Registration Dossier

Administrative data

Description of key information

Reliable chronic toxicity studies are available, with appropriate species, dosage, solvent and route of administration:

a 90-day feeding study in both the rats and mice and a 2 -year feeding carcinogenicity study in both the rat and mouse.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
23 July 1981 to 22 February 1982
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Remarks:
Non-GLP study published by recognised Governmental body (US National Cancer Institute). Study and results are well documented with full statistical analysis included. This study is used in place of sub acute / sub chronic 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:
no guideline followed
Principles of method if other than guideline:
A 90-day Subchronic feeding studies were conducted to determine the concentrations of 4,4'-oxydianiline to be used in the chronic 2-year studies. Groups of 10 males and 10 females rats were fed diets containing 0, 3, 10, 30, 100, or 300 ppm for 90 days. All animals were observed twice daily for mortality. Individual animal weights, food consumption, appearance, and behavior were recorded weekly. After 13 weeks, all the animals were killed and necropsied. Representative tissues were examined microscopically as described in the section on chronic studies.
Because no compound-related clinical signs, body weight changes, or pathologic changes were observed, a second Subchronic study was carried out using diets containing 0, 300, 600, 1,000, and 2,000 ppm.
GLP compliance:
no
Limit test:
no
Specific details on test material used for the study:
4,4'-oxydianiline
4,4'-diaminodiphenyl ether
CAS 101-80-4
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Route of administration:
oral: feed
Dose / conc.:
300 ppm
Dose / conc.:
600 ppm
Dose / conc.:
1 000 ppm
Dose / conc.:
2 000 ppm
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Alopecia, labored respiration, and cyanosis were observed with the two highest doses (1,000 and 2,000 ppm).
Mortality:
mortality observed, treatment-related
Description (incidence):
A dose-related increase in mortality was observed in both sexes of rats with the two highest doses (1,000 and 2,000 ppm).
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
A dose-related decrease in weight gain was observed in both sexes of rats with the two highest doses (1,000 and 2,000 ppm).
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
All rats receiving 600 ppm or more had diffuse parenchymatous goiter. In addition, pituitary hyperplasia, testicular degeneration, prostatic atrophy, seminal vesicular atrophy, and renal microlithiasis were detected in most of the rats receiving 600 ppm or more.
Key result
Dose descriptor:
dose level: in feeding diet
Effect level:
600 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
histopathology: non-neoplastic
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
600 ppm
System:
endocrine system
Organ:
thyroid gland
Treatment related:
yes
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
600 ppm
System:
urinary
Organ:
kidney
Treatment related:
yes
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
600 ppm
System:
male reproductive system
Organ:
seminal vesicle
testes
Treatment related:
yes
Conclusions:
This study showed effects on thyroid, testes/seminal vesicles and kidneys at dietary concentrations of 4,4'-oxydianiline of 600 ppm and above, equivalent to approximately 30 mg/kg /day using standard food consumption rates
Executive summary:

A 90-day Subchronic feeding studies were conducted to determine the concentrations of 4,4'-oxydianiline to be used in the chronic 2-year studies. Groups of 10 males and 10 females rats were fed diets containing 0, 300, 600, 1,000, and 2,000 ppm for 90 days.

This study showed effects on thyroid, testes/seminal vesicles and kidneys at dietary concentrations of 4,4'-oxydianiline of 600 ppm and above, equivalent to approximately 30 mg/kg /day using standard food consumption rates.

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
23 July 1981 to 22 February 1982
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Remarks:
Non-GLP study published by recognised Governmental body (US National Cancer Institute). Study and results are well documented with full statistical analysis included. This study is used in place of sub acute / sub chronic 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:
no guideline followed
Principles of method if other than guideline:
A 90-day Subchronic feeding studies were conducted to determine the concentrations of 4,4'-oxydianiline to be used in the chronic 2-year studies. Groups of 10 males and 10 females mice were fed diets containing 0, 3, 10, 30, 100, or 300 ppm for 90 days. All animals were observed twice daily for mortality. Individual animal weights, food consumption, appearance, and behavior were recorded weekly. After 13 weeks, all the animals were killed and necropsied. Representative tissues were examined microscopically as described in the section on chronic studies.
Because no compound-related clinical signs, body weight changes, or pathologic changes were observed, a second Subchronic study was carried out using diets containing 0, 300, 600, 1,000, and 2,000 ppm.
GLP compliance:
no
Limit test:
no
Specific details on test material used for the study:
4,4'-oxydianiline
4,4'-diaminodiphenyl ether
CAS 101-80-4
Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: NCI Frederick Cancer Research Center (Frederick, Maryland)
- Age at study initiation: 5-week old
- Weight at study initiation: not specified
- Fasting period before study: not specified
- Housing: solid-bottom polycarbonate cages (Lab Products, Inc., Garfield, New Jersey) containing Aspenbed^(aspen chips, American Excelsior, Summerville, Mass.) / housed five per cage
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 10 days

DETAILS OF FOOD AND WATER QUALITY:

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 - 32 °C
- Humidity (%): 5 - 82 %
- Air changes (per hr): Incoming air was filtered by 2-inch fiberglass Tri-dek 125-40 filters with 10 to 12 changes of room air per hour
- Photoperiod (hrs dark / hrs light): Fluorescent lighting was provided on a 12-hour per day cycle
Route of administration:
oral: feed
Details on route of administration:
gavage
Vehicle:
corn oil
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
Analysis of formulated diets were not conducted in this study. However they were conducted in the further chronic study (2-year study) on 200 and 800 ppm formulations.
Duplicate samples of 2 g each were extracted with 50 ml of 95% ethanol in 100-ml ground glass stoppered graduated cylinders by repeated inversions of the cylinders during a 15-minute period. The feed particles were allowed to settle overnight, and the absorbance of the supernatants was measured at 247 nm in a Beckman DU Spectrophotometer after appropriate dilutions with 95% ethanol. The absorbance readings were adjusted with a "blank" extract from a 2-g feed sample from the same bag as the sample and were worked up in the same manner. Concentrations were determined by direct comparisons with standard solutions of the test compound. Recovery was determined by working up controlled feed mixtures simultaneously with the samples. The controls were prepared by spiking blank feed samples in duplicate. "Corrected" concentrations were adjusted for average recovery loss.

Duration of treatment / exposure:
90 days
Frequency of treatment:
daily
Dose / conc.:
300 ppm
Dose / conc.:
600 ppm
Dose / conc.:
1 000 ppm
Dose / conc.:
2 000 ppm
Control animals:
yes, concurrent vehicle
Observations and examinations performed and frequency:
All animals were observed twice daily for mortality. Individual animal weights, food consumption, appearance, and behavior were recorded weekly. After 13 weeks, all the animals were killed and necropsied. Representative tissues were examined microscopically.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Mice receiving the two highest doses were lethargic toward the end of the study.
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
A dose-associated decrease in weight gain was observed in male mice at all doses and in female mice at doses of 600 ppm and higher.
Description (incidence and severity):
Most mice receiving 600 ppm or more had thyroid hypertrophy and hyperplasia. Hyperplastic goiter was observed in mice receiving the highest dose (2,000 ppm). Pituitary hypertrophy and hyperplasia were associated with thyroid changes in some female mice receiving 1,000 ppm and in nearly all mice receiving 2,000 ppm. Testicular degeneration was found in most male mice receiving 1,000 or 2,000 ppm.
Key result
Dose descriptor:
dose level: in feeding diet
Effect level:
600 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
histopathology: non-neoplastic
Key result
Dose descriptor:
dose level: in feeding diet
Effect level:
2 000 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
gross pathology
Key result
Dose descriptor:
dose level: in feeding diet
Effect level:
1 000 ppm
Based on:
test mat.
Sex:
female
Basis for effect level:
histopathology: non-neoplastic
Key result
Dose descriptor:
dose level: in feeding diet
Effect level:
1 000 ppm
Based on:
test mat.
Sex:
male
Basis for effect level:
histopathology: non-neoplastic
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
600 ppm
System:
endocrine system
Organ:
thyroid gland
Treatment related:
yes
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
1 000 ppm
System:
endocrine system
Organ:
pituitary gland
Treatment related:
yes
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
1 000 ppm
System:
male reproductive system
Organ:
testes
Treatment related:
yes

Analytical results of 200 and 800 ppm formulated diets from the chronic study (2 -year study):

 Theorical concentration (ppm)  Number of samples  Sample analytical mean (ppm)  Coefficient of variation (%)  Acceptable range (ppm)
 200 12  200  14.5  160 -240
 800  14  780  13.2  650 -1050
Conclusions:
This study showed effects on thyroid at dietary concentrations of 4,4'-oxydianiline of 600 ppm and above, on testes and pituitary gland at dietary concentrations of 4,4'-oxydianiline of 1000 ppm and above.
Executive summary:

A 90-day Subchronic feeding studies were conducted to determine the concentrations of 4,4'-oxydianiline to be used in the chronic 2-year studies. Groups of 10 males and 10 females mice were fed diets containing 0, 300, 600, 1,000, and 2,000 ppm for 90 days.

This study showed effects on thyroid at dietary concentrations of 4,4'-oxydianiline of 600 ppm and above, on testes and pituitary gland at dietary concentrations of 4,4'-oxydianiline of 1000 ppm and above.

Endpoint:
chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
unspecified
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Remarks:
Non-GLP study published by recognised Governmental body (US National Cancer Institute). Study and results are well documented with full statistical analysis included. This study is used in place of sub acute / sub chronic study required under section 7.5 of this data set.
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:
no guideline followed
Principles of method if other than guideline:
see details on this study in the endpoint "carcinogenicity"
GLP compliance:
no
Specific details on test material used for the study:
see details on this study in the endpoint "carcinogenicity"
Species:
mouse
Strain:
B6C3F1
Details on species / strain selection:
see details on this study in the endpoint "carcinogenicity"
Sex:
male/female
Details on test animals or test system and environmental conditions:
see details on this study in the endpoint "carcinogenicity"
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
see details on this study in the endpoint "carcinogenicity"
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
see details on this study in the endpoint "carcinogenicity"
Duration of treatment / exposure:
103 weeks
Frequency of treatment:
Ad libitum 7 days/week
Dose / conc.:
150 ppm
Remarks:
in the diet
Dose / conc.:
300 ppm
Remarks:
in the diet
Dose / conc.:
800 ppm
Remarks:
in the diet
No. of animals per sex per dose:
50 per species per sex per dose
Control animals:
yes, concurrent no treatment
Details on study design:
see details on this study in the endpoint "carcinogenicity"
Positive control:
None
Observations and examinations performed and frequency:
see details on this study in the endpoint "carcinogenicity"
Sacrifice and pathology:
see details on this study in the endpoint "carcinogenicity"
Other examinations:
None
Statistics:
see details on this study in the endpoint "carcinogenicity"
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
see details on this study in the endpoint "carcinogenicity"
Mortality:
mortality observed, treatment-related
Description (incidence):
see details on this study in the endpoint "carcinogenicity"
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
see details on this study in the endpoint "carcinogenicity"
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Non-neoplastic lesions were observed in males and in female mice.

In male mice, the main findings observed are:
> lesion of the hematopoietic system observed in the spleen in 14%, 19% and 24% of animals in the low, mid and high dose groups respectively (8% in the control group)
> thyroid follicular cell hyperplasia in 53% of animals in the high dose group (0% in the control group and in other treated groups)
> inflammation in the harderian gland in 10%, 8% and 12% of the low, mid and high dose groups respectively (0% in the control group)

In female rats, the main finidngs observed are:
> inflammation of lungs in 2%, 2% and 8% of animals in low, mid and high dose groups respectively (2% in the control group)
> lesion of hematopoiesis observed in the spleen in 19%, 10% and 24% of animals in the low, mid and high dose group respectively (10% in the control group)
> nephropathy in 6% and 10% of animals in the mid and high dose group respectively (2% in the control group)
> thyroid follicular cell hyperplasia in 52% of animals in the high dose group (0% in the control group and in other treated groups)
> lesion of hydrometra in uterus in 17%, 32% and 31% of animals in low, mid and high dose groups respectively (15% in the control group)
> cyst in ovary in 10, 12 and 12 % of animals in the low, mid and high dose group respectively (2% in the control group)
> inflammation in the harderian gland in 4% and 8% of the animals in the low and mid dose groups respectively (0% in the control group)
Histopathological findings: neoplastic:
effects observed, treatment-related
Description (incidence and severity):
see details on this study in the endpoint "carcinogenicity"
Other effects:
not specified
Details on results:
see details on this study in the endpoint "carcinogenicity"
Key result
Dose descriptor:
dose level: in the feeing diet
Effect level:
150 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
histopathology: non-neoplastic
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
150 ppm
System:
eye
Organ:
other: Harderian gland
Treatment related:
yes
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
300 ppm
System:
urinary
Organ:
kidney
Treatment related:
yes
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
800 ppm
System:
endocrine system
Organ:
thyroid gland
Treatment related:
yes

see details on this study in the endpoint "carcinogenicity"

Conclusions:
In this carcinogenicity study conducted on mice for 2 years at 150, 300 and 800 ppm in diets, non-neplastic lesions were oberved in thyroid gland, kidney and harderian gland at concentrations of 4,4'-oxydianiline of 150, 300 and/or 800 ppm (depending on the organ).
In addition, neoplastic lesions were observed in liver, thyroid gland and harderian gland (see carcinogenicity endpoint).

Under the conditions of this study, thyroid gland, kidney and and harderian gland are identified to being target organs in mice. Besides the test substance was considered carcinogenic to mice, causing increased incidences of tumors in the thyroid gland, liver and harderian gland. It should be noted that the non-neoplastic effects observed in the thyroid gland and in the harderian gland are probably early or warning signs before progression to carcinogenic effects.
Executive summary:

A study for assessment of a possible carcinogenicity was conducted by feeding diets containing 150, 300, or 800 ppm to groups of 50 male or female B6C3F1 mice for 104 weeks. Matched controls consisted of 50 untreated mice of each sex. All surviving animals were killed at 104 to 105 weeks.

A dose-related decrement in mean body weight gain was observed for all groups of dosed mice.

Survival was significantly shortened in the low- and mid-dose female mice.

Non-neplastic lesions were oberved in thyroid gland, kidney and harderian gland at concentrations of 4,4'-oxydianiline of 150, 300 and/or 800 ppm (depending on the organ).

In male and female mice, adenomas in the harderian glands occurred in all dosed groups at incidences that were significantly higher than the incidence in the matched controls.

In low-dose male mice and in high-dose female mice, hepatocellular adenomas or carcinomas occurred at incidences significantly higher than those in the matched controls.

In female mice, follicular-cell adenomas in the thyroid occurred with a positive linear trend, and in a direct comparison the incidence in the high-dose group was also significantly higher than that in the controls.

Tumors occurring among male mice at increased incidences which could not be statistically related to the chemical were adenomas in the pituitary and hemangiomas of the circulatory system.

Under the conditions of this bioassay, thyroid gland, kidney and and harderian gland are identified to being target organs in mice. Besides 4,4'-oxydianiline was carcinogenic for male and female B6C3F1 mice, inducing adenomas in the harderian glands, hepatocellular adenomas or carcinomas in both sexes, and follicular-cell adenomas in the thyroid of females. It should be noted that the non-neoplastic effects observed in the thyroid gland and in the harderian gland are probably early or warning signs before progression to carcinogenic effects.

Endpoint:
chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
unspecified
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Remarks:
Non-GLP study published by recognised Governmental body (US National Cancer Institute). Study and results are well documented with full statistical analysis included. This study is used in place of sub acute / sub chronic study required under section 7.5 of this data set.
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:
no guideline followed
Principles of method if other than guideline:
see details on this study in the endpoint "carcinogenicity"
GLP compliance:
no
Specific details on test material used for the study:
see details on this study in the endpoint "carcinogenicity"
Species:
rat
Strain:
Fischer 344
Details on species / strain selection:
see details on this study in the endpoint "carcinogenicity"
Sex:
male/female
Details on test animals or test system and environmental conditions:
see details on this study in the endpoint "carcinogenicity"
Route of administration:
oral: feed
Details on route of administration:
see details on this study in the endpoint "carcinogenicity"
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
see details on this study in the endpoint "carcinogenicity"
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
see details on this study in the endpoint "carcinogenicity"
Duration of treatment / exposure:
103 weeks
see details on this study in the endpoint "carcinogenicity"
Frequency of treatment:
Ad libitum 7 days/week
see details on this study in the endpoint "carcinogenicity"
Dose / conc.:
200 ppm
Remarks:
in the diet
Dose / conc.:
400 ppm
Remarks:
in the diet
Dose / conc.:
500 ppm
Remarks:
in the diet
No. of animals per sex per dose:
50
see details on this study in the endpoint "carcinogenicity"
Control animals:
yes, concurrent no treatment
Details on study design:
see details on this study in the endpoint "carcinogenicity"
Positive control:
None
Observations and examinations performed and frequency:
see details on this study in the endpoint "carcinogenicity"
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Other examinations:
None
Statistics:
see details on this study in the endpoint "carcinogenicity"
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
see details on this study in the endpoint "carcinogenicity"
Mortality:
mortality observed, treatment-related
Description (incidence):
see details on this study in the endpoint "carcinogenicity"
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
see details on this study in the endpoint "carcinogenicity"
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Non-neoplastic lesions were observed in males and in female rats.

In male rats, the main findings observed are:
> inflammation of lungs in 10% of animals in low and mid dose groups, in 16% of animals in high dose group (0% in the control group)
> lesion of the hematopoietic system observed in the spleen in 16% of animals in low dose group, 20% of animals in the mid dose group and 16 % in the high dose group (6% in the control group)
> cystic hepatic lesions in 8% of animals in the mid dose group and 6% in the high dose group (0% in the control group)
> mineralization in kidney in 2% of animals in the low dose group and in 22% of animals in the high dose group (0% in the control group)
> epithelial hyperplasia in kidney in 4%, 8% and 14% of animals in the low, mid and high dose groups respectively (2% in the control group)
> follicular cyst in thyroid in 24% and 6% of animals in the mid and high dose groups respectively (0% in the control group) and follicular-cell hyperplasia in 2%, 24% and 26% of animals in the low, mid and high dose groups respectively (0% in the control group); C-cell hyperplasia in 4 and 7% of animals in low and mid dose groups (2% in the control group)
> testis mineralization in 2%, 4% and 8% in the low, mid and high dose groups respectively (0% in the control group); testis atropy in 2%, 6% and 14% of animals in the low, mid and high dose groups respectively (4% in the control group); interstitial cell hyperplasia in testis in 6% of animals in the high dose group (0% in the control group)

In female rats, the main findings observed are:
> inflammation of lungs in 4%, 12% a,d 12% of animals in low, mid and high dose groups respectively (4% in the control group)
> hemosiderosis in the spleen in 10% of animals in the high dose group (0% in the control group or other treated groups)
> mineralization in kidney in 20%, 14% and 33% of animals in the low, mid and high dose group respectively (6% in the control group) and focal calcification in 29% of animals in the high dose group (0% in the control group)
> epithelial hyperplasia in kidney (pelvis) in 4%, 10% and 8% of animals in the low, mid and high dose groups respectiveley (0% in the control group)
> pituitary hyperplasia in 11% of animals in the high dose group (0% in the control group)
> thyroid follicular-cell hyperplasia in 2%, 13% and 44% of animals in the low, mid and high dose groups respectively (0% in the control group)
Histopathological findings: neoplastic:
effects observed, treatment-related
Description (incidence and severity):
see details on this study in the endpoint "carcinogenicity"
Other effects:
not specified
Details on results:
see details on this study in the endpoint "carcinogenicity"
Key result
Dose descriptor:
dose level: in feeding diet
Effect level:
200 ppm
Based on:
test mat.
Sex:
male
Basis for effect level:
histopathology: non-neoplastic
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
400 ppm
System:
hepatobiliary
Organ:
liver
Treatment related:
yes
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
200 ppm
System:
urinary
Organ:
kidney
Treatment related:
yes
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
200 ppm
System:
male reproductive system
Organ:
testes
Treatment related:
yes
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
400 ppm
System:
endocrine system
Organ:
thyroid gland
Treatment related:
yes

see details on this study in the endpoint "carcinogenicity"

Conclusions:
In this carcinogenicity study conducted on rats for 2 years at 200, 400 and 500 ppm in diets, non-neplastic lesions were oberved in liver, thyroid gland, testes and kidneys at dietary concentrations of 4,4'-oxydianiline of 200, 400 and/or 500 ppm (depending on the organ).
In addition, neoplastic lesions were observed in liver and thyroid gland (see carcinogenicity endpoint).

Under the conditions of this study, liver, thyroid gland, kidney and testis are identified to being target organs in rats. Besides the test substance was considered carcinogenic to F344 rats, causing both increased incidences of follicular-cell neoplasms of the thyroid gland and liver neoplasms. It should be noted that the non-neoplastic effects observed in liver and thyroid gland are probably early or warning signs before progression to carcinogenic effects.
Executive summary:

A study for assessment of possible carcinogenicity was conducted on the test item by feeding diets containing 200, 400, or 500 ppm of the test chemical to groups of 50 male or female F344 rats for 104 weeks.

Matched controls consisted of 50 untreated rats. All surviving animals were killed at 104 to 105 weeks.

A dose-related decrement in mean body weight gain was observed for all groups of dosed rats. Survival was significantly shortened in the high-dose female rats.

Non-neplastic lesions were oberved in liver, thyroid gland, testes and kidneys at dietary concentrations of 4,4'-oxydianiline of 200, 400 and/or 500 ppm (depending on the organ).

In male and female rats, hepatocellular carcinomas or neoplastic nodules occurred at incidences that were dose-related, and the incidences in all dosed groups (except low-dose females) were higher than those in the controls.

The occurrence of follicular-cell adenomas or carcinomas of the thyroid was dose-related. Among groups of male and female rats,.the incidences in the mid- and high-dose groups of either sex were significantly higher than those of the corresponding controls.

In addition to classification for carcinogenic properties, the sacrifice showed non-neoplastic lesions on liver, thyroid gland, testes/seminal vesicles and kidneys at dietary concentrations of 4,4'-oxydianiline of 400 and/or 500 ppm (depending on the organ).

Under the conditions of this study, liver, thyroid gland, kidney and testes are identified to being target organs in rats. Besides the test substance was considered carcinogenic to F344 rats, causing both increased incidences of follicular-cell neoplasms of the thyroid gland and liver neoplasms. It should be noted that the non-neoplastic effects observed in liver and thyroid gland are probably early or warning signs before progression to carcinogenic effects.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Study duration:
subchronic
Species:
other: rats and mice
System:
other: hepatobiliary; endocrine system; male reproductive system; eye; urinary
Organ:
kidney
liver
seminal vesicle
testes
thyroid gland
other: eye

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for classification or non-classification

The classification is based on effects noted in the 90 -day studies (conducted to define the tested doses for further carcinogenicity studie) and on the carcinogenicity studies.

In rats, the sacrifice at 90 days in the chronic oral bioassay showed effects on thyroid, testes/seminal vesicles and kidneys at dietary concentrations of 4,4'-oxydianiline of 600 ppm and above, equivalent to approximately 30 mg/kg /day using standard food consumption rates.

In the carcinogenicity study, non-neplastic lesions were observed in kidney and testes at 200 ppm and above, and in liver and thyroid gland at 400 ppm and above. Since 4,4'-oxydianiline is considered to induce tumors in rats in thyroid gland and liver, the non-neoplastic effects observed in thyroid gland and/or in the liver are probably early or warning signs before progression to carcinogenic effects.

In mice, the sacrifice at 90 days in the chronic oral bioassay showed effects on thyroid at dietary concentrations of 4,4'-oxydianiline of 600 ppm and above, on testes and puitary gland at dietary concentrations of 4,4'-oxydianiline of 1000 ppm and above.

In the carcinogenicity study, non-neplastic lesions were observed in the harderian gland at 150 ppm and above, in the kidney at 300 ppm and above, and in the thyroid gland at 800 ppm and above. Since 4,4'-oxydianiline is considered to induce tumors in mice in thyroid gland, liver and harderian gland (eye), the non-neoplastic effects observed in the thyroid gland and/or in the harderian gland are probably early or warning signs before progression to carcinogenic effects.

It should be noted that the toxic effects on thyroid gland, liver and harderian gland (eyes) are already covered by the classification for carcinogenicity. Since the classification for STOT-RE (Specific Target oragn Toxicity - repeated Exposure) is applied for testes, seminal vesicles and kidney, it was decided to maintain also this classification for thyroid gland, liver and eye as a precautionary approach.

All these results from chronic bioassays trigger classification for repeated-dose toxicity STOT-RE 2, H373 (with the target organs thyroid, testes, seminal vesicles, kidney, liver and eyes) according to the CLP regulation.