4-(p-nitrophenylthio)aniline

Carcinogenicity

Description of key information

No experimental data is available for 4-(p-nitrophenylthio)aniline. Based on the structure similarity with 4,4'-Thiodianiline (TPA), 4-(p-nitrophenylthio)aniline is expected to be carcinogen in rats and mice.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

carcinogenicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Justification for type of information:

4-(p-nitrophenylthio)aniline - DAPEA (chemical target) and 4,4'-Thiodianiline - TDA (chemical source) share the larger part of the chemical structure, included the main structural alerts for DNA binding and getotoxicity.

Reason / purpose for cross-reference:

read-across source

Mortality:

mortality observed, treatment-related

Description (incidence):

All high-dose animals died by week 77, and all low-dose animals died by week 79.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Body weight was significantly reduced in both sexes; however, the high and low doses caused about the same reduction in body weight.

Histopathological findings: neoplastic:

effects observed, treatment-related

Description (incidence and severity):

The liver and thyroid gland were the primary target tissues in both sexes.
The time to the first observed liver tumor in mice exposed to TDA at 5,000 ppm was 40 weeks in female mice and 50 to 54 weeks in male mice. At the low dose (2,500 ppm), liver tumors appeared at 54 weeks in both sexes. Spontaneous liver tumors occurred at 88 weeks in male controls. The first thyroid tumors appeared at 40 weeks in high-dose females, 54 weeks in high-dose males, 59 weeks in low-dose females, and 63 weeks in low-dose males.
The incidence of hepatocellular carcinoma was significantly increased in both sexes at both dose levels. These tumors were metastatic to the lungs and kidney. The incidence of thyroid follicular-cell carcinoma was significantly increased at both dose levels in males, but only at the high dose in females. These tumors were metastatic to the lungs. In addition, two unspecified thyroid adenomas occurred in the high-dose females. The incidences of total tumors of the thyroid gland (follicular-cell adenoma or carcinoma combined) and liver (hepatocellular adenoma or carcinoma combined) were significantly increased in both sexes at both dose levels.

Remarks on result:

not determinable

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

2 500 ppm

System:

hepatobiliary

Organ:

liver

thyroid gland

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

not specified

In addition to the neoplastic lesions, several degenerative, proliferative, and inflammatory changes occurred in mice of the TDA-exposed and control groups. Although most of these lesions are typical for aged mice, follicular-cell hyperplasia of the thyroid was observed only in the TDA-exposed mice and was believed to be exposure-related. This lesion occurred in 29 of 33 males and 31 of 33 females in the low-dose groups and in 4 of 23 males and 26 of 30 females in the high-dose groups.

Conclusions:

The NCI concluded that TDA was carcinogenic in B6C3F1 mice.
Based on the similarity between the chemical source (TDA) and the chemical target (DAPEA), study results can be reliably extrapolated to DAPEA.

Reference 2

Endpoint:

carcinogenicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Justification for type of information:

4-(p-nitrophenylthio)aniline - DAPEA (chemical target) and 4,4'-Thiodianiline - TDA (chemical source) share the larger part of the chemical structure, included the main structural alerts for DNA binding and getotoxicity.

Reason / purpose for cross-reference:

read-across source

Mortality:

mortality observed, treatment-related

Description (incidence):

A significant (P ≤ 0.001, Tarone test) dose-related trend in mortality was observed. All animals in the control groups survived as long as week 52, and 6 males (40%) and 5 females (33%) survived until the end of the study (104 weeks). Among TDA-exposed males, 23 (66%) in the low-dose group and 18 (51%) in the high-dose group survived to week 52. Survival of females was a little higher, with 32 (91%) in the low-dose group and 21 (60%) in the high-dose group surviving to week 52. However, all high-dose rats died by week 69, and all low-dose rats died by week 72.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Throughout the study, body weight was significantly lower in all exposed groups than in the control group.

Histopathological findings: neoplastic:

effects observed, treatment-related

Description (incidence and severity):

All TDA-exposed rats except one had tumors at one or more sites, including the ear canal, lung, liver, and thyroid gland. Additionally, skin and colon tumors occurred in males, and uterine tumors in females. Tumor incidences were signficantly increased in at least one sex. The times to the first observed tumors in TDA-exposed rats were 25 weeks for ear-canal tumors in males, 32 weeks for thyroid tumors in males, 44 weeks for liver and colon tumors in males and thyroid and uterine tumors in females, 46 weeks for ear-canal tumors in females, and 61 weeks for liver tumors in females. Liver and colon tumors appeared earlier in the lowdose groups than in the high-dose groups, as did ear-canal tumors in females. Skin tumors occurred only in low-dose males and were observed at 48 weeks. Lung tumors were observed at 50 weeks in low-dose males and 63 weeks in low-dose females.
The incidences of liver, thyroid, and ear-canal tumors were significantly increased in male rats, and the incidences of thyroid and uterine tumors were significantly increased in female rats. Although the increased incidences of colon tumors in males and ear-canal tumors in females were not statistically significant, they were considered to be related to TDA administration because they were not observed in the concurrent controls or in 235 historical control animals. For similar reasons, the increased incidence of skin tumors in male rats may have been associated with TDA exposure (tumors were not observed in concurrent controls and were observed in only 1 of 235 historical controls).
All tumors were epithelial in origin, and most of them were malignant. These included squamous-cell papilloma and carcinoma of the skin; squamous-cell papilloma and carcinoma of the external ear canal and adjacent subcutaneous tissues; squamous-cell carcinoma, alveolar-cell carcinoma, and bronchiolar adenoma of the lungs; hepatocellular adenoma and carcinoma; adenocarcinoma of the colon; follicular-cell adenoma and carcinoma of the thyroid; and adenocarcinoma of the uterus. Many of these tumors had invaded surrounding tissue or metastasized to the lungs, lymph nodes, liver, or spleen. The ear-canal tumors currently are classified as Zymbal gland tumors.

Remarks on result:

not determinable

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

1 500 ppm

Organ:

liver

lungs

thyroid gland

zymbal gland

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

not specified

In addition to the neoplastic lesions, a number of chemically induced degenerative, proliferative, and inflammatory lesions were observed. These included lesions in the lung (epidermal inclusion cyst formation, alveolar-cell hyperplasia, and alveolar and bronchiolar squamous metaplasia), liver (hepatocellular nodular hyperplasia and bile duct hyperplasia), and thyroid gland (follicular-cell hyperplasia). These lesions were not observed in any of the control animals. Epidermal inclusion cysts, alveolar-cell hyperplasia, and alveolar and bronchiolar squamous metaplasia were observed, respectively, in 5, 15, and 12 of 33 low-dose males and 2, 13, and 4 of 32 low-dose females. Thyroid follicular-cell hyperplasia occurred in 1 of 33 low-dose males and 7 of 33 low-dose females. Thyroid and lung lesions were not observed in the high-dose groups. Liver nodular hyperplasia occurred in 4 of 33 low-dose and 10 of 33 high-dose males and 1 of 32 low-dose and 9 of 33 high-dose females. Bile-duct hyperplasia occurred in 8 of 33 low-dose and 25 of 33 high-dose males and in 6 of 33 low-dose and 12 of 33 high-dose females.

Conclusions:

TDA was carcinogenic in rats.
Based on the similarity between the chemical source (TDA) and the chemical target (DAPEA), study results can be reliably extrapolated to DAPEA.

Justification for classification or non-classification

Since 4-(p-nitrophenylthio)aniline is structurally similar to 4,4'-Thiodianiline (which has a harmonized classification as Carc 1B, H351) and considering the positive results revealed by the bacterial revers mutation assays, 4-(p-nitrophenylthio)aniline is suspected to be carcinogen. Therefore, classification as Carc. 2 H351 applies, in accordance with CLP Regulation.