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Description of key information

The toxicity of TPA has been investigated in studies using repeated dose dietary exposure and repeated inhalation exposure in studies in the rat. No adverse effects were noted in the key inhalation study in the rat. The critical effect of oral exposure is urolithiasis, the formation of urinary calculi and secondary effects on the urinary system including inflammation, hyperplasia, haematuria and increased kidney weights. Effects at high dose levels result in mortality.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
125 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
A number of sub-chronic rat studies of variable quality are available.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
10 mg/m³
Study duration:
subacute
Species:
rat
Quality of whole database:
A recent, guideline-compliant study is supported by an older study

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
10 mg/m³
Study duration:
subacute
Species:
rat
Quality of whole database:
A recent, guideline-compliant study is supported by an older study

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

Repeated dose oral toxicity

Studies with TPA

In an older study (Williams, 1955), male and female albino rats were fed terephthalic acid in the diet for 90 days, at levels of 0, 1, 3.2 and 10%. All groups showed a tendency towards anaemia. Pathological examination of the 3.2% group revealed mild injury to the urinary tract in 2 of 12 rats. Rats fed 10% showed decreased food consumption and growth rate, and exhibited recurring haematuria. Males were more affected than females. Pathological examination revealed the presence of calculi in the urinary tract. A NOAEL of 1% (approximately equivalent to 1000 mg/kg bw/d) can be determined for this study, however it is noted that the investigations in this study were limited.

In a further study, a single dose level of terephthalic acid was fed to rats in the diet for 90 days (Vogin, 1972). The initial dose level was 5%, but this was reduced to 3% one week into the study because the rats showed decreased body weight gain. There were no substance related mortalities. Occult blood was found in the urine, and crystalluria was seen after 90 days. There was an increase in kidney weights, but as no other organs were affected this was not thought to be biologically significant. Bladder and kidney calculi formed, with a higher incidence in males than females. The only effect noted at necropsy was a mild to moderate epithelial hyperlasia of the bladder and evidence of chronic cystitis. The dose level in this study is estimated to be equivalent to 3000 mg/kg bw/d (using default conversion factors); 2070 and 2490 mg/kg bw/d in males and females respectively using food consumption and terminal bodyweight values.

In a further study (Kohn, 1970), terephthalic acid was fed to male and female albino rats for 15 weeks to determine the oral toxicity of the substance. Dietary dose levels were 0.05, 0.16, 0.5, 1.6 and 5% (w/w). Two additional groups were fed plain diet to serve as controls. Interim sacrifices were conducted following 30, 60 and 90 days of testing on 3 males and 3 females from each group. The remaining 10 rats/sex/group were necropsied at the end of the 15 week feeding period. Blood and urine samples were obtained immediately prior to the start of the test and at 1, 2 and ~3 months later. Males and females in the high dose group exhibited a small reduction in body weight gain, but food consumption and utilisation were apparently unaffected. Haematuria was observed on a sporadic basis amongst the high dose males during the second and third months of the study, haematuria was not seen in females. However, urinalysis revealed occult blood was present at various time points in males in the 0.16, 0.5, 1.6 and 5% groups, and in females in all dose groups. It appeared that the majority of terephthalic acid was exrected in the urine. Gross pathology revealed significant effects of treatment on the urinary bladder of high dose males. A high incidence of bladder stones were found in this group, and microscopic examination revealed proliferative changes characterised by a thickening of the epithelium, and in some cases a narrowing of the lumen of the bladder was observed. It appears that males were more affected by treatment than females.

Dose levels based on default conversion factors are calculated to be equivalent to 0, 50, 160, 500, 1600 and 5000 mg/kg bw/d. Using figures for bodyweight and food consumption for the final week of the study, actual intakes of 0, 31, 96, 313, 980 and 2820 mg/kg bw/d are calculcated for males; values of 0, 39, 121, 372, 1186 and 3922 mg/kg bw/d are calculated for females.

The isolated findings of urinary occult blood seen at all dose levels in this study are difficult to interpret. Findings are reported semi-quantitatively (classed as 'negative', 'small', 'moderate' and 'large' for pooled urine samples taken from 2 rats/sex/group pre-test and after treatment for 1, 2 and 3 months. It is notable that the results of uirnalysis from the chronic toxicity and carcinogenicity study of Preache et al (1983) do not report any effects on the incidence of urinary occult blood (measured in 5 rats/sex at 6 and 12 months and in 20 rats /sex at 18 and 24 hours) with the exception of both sexes at the highest dose level of 1000 mg/kg bw/day at 18 months. The effects seen at lower dose levels in the Kohn study are therefore not considered to be reliable due to the small sample size and the potential for cross-contamination.

In a further 90 -day study (Ledoux et al, 1982), terephthalic acid was fed to groups of male and female Wistar and CD rats for 90 days, to investigate TPA-induced urolithiasis. Nominal dietary concentrations were 0, 0.03, 0.125, 0.5, 2.0 and 5.0%. Sacrifices were carried out at 30, 60 and 90 days for gross pathology and histopathological examination of the urinary tract. Urine was collected at the time of sacrifice. Ten rats/sex/strain/group were not sacrificed, and instead continued onto a reproductive toxicity study. Toxicity was evident in rats fed diets containing 0.5% TPA and above; these rats exhibited reduced weight gain compared to controls. CD males fed 0.03% also exhibited significanty reduced weight gain. Five deaths occurred between 4 and 13 weeks in the rats fed 5% TPA; these rats did not have bladder calculi. Diarrhoea was observed in some of the rats exposed to high TPA concentrations. A small number of bladder calculi were found in rats fed the 5% TPA-diet for 90 days; calculi were more frequently observed in Wistar rats (6/20) than CD rats (1/20). TPA-administration resulted in a decrease in urinary pH. Chronic inflammatory lesions of the bladder and urethra were observed in treated rats, with the highest incidence occurring in rats fed 5% TPA. Nodules and cysts contaiing parasitic larvae were discovered in the liver of a number of treated rats. Some small strain differences were present, but it was concluded that there is no substantial difference in TPA toxicity between CD and Wistar rats. Based on body weight reductions, the NOAEL can be considered to be 0.125% TPA in the diet.

Study with DEHT/DOTP

In a 90 -day rat study performed with the read-across substance DEHT, effects of treatment were limited to reduced erythrocyte parameters at 0.5% and 1.0% and increased relative liver wieght at 1.0%. Effects on haematological parameters at 0.5% (reduced MCV in males; reduced MCV and MCH in females) are not considered to be of toxicological significance in the absence of effects on erythrocyte count or haematocrit. A NOAEL of 0.5% is therefore determined for this study, equivalent to mean achieved intakes of 277 and 309 mg/kg bw/d in males and females, respectively. Based on the hydrolysis of DEHT to form TPA in the gastrointestinal tract, mean intakes of TPA at the NOAEL are calculated to be 118 and 131 mg/kg bw/d in males and females, respectively. The NOAEL is therefore comparable with TPA studies.

Repeated inhalation toxicity

In one inhalation study (Leach & Hatoum, 1987), terephthalic acid was administered as an aerosol by inhalation at target concentrations of 0, 0.5, 1.0 and 3.0 mg/m³ to four groups of 10 male and 10 female Sprague-Dawley rats each. The rats were exposed 6 hours per day, 5 days per week, for 4 weeks. In addition, 6 rats per sex, designated for pulmonary function assessment, were included in the control and high exposure groups. The analytical time weighted average concentrations were 0, 0.52, 1.19 and 3.31 mg/m³ for the filtered air control, low, medium and high exposure groups, respectively. No deaths occurred during the study. The minimal adverse clinical signs noted were of comparable incidences among all groups including controls, and there were no effects of test article exposure on observations noted at necropsy. Histopathological findings consisted of minimal tracheal epithelial lining degeneration, occurring at an incidence of 5%, 30%, 65% and 95% in the control, 0.5, 1.0 and 3.0 mg/m³ groups, respectively. A slight increase of small areas of haemorrhage at the respiratory lymph nodes was also noted in test article exposed females. There were no statistically significant effects of treatment on body weights, organ weights, haematology or clinical chemistry parameters. Pulmonary function assessments did not reveal any significant differences between the control and high exposure groups. A NOEC could not be identified due to histopathological evidence of tracheal irritation in all exposure groups. The lowest exposure concentration of 0.5 mg/m3 can be considered a minimal LOEC, however the toxicological significance of these findings is unclear.

In order to further characterise the inhalation toxicity of TPA and specifcally to elucidate the local tracheal effects seen in the previous study, a further 28 -day inhalation toxicity study was performed. In this study (Fuhst, 2008), male and female Sprague-Dawley rats 10/sex/group) were exposed for 6 hrs/day, 5days/week for 4 weeks to clean air or terephthalic acid at analytical concentrations of 1.03, 2.93 and 10.05 mg/m3. The study included an additional control and high dose group of 5/sex that were permitted a 14-day recovery period prior to sacrifice. No adverse compound-related effects were observed in clinical observations, body weight, food consumption, water consumption, organ weights, and gross pathology findings. There were no ophthalmological findings, or any effects on locomotion and a functional observation battery. There were some effects of exposure on clinical chemistry parameters (cholinesterase, bilirubin and plasma glucose), however the changes were reversed in the recovery group and therefore considered to be of limited toxicological relevance. Statistically significant treatment-related histopathological lesions were not observed in the main or recovery groups, either in the target organs or in any other organ. Specifically, the tracheal effects reporetd in all treated groups in the previous study were not reproduced. The 28 day inhalation NOAEL of terephthalic acid in Sprague Dawley rats was therefore >10.05 mg/m³.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Most recent study, specificaly investigating the most sensitive endpoint

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
Most recent study

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
Most recent study

Justification for selection of repeated dose toxicity dermal - local effects endpoint:
No local effects identified in dermal irritation or dermal toxicity studies.

Repeated dose toxicity: via oral route - systemic effects (target organ) urogenital: urinary bladder

Justification for classification or non-classification

No classification for specific target organ toxicity is proposed.

Although specific organ toxicity has been identified in repeated dose oral toxicity studies with TPA, findings (effects on the urinary bladder secondary to urolithiasis) were not seen at relevant dose levels (i.e. <10 mg/kg bw/d or <100 mg/kg bw/d). NOAELs for the available studies are consistently approximately 1000 mg/kg bw/d with evidence of urolith formation in more sensitive weanling rats at dose levels of above 250 mg/kg bw/d. Additionally, the relevance of these effects to humans is questionable since, for anatomical reasons, rodents are more susceptible to urolithiasis than humans. Although an initital inhalation study (Leach & Hatoum, 1987) reported local microscopic effects on the tracheal lining (minimal degradation) at all exposure levels, these were not reproduced in a more recent study performed at higher exposure concentrations (Fuhst, 2008). As the Fuhst 2008 study was carried out at a specialist inhalation toxicology laboratory with special attention to respiratory tract pathology and a higher exposure concentration the results of this study are concluded to take precedence over those reported by Leach & Hatoum, (1987 .