:
reference to same study
Reference
Endpoint:
fertility, other
Remarks:
other: 13-wk inhalation toxicity study
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: Generally in compliance with OECD TG 413 and EC TM B26 Dir. 87/302/EEC 30/05/88.
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
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
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
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
- 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
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/wk
Details on study schedule:
No information
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
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
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
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):
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
Clinical signs:
effects observed, treatment-related
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Ophthalmological findings:
not specified
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
not considered biologically signficant
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
not considered biologically signficant
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
not considered biologically signficant
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: oestrous cycle:
effects observed, treatment-related
Reproductive function: sperm measures:
effects observed, treatment-related
Reproductive performance:
not examined
TOXIC RESPONSE/EFFECTS BY DOSE LEVEL: 
For detailed data on toxicity : see 7.5.2 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.
Dose descriptor:
NOAEL
Effect level:
0.1 mg/m³ air
Based on:
test mat.
Sex:
female
Basis for effect level:
reproductive function (oestrous cycle)
other: increase in estrous cycle length
Dose descriptor:
NOAEL
Effect level:
0.1 mg/m³ air
Based on:
test mat.
Sex:
male
Basis for effect level:
reproductive function (sperm measures)
other: Decrease in spermatid head count and spermatid count in testes
Dose descriptor:
LOAEL
Effect level:
1 mg/m³ air
Based on:
test mat.
Sex:
female
Basis for effect level:
reproductive function (oestrous cycle)
other: increase in estrous cycle length
Dose descriptor:
LOAEL
Effect level:
1 mg/m³ air
Based on:
test mat.
Sex:
male
Basis for effect level:
reproductive function (sperm measures)
other: Decrease in spermatid head count and spermatid count in testes
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
Not applicable
Dose descriptor:
NOAEL
Generation:
F1
Remarks on result:
not measured/tested
Reproductive effects observed:
not specified

none


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.

Reason / purpose for cross-reference:
reference to same study
Reference
Endpoint:
fertility, other
Remarks:
other: 13-wk inhalation toxicity study
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 restrictions. Generally in compliance with OECD TG 413 and EC TM B26 Dir. 87/302/EEC 30/05/88.
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
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
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
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
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
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
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: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
not specified
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.
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
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
Not applicable
Dose descriptor:
NOAEL
Generation:
F1
Sex:
male/female
Remarks on result:
not measured/tested
Reproductive effects observed:
not specified

None

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.

Reason / purpose for cross-reference:
reference to same study
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
No information
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Qualifier:
equivalent or similar to guideline
Guideline:
other: EC TM B31 Dir. 87/302/EEC 30/05/88
Deviations:
not specified
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes
Remarks:
in compliance with United States FDA GLP regulations (21 CFR, Part 58)
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Simonsen Laboratories (Gilroy, CA)
- Age at study initiation: 14 wk
- Weight at study initiation: Female : 92-94 (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

Route of administration:
inhalation
Vehicle:
unchanged (no vehicle)
Mass median aerodynamic diameter (MMAD):
>= 1.1 - <= 1.6 µm
Details on exposure:
Particle size: MMAD = 1.1 - 1.6 µm, GSD : 1.7-1.8
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No information
Details on mating procedure:
2 to 3 females were cohoused overnight with each males. On the first day of vaginal plug or sperm detection (gestation d 0), positively mated females were assigned to exposure groups by weights. Breeding was conducted for 3 consecutive nights.
Duration of treatment / exposure:
Gestation Day 4-19
Frequency of treatment:
6h and 16 min/d; 7 d/wk
Duration of test:
Sacrifice on Gestation Day 20
Dose / conc.:
0 mg/m³ air
Dose / conc.:
0.05 mg/m³ air
Dose / conc.:
0.5 mg/m³ air
Dose / conc.:
2 mg/m³ air
No. of animals per sex per dose:
32 positively mated females/ exposure group
Control animals:
yes
Details on study design:
No information
Maternal examinations:
PARAMETERS ASSESSED DURING THE STUDY
Clinical observations performed and frequency: recorded twice daily rats were weighed on gestation Days 0, 4, 6, 10, 14, 17 and on the day of necropsy
Parameters assessed during study (maternal):
- Maternal livers, kidneys and uteri were weighed.
- Corpora lutea, implantation sites, resorptions were counted.        
- Extra-gestational weight change was calculated by subtracting the gravid uterine weight from the maternal body weight.       
- Uteri with no visible implantation sites were stained with ammonium sulfide to detect very early resorptions.       
- Placentas were examined and discarded unless abnormal.       
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of resorptions: Yes

Fetal examinations:
Parameters assessed during study (maternal):
- Live and dead fetuses were counted
- Live fetuses were weighed and examined for gross defects and then killed and sexed.       
- Half of the fetuses from each litter as fetuses wth gross external abnormalities were examined for visceral defects using methods adapted from Staples (1974). The other half of the fetuses were decapitated; heads were fixed in Bouin's fixative, sectioned and examined for soft-tissue craniofacial defects. All carcasses were double stained with Alcian blue and alizarin Red S and examined for skeletal malformations.
Statistics:
Exposure-related trends in pregnancy indices were determined by the Cochran-armitage test (Armitage, 1971). Each exposed group was compared 
to the control group with a chi-square test (Conover, 1971).  Organ and bosy weight data, which have approximately normal distributions, were analyzed with the parametric multiple comparisons procedures of Williams (1971, 1972) and Dunnett (1955).  Exposure group means for data with skewed distributions were analyzed using the nonparametric multiple comparisons methods of Shirley (1977) or Dunn (1964).  Jonckheere's test (1954) was used to assess the significance of dose-response trends and to determine whether a trend-sensitive test (William' or Shirley's 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 Joncheere's test was significant at a P-value less than 0.1. The significance of the dose-response trend for extra-gestational weight
change was tested with the SAS General Linear Models Procedure (SAS, 1985). For fetal malformations and variations, the arc sine transformation of 
each proportional incidence was analyzed against the class variable, "treatment", using a one-way analysis of variance test. A Tukey's t-test (two-tailed) was used to assess statistically significant differences between control and exposed groups. If appropriate, the dose-response relationship was
determined by an orthogonal trend test (Winer, 1971).
Indices:
No information
Historical control data:
No information
Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
TOXIC RESPONSE/EFFECTS BY DOSE LEVEL: 
Maternal data : One female rat in the highest exposure group died on gestation Day 17. Pregnancy index were respectively  81%, 88 %, 91 % and 97 % in the control, low, medium and high dose groups. Clinical signs of toxicity included dyspnea in all exposed groups ; the incidence, duration and severity being dose-related. In addition, hypoactivity was noted in most rats at 2 mg/m3.  Mean body weight and body weight gain of pregnant females from the highest exposure group were significantly lower than those of the control group (respectively 87 % and 59 % of the control). In addition, at this  dose level, absolute and relative liver weights and absolute kidney weight were significantly lower than in the controls (respectively 82 %, 95 % and 91 % of the controls), while relative uterine and kidney weights were significantly greater than the controls (respectively 110 % and 105 %).
Dose descriptor:
NOAEL
Effect level:
0.5 mg/m³ air
Based on:
test mat.
Basis for effect level:
body weight and weight gain
clinical signs
organ weights and organ / body weight ratios
Dose descriptor:
LOAEL
Effect level:
2 mg/m³ air
Basis for effect level:
body weight and weight gain
clinical signs
organ weights and organ / body weight ratios
Abnormalities:
not specified
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
Foetal data : No effect on the number of implantations per dam, litters with resorptions or resorptions per litter were noted. In addition, no statistically significant differences in fetal mortality, number of live fetuses per litter or sex ratios were observed.  Mean body weights of male and female fetuses from the highest exposed group were significantly lower than those of the controls (84 % of the control for M and 83 % of the control for F).  No significant increase of the incidence of total fetal malformations or of the mean percent of malformed fetuses per litter. In addition, no statistically significant differences were observed between the control and exposed groups in the overall incidence of fetal variations (14.6 %, 21.7 %, 20.6 % and 28.3 %) or the mean percent of fetuses per litter with variations (14.3 %, 21.2 %, 20.6 % and 27.8 %). However, the mean percent of fetuses per litter with reduced ossifications of the pelvis (2.4 %, 2.3 %, 3.4 % and 12 %) and sternabrae (4.4 %, 7.5 %, 8.4 % and 24.7 %) dose-relately increased, with both parameters being significantly greater at 2 mg/m3.
Dose descriptor:
NOAEL
Effect level:
0.5 mg/m³ air
Based on:
test mat.
Sex:
female
Basis for effect level:
fetal/pup body weight changes
skeletal malformations
Dose descriptor:
LOAEL
Effect level:
2 mg/m³ air
Based on:
test mat.
Sex:
female
Basis for effect level:
fetal/pup body weight changes
skeletal malformations
Abnormalities:
effects observed, treatment-related
Localisation:
skeletal: sternum
skeletal: pelvic girdle
Description (incidence and severity):
the mean percent of fetuses per litter with reduced ossifications of the pelvis and sternabrae was dose-relately increased with both parameters being significantly greater at 2 mg/m3
Developmental effects observed:
yes
Lowest effective dose / conc.:
2 mg/m³ air
Treatment related:
yes
Relation to maternal toxicity:
not specified
Dose response relationship:
yes
Relevant for humans:
not specified

None

Conclusions:
Maternal toxicity was observed in rats exposed to 2 mg/m3 CdO as evidenced by a decrease in body weight and body weight gain and presence of clinical signs of toxicity. There was no evidence of embryolethality at any exposure level. However, in rats exposed to 2 mg/m3, developmental toxicity was evidenced by lower fetal weights and a significant increase in the incidence of reduced skeletal ossification.
Executive summary:

A study was conducted to evaluate the teratogenic effects of the test material in SD rats.

Sperm-positive female Sprague-Dawley rats were exposed to 0, 0.05, 0.5, or 2 mg/m3 cadmium oxide 6 h/d, 7 d/wk, from gestation Day 4 through 19.

Maternal toxicity was observed in Sprague-Dawley rats exposed to 2 mg/m3 cadmium oxide and included body weights lower than those of the controls and clinical signs of toxicity (dyspnea and hypoactivity). There was no evidence of embryolethality in rats at any exposure level. However, in rats exposed to 2 mg/m 3, developmental toxicity was evidenced by lower fetal weights and a significant increase in the incidence of reduced skeletal ossifications.

Reason / purpose for cross-reference:
reference to same study
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
No information
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Reason / purpose for cross-reference:
reference to same study
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Qualifier:
equivalent or similar to guideline
Guideline:
other: EC TM B31 Dir. 87/302/EEC 30/05/88
Deviations:
not specified
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes
Remarks:
in compliance with United States FDA GLP regulations (21 CFR, Part 58)
Limit test:
no
Species:
mouse
Strain:
Swiss
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories (Raleigh, NC)
- Age at study initiation: 14 wk
- 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: 32-33 d


ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
inhalation
Vehicle:
unchanged (no vehicle)
Mass median aerodynamic diameter (MMAD):
>= 1.1 - <= 1.6 µm
Details on exposure:
Particle size: MMAD = 1.1 - 1.6 µm, GSD : 1.7-1.8
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)
Details on mating procedure:
2 to 3 femlaes were housed overnight with each male. On the first day of vaginal plug or sperm detection (gestation Day 0), positively mated female were assigned to exposure groups by weights. Breeding was conducted for 3 consecutive nights.
Duration of treatment / exposure:
Gestation Days 4-17
Frequency of treatment:
6h and 16 min/d; 7 d/wk
Duration of test:
Sacrifice on Gestation Day 18
Dose / conc.:
0 mg/m³ air
Dose / conc.:
0.05 mg/m³ air
Dose / conc.:
0.5 mg/m³ air
Dose / conc.:
2 mg/m³ air
No. of animals per sex per dose:
33 positively mated females /exposure group
Control animals:
yes
Details on study design:
No information
Maternal examinations:
PARAMETERS ASSESSED DURING THE STUDY
Clinical observations performed and frequency: recorded twice daily rats were weighed on gestation Days 0, 4, 6, 10, 14, 17 and on the day of necropsy
Parameters assessed during study (maternal):
- Maternal livers, kidneys and uteri were weighed.
- Corpora lutea, implantation sites, resorptions were counted.
- Extra-gestational weight change was calculated by subtracting the gravid uterine weight from the maternal body weight.
- Uteri with no visible implantation sites were stained with ammonium sulfide to detect very early resorptions.
- Placentas were examined and discarded unless abnormal.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of resorptions: Yes
Fetal examinations:
Parameters assessed during study (maternal):
- Live and dead fetuses were counted
- Live fetuses were weighed and examined for gross defects and then killed and sexed.
- Half of the fetuses from each litter as fetuses wth gross external abnormalities were examined for visceral defects using methods adapted from Staples (1974). The other half of the fetuses were decapitated; heads were fixed in Bouin's fixative, sectioned and examined for soft-tissue craniofacial defects. All carcasses were double stained with Alcian blue and alizarin Red S and examined for skeletal malformations.
Statistics:
Exposure-related trends in pregnancy indices were determined by the Cochran-armitage test (Armitage, 1971). Each exposed group was compared 
to the control group with a chi-square test (Conover, 1971).  Organ and BW data, which have approximately normal distributions, were analyzed with
the parametric multiple comparisons procedures of Williams (1971, 1972) and Dunnett (1955).  Exposure group means for data with skewed 
distributions were analyzed using the nonparametric multiple comparisons methods of Shirley (1977) or Dunn (1964).  Jonckheere's test (1954) was used to assess the significance of dose-response trends and to determine whether a trend-sensitive test (William' or Shirley's 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 Joncheere's test was significant at a P-value less than 0.1. The significance of the dose-response trend for extra-gestational weight
change was tested with the SAS General Linear Models Procedure (SAS, 1985). For fetal malformations and variations, the arc sine transformation of 
each proportional incidence was analyzed against the class variable, "treatment", using a one-way analysis of variance test. A tukey's t-test (two-tailed) was used to assess statistically significant differences between control and exposed groups. If appropriate, the dose-response relationship was
determined by an orthogonal trend test (Winer, 1971).
Indices:
No information
Historical control data:
No information
Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
One female rat in the highest exposure group died on gestation Day 17. Pregnancy index were respectively  81%, 88 %, 91 % and 97 % in the control, 
low, medium and high dose groups. Clinical signs of toxicity included dyspnea in all exposed groups ; the incidence, duration and severity being dose-related. In addition, hypoactivity was noted in most rats at 2 mg/m3.  Mean body weight and body weight gain of pregnant females from the highest exposure group were significantly lower than those of the control group (respectively 87 % and 59 % of the control). In addition, at this  dose level, absolute and relative liver weights and absolute kidney weight were significantly lower than in the controls (respectively 82 %, 95 % and 91 % of the controls), while relative uterine and kidney weights were significantly greater than the controls (respectively 110 % and 105 %).
Dose descriptor:
NOAEL
Effect level:
0.05 mg/m³ air
Based on:
test mat.
Basis for effect level:
body weight and weight gain
changes in number of pregnant
clinical signs
organ weights and organ / body weight ratios
Dose descriptor:
LOAEL
Effect level:
0.5 mg/m³ air
Based on:
test mat.
Basis for effect level:
body weight and weight gain
changes in number of pregnant
clinical signs
organ weights and organ / body weight ratios
Abnormalities:
not specified
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
No statistically significant differences in implantations per dam, litters with resorptions, fetal mortality or live fetuses per litter were noted between the control and exposed groups. However, the total incidence of resorptions per litter was significantly greater at 2 mg/m3 (respectively 0.567 and 4.333 in the control and high dose group), even though early and late resorptions per litter were not significantly greater than in the control.
The mean BW of male and female fetuses were significantly lower in the two highest dose groups (for M : 91 % and 71 of the control and for F : 92 % and 70 % of the control) ; in addition, the percentage of live male fetuses per litter was significantly less at 2 mg/m3 (73 % of the control).
Total fetal malformations and the mean percent of malformed fetuses per litter noted for exposed groups were not significantly greater than those of the control group. There was no statistically significant difference on the incidence of litters with variations (96.7 %, 81.3 %, 95.7 % and 100.0 %), however, there was a dose-related increase in the mean percent of fetuses per litter with variations (24.9 %, 29.8 %, 39.1 % and 73.1 %). The mean percent of fetuses per litter with reduced ossification of the sternabrae also increased in an dose-related manner, with significantly more occurences in the high dose group than in the control (6 %, 7.1 %, 11.1 % and 65.8 %).
Dose descriptor:
NOAEL
Effect level:
0.05 mg/m³ air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
fetal/pup body weight changes
skeletal malformations
Dose descriptor:
LOAEL
Effect level:
0.5 mg/m³ air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
fetal/pup body weight changes
skeletal malformations
Abnormalities:
effects observed, treatment-related
Localisation:
skeletal: sternum
skeletal: pelvic girdle
Description (incidence and severity):
The mean percent of fetuses per litter with reduced ossification of the sternabrae also increased in an dose-related manner, with significantly more occurences in the high dose group (2 mg/m3) than in the control
Developmental effects observed:
yes
Lowest effective dose / conc.:
0.5 mg/m³ air
Treatment related:
yes
Relation to maternal toxicity:
not specified
Dose response relationship:
yes
Relevant for humans:
not specified

None

Conclusions:
Maternal toxicity was observed in mice exposed to 0.5 and 2 mg/m3 CdO as evidenced by clinical signs of toxicity, lower body weight and body weight gain and a lower pregnancy rate. Total number of resorptions/litter increased at 2 mg/m3. Developmental toxicity was evidenced by lower fetal weights and an increase related increase in the mean percent of fetuses per litter with variations at 0.5 and 2 mg/m3 and an increase in the incidence of reduced sternebral ossification at 2 mg/m3.
Executive summary:

A study was conducted to evaluate the teratogenic effects of the test material in Swiss CD-1 mice.

Sperm-positive female Swiss CD-1 mice were exposed to 0, 0.05, 0.5, or 2 mg/m3 cadmium oxide 6 h/d, 7 d/wk, from gestation Day 4 through 19.

Maternal toxicity was observed in Swiss (CD-1®) mice exposed to 2 mg/m3 cadmium oxide. Clinical signs were dyspnea, hypoactivity, lower body weight, and a lower pregnancy rate (30% vs. 97% in the control group). The total number of resorptions per litter was increased at the 2 mg/m3 level. Developmental toxicity was evidenced by lower fetal weights in the 0.5 and 2 mg/m3 groups and an increase in the incidence of reduced sternebral ossification in the 2 mg/m3 group.

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)
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

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 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)
Mass median aerodynamic diameter (MMAD):
>= 1.1 - <= 1.6 µm
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 / concentrationsopen allclose all
Dose / conc.:
0.025 mg/m³ air
Remarks:
mgCdO/m3
Dose / conc.:
0.05 mg/m³ air
Remarks:
mgCdO/m3
Dose / conc.:
0.1 mg/m³ air
Remarks:
mgCdO/m3
Dose / conc.:
0.25 mg/m³ air
Remarks:
mgCdO/m"
Dose / conc.:
1 mg/m³ air
Remarks:
mgCdO/m3
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:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food efficiency:
not specified
Ophthalmological findings:
not specified
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
not considered biologically signficant
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
not considered biologically signficant
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
not considered biologically signficant
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:
effects observed, treatment-related
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

open allclose all
Dose descriptor:
NOAEL
Effect level:
0.025 mg/m³ air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: lung effects
Dose descriptor:
LOAEL
Effect level:
0.05 mg/m³ air
Based on:
test mat.
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.