Terephthalic acid

Carcinogenicity

Description of key information

Data indicate that the chronic administration of terephthalic acid at high concentrations results in the formation of urinary bladder tumours as a consequence of chronic inflammation secondary to calculi formation.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

17 January 1978 to 15 March 1980

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The study is a well conducted proprietary study however there are several factors that may have affected the results

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)

GLP compliance:

no

Remarks:

: study pre-dates GLP

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

Male and female Fischer 344 rats, approximately 4 weeks of age, were obtained from Charles River Breeding Laboratories, Michigan. They were housed in groups of 3 in polycarbonate cages. Control animals were housed separately from treated animals in an adjacent room. Hardwood chips were used as bedding (Ab-sorb-dri, NJ). Food and tap water were available ad libitum. The basal diet was NIH 31 powdered meal (supplied by Zeigler Brothers). Test diets were prepared weekly by mixing terephthalic acid with the powdered diet. Animals were assigned to groups at 7 weeks of age using a random number table. At this time, the males weighed 135-179 g, and the females weighed 99-124 g. Light cycles were intended to be 12 hour light: 12 hour dark, however it appears that the system failed and the rats were exposed to continuous lighting for an undefined period.

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on exposure:

Terephthalic acid was administered in the diet at concentrations equivalent to intakes of 20, 142 and 1000 mg/kg/day. Test diets were prepared weekly; the apropriate quantity of terephthalic acid was added to 500 g of the basal diet and premixed by stirring with a large spatula. The premix was then added to a twin-shell blender and mixed for at least 1 minute/kg. Doses were calculated weekly on a mg/kg body weight basis.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

A sample of each diet was removed, frozen and stored for chemical determination of the concentration of terephthalic acid. Samples of diets mixed for the males in the low, middle and high dose groups were analysed for 8 of the first 24 weeks of the study.

Duration of treatment / exposure:

24 months; with interim sacrifices at 6, 12 and months

Frequency of treatment:

Daily in diet

Post exposure period:

None

Remarks:

Doses / Concentrations:0, 20, 142 and 1000 mg/kg/ bodyweight/dayBasis:actual ingested

No. of animals per sex per dose:

63

Control animals:

yes, plain diet

Details on study design:

Male and female rats were randomly assigned to treatment groups and fed powdered diet containing 0, 20, 142 or 1000 mg/kg bw/day terephthalic acid for 24 months. At 6 and 12 months, five animals of each were sacrificed. At 18 months 20 rats of each sex were sacrificed. The surviving rats were sacrificed at 24 months.

Positive control:

Not relevant

Observations and examinations performed and frequency:

All animals were observed twice daily (7 days/week) for general physical appearance and a record kept of dead or moribund animals. Food consumption (per cage group) was measured by weighing the food at the start and end of the week on a weekly basis for the first 13 weeks, bi-weekly for the succeeding 12 weeks, and monthly thereafter. Individual body weights were recorded, observations for signs of toxicity and pharmacologic effects were made, and the rats were palpated for masses at the same intervals as food consumption measurements.Haematology, clinical chemistry and urinalyses (see below) were performed on 5 animals/sex/group at 6 and 12 months, and 20 animals/sex/group at 18 and 24 months. Blood and urine samples were collected from animals fasted for 16 hours. Water consumption and urine output were also recorded at these time points. Blood samples were obtained from the abdominal aorta at the time of sacrifice. Both eyes of each animal to be sacrificed were examined with an indirect ophthalmoscope prior to the 6, 12, 18 and 24 month sacrifices. Mydriasis was induced with Mydriacil (Alcon Laboratories, Texas).An evaluation of neurological function was made on animals at the scheduled sacrifices. This included an assessment of posture and gait, tone of facial muscles and an examination of pupillary, palpebral, extensor thrust, and crossed extensor reflexes.

Sacrifice and pathology:

Satellite groups were sacrificed and necropsied at 6, 12 and 18 months. Surviving animals were sacrificed and necropsied at after 24 months on the study. Animals were anaesthetised by pentobarbital injection at the 6 month sacrifice and by CO2 gas thereafter. Animals found dead or sacrificed due to a moribund state were also necropsied. Animals necropsied at the interim sacrifices, and for 20-22 animals sacrificed at study termination, fresh unstained impression smears of liver were examined microscopically for porphyrin fluorescence by exposure to UV light.The following organs were excised, trimmed, blotted dry and weighed prior to fixation: brain, heart, liver, kidneys, lungs, and testes or ovaries. The following tissues from each rat were preserved in 10% neutral buffered formalin: brain (including optic nerves), peripheral nerves, pituitary, thyroid, parathyroid, submaxillary salivary glands, heart, lungs, spleen, liver, pancreas, adrenals, lymph nodes, kidneys, urinary bladder, ovaries, uterus, oviducts, stomach, small intestine, large intestine, skeletal muscle, skin, mammary glands, bone marrow, aorta, ear canal, nasal turbinate, trachea, spinal cord and ganglia, oesophagus, thymus, prostate, seminal vesicles, epididymis and any gross lesions. The testes were fixed in Bouin's solution. The eyes were fixed in Bouin's solution if collected during the first 16 months of the study, and in 3% glutaraldehyde thereafter.All tissues were stained with haematoxylin and eosin and examined microscopically.

Other examinations:

None reported.

Statistics:

ANOVA. Chi-square.

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

During the first 12 months, the majority of weekly body weight values were significantly lower in treated groups compared to the control group

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Reduced food consumption was observed in treated males and females, compared to controls

Food efficiency:

not examined

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

effects observed, treatment-related

Description (incidence and severity):

Water consumption was increased over control values at 18 months for the females in the high dose group and at 24 months for the males in the high dose group

Ophthalmological findings:

effects observed, treatment-related

Description (incidence and severity):

Findings caused by lighting malfunction

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Description (incidence and severity):

Reduced serum ALT activity was observed but is not considered to be of toxicological signifcance

Urinalysis findings:

effects observed, treatment-related

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

: increased relative liver weights

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

effects observed, treatment-related

Details on results:

MORTALITY19 females (5 control, 3 low dose, 9 middle dose and 2 high dose) and 4 males (1 low dose, 1 middle dose and 2 high dose) died or were sacrificed in a moribund state during the first 12 months. Amongst the females, the main cause of death was generalised septicaemia, an incidental finding was the presence of unilateral ovarian abscesses. E. coli (non-enteropathogenic) was isolated in pure culture from the ovaries of the 3 rats with grossly observed abscesses. An additional 45 rats died and 24 were sacrificed during the 12-18 month period. All treated groups had slightly fewer rats alive at 18 months compared to controls; however this difference was not statistically significant. There was no predominant cause of death for males dying between 12 and 18 months. In females, the predominant cause of death between 12 and 18 months was uterine adenocarcinoma. The frequency of spontaneous deaths and the number of animals sacrificed in a moribund state increased during the last 6 months of the study: 75 males died between 18 and 24 months, an additional 36 were sacrificed; in female animals there were 105 deaths and 33 sacrifices. Control and treated groups of males had comparable numbers of animals surviving to study termination. There were more females surviving to study termination in the control group compared to treated groups, however among the treated groups the low dose group had the fewest survivors and the high dose group had the most. The most common cause of death in males dying in the final 6 months of the study were myelomonocytic leukaemia (4/28 controls, 7/34 high dose) and chromophobe adenomas (2/28 controls, 7/34 high dose). 5 control males and 2 high dose males died of malignant lymphomas. There was no other predominant cause of death. In the middle and low dose groups of males pituitary masses were the probable cause of death for 15 animals, and an enlarged spleen for 8 animals. In females during the final 6 months of the study, uterine tumours were the common cause of death in both treated and control groups. Chromophobe adenomas and pituitary masses were also reported as causes of death.CLINICAL SIGNSAt 12 months, the overall incidence of overt clinical signs was low. 17 of the surviving rats were noted as having skin rashes, small skin masses, eye opacities, and one animal had localised alopecia. The signs were observed across treatment and control groups. Between 12 and 18 months, the number of rats showing clinical signs increased substantially for all groups. The percentage of rats that appeared normal at the 18 month examination was significantly lower in all treated groups compared to controls. The majority of clinical signs observed were related to eye opacity. External or subcutaneous masses were seen in 5-10% of all males at the last examination, but did not appear treatment related. At the 18 month examination, females had a lower incidence of eye abnormalities than males, but more frequently had crusting around the eyes. External and subcutaneous masses were observed in 3% or fewer animals, with the highest incidence occurring in the control group. At the 23 month examination all animals except 2 (1 control and 1 mid dose) were showing clinical signs. Cloudy or opaque eyes were present in >95% of the males in all groups. Other eye abnormalities were noted, including yellow eyes, but there was no evidence of a treatment-related effect. External or subcutaneous masses were present at frequencies of 19-26% of in all groups of males, except the middle dose which was 6%. Hyperreactivity (as evidenced by resistance to handling) was reported for about 10% of the males in each treated group, and 1% of the controls. Only 2 female (controls) were recorded as normal at the 23 month observation. The predominant clinical sign reported was opaque or cloudy eyes, present in 91% control and 96-100% of the treated females. Matter crusted round the eyes occurred in the mid and high dose females at frequencies of 15-20% and in controls and low dose females at <6%. External or subcutaneous masses were present in 15-22% of all groups. All neurological parameters were found to be within normal limits for rats sacrificed at 6 and 12 months. The pupillary reflex could not be detected in a number of animals at 18 months due to eye opacity. By study termination all animals possessed opaque eyes therefore pupillary reflexes could not be determined. 3 rats and 18 months and a small number in each group (≤10) at study termination exhibited either abnormal posture or abnormal gait. Accompanying clinical signs (hunching, instability, awkward locomotion due to the presence of a large mass) indicated that these observations were more likely a result of poor condition rather than neurological defecits. BODYWEIGHTDuring the first 12 months, the majority of weekly body weight values were significantly lower in treated groups compared to the control group (within each sex). However, the different groups of rats were weighed on different days which may have been responsible for the differences observed. Because of this, weight changes from the start of treatment were analysed at weeks 52, 68 and 85 for males and females, and also at 104 for females. High dose males gained significantly less weight than control males at 52 weeks but not at the other two periods considered, and weight gains for the low and middle dose males were either significantly greater than those of controls (week 52) or not different. High dose females had body weight gains that were significantly lower than control values at weeks 52, 85, and 104 but not at week 68. The only significant differences observed for the other two groups of females was a greater than control weight gain for females in the low dose group at week 68. It appears that female body weights were more strongly affected by test-substance administration than the males, with the majority of the effects occurring in the first 6 months of the study.FOOD AND WATER CONSUMPTIONReduced food consumption was observed in treated males and females, compared to controls, during the first few months of the study. However the difference was reversed in females between months 6 and 18. Water consumption was increased over control values at 18 months for the females in the high dose group and at 24 months for the males in the high dose groupOPHTHALMOSCOPYAt 6 months cataracts were found only in the terephthalic acid treated animals with the highest incidence (three of five rats examined) occurring in male rats receiving the high dose. Treated males had a high incidence of cataracts at 12 months, and cataracts were found in several treated females, as well as in 1 male and 1 female control. A t 18 months, all animals examined had cataracts. With the exception of five control female rats, all cataracts had progressed to maturity in at least one eye. Inflammation of the iris (in some cases associated with haemorrhage) was present in 239 of the 275 males and 182 of the 220 females examined at 24 months. These lesions were equally distributed among the treatment groups. Approximately 23% of the females and 6% of the males showed dark brown haemorrhagic staining around one or both the eyelids. Other findings included the presence of corneal crystals or vascularisation evidence of anaemia, iris-corneal adhesions and a single eyelid tumour.URINALYSISA significant increase in urine output was observed for male animals in the middle dose group at 12 months. At 18 months it appeared that both the male and female high dose groups more frequently had blood in the urine and in several cases where the value was on the high end of the scale, this was associated with high red blood cell counts. At 24 months, blood in the urine was a relatively common finding for females (46% of all females examined) but was less frequently observed in males (24%) and in neither case did the treated groups appear different from the controls. At 18 and 24 months high dose males exhibited a lower urine pH than other groups alongside an absence of triple phosphates.CLINICAL CHEMISTRYThe SGPT (ALT) mean value for females fed terephthalic acid at the high dose was significantly lower than the control value for females sacrificed at 12 months (26 ± 2 vs 47 ± 18). No other differences were detected. HAEMATOLOGYThere were some statistical differences in haematological parameters between treated and control rats at 6 and 12 months (haematocrit, haemoglobin, erythrocyte count and leukocyte count). At 18 and 24 months there were no significant differences between treated and control groups. ORGAN WEIGHTSTerminal body weights for males fed the high dose were reduced at 18 months but did not differ significantly from those of controls at other sacrifice times. For male rats treated with the high dose of terephthalic acid, there was a significant reduction, compared to control values, in the weight of the lung, heart, liver, and kidney at study termination and the kidney weight for this group was also reduced at 18 months. Prior to 18 months the only significant reduction in organ weights for male animals was a decrease in heart weight, reflected in both absolute and relative weights, in the high dose group at 12 months. At 6 months, the weight of the testes in the low dose group was greater than that of controls. Heart and kidney weights were reduced in females in the high and middle dose groups sacrificed at 24 months. At this time as well as at 18 months, the relative brain weight was increased for females in the high dose groups. This finding in association with significantly reduced body weights at both 18 and 24 months suggest that the organ weight reductions were a result of an overall weight loss. At 6 and 12 months, the ratio of liver weight to body weight was significantly greater than control values for females fed the high dose of the test material. An increase in the weight of the ovaries was observed for high dose females sacrificed at 12 months but was not present at later periods.PATHOLOGYThe unstained impression smears of the liver were negative for porphyrin fluorescence. A variety of spontaneous lesions were observed in all group but they did not appear to be related to the experimental regimen. The most frequent lesion was related to chronic murine pneumonia and consisted of a trace level of peribronchial lymphoid infiltration in the lungs of all animals. Various levels of mammary hyperplasia and galactocoele occurred in most males and a few females, treated and control, with no apparent relationship to treatment. At the 12-month sacrifice, no abnormalities were observed at necropsy in control animals of either sex or in males treated with the highest dose. All other groups contained at least one animal in which there was a notable lesion or tissue variation. For animals that died or were sacrificed moribund during the first 12 months of this study, lesions or tissue variations were noted in all groups except the male control group in which no animals died. A variety of spontaneous lesions were noted at histopathology but they did not appear to be treatment related. A few hyperplastic and neoplastic lesions occurred without relationship to treatment and these lesions are also expected in animals of this strain and age: clear cell hyperplasia of the thyroid was seen in 2 control males; a single islet cell adenoma was present in the pancreas of a treated male; a single testicular interstitial cell tumour was present in a control male; focal interstitial cell hyperplasia occurred in the testes of 1 control and 1 treated male.Neoplastic lesions were observed in animals that were sacrificed moribund or died during the first 12 months of the study: a transitional papilloma of the urinary bladder, a malignant mesothelioma, and an adenoma (salivary gland or pancreas) were each observed in 1 male of either the high, middle or low dose groups; there was a single case of each of four lesions in high dose females — focal granuloma or lymphoma in the brain, a malignant lymphoma in the ileum, and a lung lymphoma; 1 control female had an adenoma of the adrenal cortex. Bladder lesions were seen in 5/7 high dose males that died or were sacrificed during the first 12 months.The number of different lesions increased substantially during the 12-18 month period, as would be expected given the increasing age of the rats. The majority of the lesions were present in control and treated rats. Uterine abnormalities occurred more frequently in the treated groups and uterine masses occurred only in the treated groups. The incidence of adenoma or adenocarcinoma of the uterus appeared dose related with a 40% incidence of neoplasia in the high dose group sacrificed at 18 months. No uterine tumours were present in the control animals. Bladder lesions were seen at histopathological examination, mainly in high dose females.At study termination, urinary bladder stones were found in high dose females. The uterine masses that first appeared during the 12-18 month period of the study had increased substantially in number by the final study period. At the terminal sacrifice 20-30% of the females in each group, including the control group, bore such masses and the comparable percentages for animals that died or were sacrificed moribund during the last period of the study ranged between 35% and 50%. There was a compound related increase In tumours, hyperplasia and metaplasia of the urinary bladder among females which were sacrificed terminally or which died on study between 18 months and terminal sacrifice. Calculi were observed either grossly or microscopically in 9 of the 15 high dose females with transitional cell adenomas and in both of the females with transitional cell carcinomas, in two high dose females a bladder stone was present in the absence of a tumour.

Relevance of carcinogenic effects / potential:

Evidence of a carcinogenic effect was seen at the high dose level in this study; transitional cell tumours were increased in high dose females, findings were associated with a chronic proliferative response to urolithiasis and therefore represent a non-genotoxic and threshold mode of action of limited relevance to the human risk assessment.

Dose descriptor:

NOAEL

Effect level:

142 mg/kg bw/day

Based on:

test mat.

Sex:

female

Basis for effect level:

other: see 'Remark'

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

Dose descriptor:

NOAEC

Effect level:

1 000 mg/kg bw/day

Based on:

test mat.

Sex:

male

Basis for effect level:

other: No effects were seen at the highest dose level

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

Two lesions, atrophy and fibrosis of the retina and uterine adenocarcinoma, had an unusually high incidence in this study. However, these lesions were present in similar numbers in control and treated animals and they were not considered to be related to treatment. Atrophy and fibrosis of the retina was present in both sexes and was a very severe lesion, with most animals affected. The functional tissue of the retina was essentially obliterated and replaced with fibrotic tissue in these animals. The lesions represent a severe and end-stage lesion of light-induced retinopathy and is a consequence of the laboratory lighting malfunction. Uterine adenocarcinoma is not a common spontaneous lesion in this strain of rat. The lesions were especially malignant with numerous metastases to abdominal lymph nodes, other abdominal tissues and the lungs. Metastasis often occurred while the primary lesion was still quite small. The tumours appeared to grow through the uterine wall to the serosal surface and to metastasise at that point. The tumours were very fibrous when growing on the serosal surfaces. The reason for the high incidence of uterine tumours cannot be established with certainty but light-induced increases in circulating oestrogen is considered as a possible cause. The severe retinal lesions support this interpretation.

Dietary analysis revealed deviations from the target intakes, and a high level of variability:

Target intake (mg/kg bw/d)	Mean deviation from intended intake	Range
20	17%	-13% to +71%
142	9%	-15% to +22%
1000	8%	-11% to +15%

Terminal mean body weights (g) and organ weights (g) of male and female rats sacrificed at 18 or 24 months

mg/kg bw/d	Body weight	Brain	Lungs	Heart	Liver	Kidneys	Gonads
Males at 18 months
Controls	444 ± 30	2.06 ± 0.10	2.96 ± 0.56	1.33 ± 0.15	12.09 ± 1.17	3.16 ± 0.18	5.98 ± 0.92
1000	418*± 24	2.04 ± 0.11	3.01 ± 0.43	1.27 ± 0.12	11.90 ± 1.25	2.87*± 0.21	5.61 ± 0.88
142	444 ± 27	2.04 ± 0.11	2.79 ± 0.53	1.28 ± 0.12	11.48 ± 0.90	3.10 ± 0.16	5.42 ± 1.25
20	431 ± 38	1.99 ± 0.09	2.78 ± 0.50	1.28 ± 0.10	11.31 ± 0.65	3.08 ± 0.16	5.39 ± 0.74
Females at 18 months
Controls	257 ± 17	1.83 ± 0.05	2.13 ± 0.44	0.83 ± 0.07	6.79 ± 0.63	1.96 ± 0.14	0.18 ± 0.7
1000	228^S± 23	1.82 ± 0.07	1.84 ± 0.28	0.78 ± 0.08	6.39 ± 0.51	1.69 ± 0.12	0.18 ± 0.9
142	250 ± 30	1.81 ± 0.06	1.94 ± 0.31	0.81 ± 0.07	6.73 ± 0.68	1.99 ± 0.71	0.57 ± 1.82
20	249 ± 20	1.82 ± 0.07	1.97 ± 0.37	0.83 ± 0.07	6.67 ± 0.65	1.99 ± 0.59	0.30 ± 0.52
Males at 24 months
Controls	399 ± 56	1.96 ± 0.14	3.18 ± 0.61	1.27 ± 0.21	14.96 ± 2.52	3.47 ± 0.51	5.16 ± 1.79
1000	385 ± 51	1.99 ± 0.14	2.80*± 0.48	1.18*± 0.11	13.31*± 2.21	3.03*± 0.27	4.44 ± 1.48
142	404 ± 44	1.98 ± 0.16	3.06 ± 0.53	1.22 ± 0.13	14.50 ± 2.32	3.34 ± 0.49	4.64 ± 1.85
20	390 ± 43	1.94 ± 0.12	3.02 ± 0.40	1.23 ± 0.12	13.90 ± 2.17	3.38 ± 0.51	4.57 ± 2.06
Females at 24 months
Controls	283 ± 40	1.79 ± 0.13	2.17 ± 0.32	0.96 ± 0.09	9.63 ± 1.69	2.32 ± 0.23	0.27 ± 0.39
1000	249*± 37	1.79 ± 0.09	2.03 ± 0.26	0.88* 0.05	8.91 ± 2.33	2.02*± 0.20	0.18 ± 0.05
142	264 ± 36	1.78 ± 0.09	2.11 ± 0.34	0.88*± 0.08	8.90 ± 1.89	2.18*± 0.28	0.44± 1.07
20	272 ± 44	1.77 ± 0.17	2.19 ± 0.70	0.93 ± 0.13	8.92 ± 1.65	2.21 ± 0.17	0.20 ± 0.06

*= Significantly lower than controls (p<0.05)

Conclusions:

Evidence of transitional cell carcinogenicity was seen in females at the highest dose level in this study.

Executive summary:

Terephthalic acid was evaluated for chronic toxicity and carcinogenicity in male and female Fischer 344 rats using dietary administration at levels equivalent to 0 (basal diet only), 20, 142 or 1000 mg/kg bw/d. The number of control female rats surviving to study termination was greater than the number surviving in groups treated with terephthalic acid; however there was no evidence of a dose-response relationship in survival rates. Clinical observations revealed no signs that could be directly attributable to treatment with terephthalic acid. Bodyweights and food consumption were initially lower than controls for males administered terephthalic acid at 1000 mg/kg/ bw/d and for all treated groups of females. The body weight differences for the high dose group was sustained, whereas for females in the low dose group the major effects were apparent during the first 6 months of the study. Neither the neurological nor the ophthalmologic evaluations provided evidence of effects of treatment. Analysis of organ weight data indicated that at 6 and 12 months, relative liver weight was higher in females at the highest dose level. At study termination, heart and kidney weights were reduced in females of the high or middle dose groups; there was also an increase in relative brain weight at these time points and at 18 months. For high dose males, weights of the lungs, heart, liver, and kidneys were reduced at study termination; reductions were generally consistent with an overall reduction in body weight. Other than a reduction in urine pH for high dose males at study termination, clinical laboratory evaluations (urinalyses, haematology, and clinical chemistry) did not show treatment-related effects. Over the course of the study, terephthalic acid induced bladder stones or sand-like particles in 13/126 high dose females; three further females in this group showed microconcretions or calculi at histopathologic evaluation. The incidence of bladder tumours in high dose females was 19/118; for 6 of these 19 females, there was no gross or histologic evidence of urolith formation. Squamous metaplasia, present in the bladder of 11/118 high dose females and not in controls, was associated with bladder tumours in all cases. Bladder epithelial hyperplasia may have also been increased in high dose females, but this lesion also occurred in control females as well as in males. An abnormally high incidence of eye lesions (cataracts and associated lesions as well as retinal lesions) in all groups; a high incidence of uterine adenocarcinomas was also observed cross all groups of females. These lesions were seen in both control and treated rats, and are likely to have been a result of exposure to continuous lighting. Evidence of a carcinogenic effect was seen at the high dose level in this study; transitional cell tumours were increased in high dose females, findings were associated with a chronic proliferative response to urolithiasis and therefore represent a non-genotoxic and threshold mode of action of limited relevance to the human risk assessment.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

142 mg/kg bw/day

Study duration:

chronic

Species:

rat

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

No classification is proposed for carcinogenicity. Increased incidences of urinary bladder transitional cell tumours were seen in two seperate rat studies at 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 clear threshold effect associated with chronic mechanical irritation.

Additional information

Evidence of carcinogenicity was seen in a chronic rat study (Preache, 1983; Ackerman, 1983) in which female rats had an increased incidence of transitional cell adenomas and carcinomas at the highest dietary concentration equivalent to approximately 1000 mg/kg bw/d. Findings were secondary to urolithiasis and were associated with inflammation and irritation. Similar findings in the bladder were reported in the study of Gross (1974), in which bladder 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). Data therefore indicate that chronic exposure to a very high level of terephthalic acid in the diet results in bladder carcinogenicity as a consequence of urolith formation and consequent irritation and inflammation of the urothelium. The mechanism of carcinogenicity is therefore non-genotoxic, has a clearly identified threshold and is of little relevance to the human risk assessment.

Justification for selection of carcinogenicity via oral route endpoint:
Guideline compliant study with some limitations but with supporting weight of evidence obtained from other studies

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