Isophthalic acid

Carcinogenicity

Description of key information

Urinary tract carcinogenicity can be predicted for isophthalic acid, based on read-across from the substance terephthalic acid which is both structurally related and has a comparable toxicological profile.  This effect is considered to have a threshold mode of action and is of limited relevance to the human risk assessment.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion

Dose descriptor:

NOAEL

142 mg/kg bw/day

Justification for classification or non-classification

No classification is proposed for isophthalic acid (IPA) for carcinogenicity, based on read-across from the structurally-related and toxicologically comparable substance, terephthalic acid (TPA).

Increased incidences of urinary bladder transitional cell tumours were seen in two seperate rat studies at TPA dose levels equivalent to 1000 mg/kg bw/d and higher. Findings are secondary to chronic irritation caused by urolithiasis as a consequence of the precipitation of the substance in the urine at high dose levels and are only seen where the limit of solubility of TPA in the urine is exceeded.

Findings were only seen at dose levels that will not be encountered by humans following occupational exposure and, additionally, rats are known to be more susceptible to urolithiasis. TPA is non-genotoxic and the carcinogenicity seen in rats is a threshold effect associated with chronic mechanical irritation.

The critical toxicological effect of TPA has also been seen in a 90-day oral toxicity study with IPA (Vogin, 1992), in which effects on the urinary tract (kidney and bladder) were associated with urolithiasis following prolonged exposure. It can also be predicted that IPA will cause comparable carcinogenic effects on the urinary bladder following chronic administration due to the existance of a similar threshold (non-genotoxic) mode of action.

Additional information

Studies of carcinogenicity have been performed with the structurally-related read-across substance terephthalic acid (TPA). This read-across is relevant to isophthalic acid (IPA) as the critical effect of the repeated dose toxicity is the same for both substances, namely effects on the urinary tract secondary to urolithiasis. The substances are chemically similar and are shown to be similar in terms of their toxicokinetics and toxicity in acute and short-term studies. Both substances are well absorbed, distributed and excreted, with limited toxicity and the same target organ (i.e. the urinary tract secondary to uroliethiasis).

It can be predicted that IPA will also cause urinary tract carcinogenicity due to chronic irritant effects secondary to urolithiasis, however a clear threshold has been demonstrated for this effect which is addtionally not considered to be of direct relevance to humans at rpedicted exposure levels. IPA and TPA are not considered to be genotoxic.

Terephthalic acid was evaluated for toxicologic and/or carcinogenic effects in male and female Fischer 344 rats following dietary administration at levels of 0 (basal diet only), 20, 142 or 1000 mg/kg/day (Preache, 1983). The author found no definitive evidence that terephthalic acid is carcinogenic to rats. The rats may have been exposed to continuous lighting for a large portion of the study, resulting in a high incidence of eye lesions. Also, there was a large variation in diet dose levels determined which may have been responsible for the lack of clear dose-response relationships. The histopathology slides from the Preache (1983) were re-evaluated by another laboratory (Ackerman, 1983). Transitional cell adenomas and a single carcinoma were identified in female rats at the high dose level; findings were associated with diffuse epithelial hyperplasia. Evidence of bladder carcinogenicity was seen in females at the highest dose level in this study. Similar findings were reported in the study of Gross (1974), in which tumour incidences were increased at dietary dose levels of 2% and 5% (equivalent to approximately 1000 mg/kg bw/d and 2500 mg/kg bw/d, respectively). A NOAEL of 1% (equivalent to approximately 500 mg/kg bw/d) was derived for this study.

The US EPA (1984) reviewed the available literature and concludes that low levels (<1%) of terephthalic acid do not seen to induce carcinogenic effects. However, at 5% terephthalic acid formation of bladder and ureteral neoplasms were noted in male and female rats.

Carcinogenicity: via oral route (target organ): urogenital: urinary bladder