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Description of key information

15-weeks, rat NOAEL = 1220 (males), 1456 (females) mg/kg/day (1.6% of diet) based on bladder calculi and subsequent hyperplasia [CAS# 100-21-0], Reliability = 2

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
sufficient for the derivation of the long term systemic DNEL
Justification for type of information:
The test substance rapidly hydrolyses to terephthalic acid (TPA). Therefore, the study with TPA is being used to determin DNEL values. Additional documentation, provided within the IUCLID Assessment Reports section, supports the read-across approach.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
other: Carworth Farm CFN
Sex:
male/female
Details on test animals or test system and environmental conditions:
The animals were weanling albino rats obtained from Carworth Farms CFN, weighing 66-79 g on arrival. They were housed individually in wire-bottom cages. Food (Rockland Rat Diet) and water were provided ad libitum.
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
The test diets were prepared by blending the test material into pulverised Rockland Rat Diet using a Hobart mixer. Diets were distributed on a weekly basis.
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
Diets and test substance were mixed on a w/w basis, no analyses of test substance content or stability were performed.
Duration of treatment / exposure:
15 weeks
Frequency of treatment:
Feed was available ad libitum.
Dose / conc.:
0.05 other: %
Remarks:
nominal in diet
Dose / conc.:
0.16 other: %
Remarks:
nominal in diet
Dose / conc.:
0.5 other: %
Remarks:
nominal in diet
Dose / conc.:
1.6 other: %
Remarks:
nominal in diet
Dose / conc.:
5 other: %
Remarks:
nominal in diet
No. of animals per sex per dose:
30
Control animals:
yes, plain diet
Details on study design:
Rats were randomly assigned to treatment groups; five test groups each fed diet containing one of five concentrations of terephthalic acid and two control groups fed plain diet.
Positive control:
Not examined
Observations and examinations performed and frequency:
Daily observations were performed for mortality, signs and/or symptoms of toxicity. Body weights were recorded at the start of the test, and weekly thereafter. Food consumption was measured weekly on an individual animal basis. Food utilisation data were calculated based on consumption and weight gain.
Haematology analysis was carried out just prior to the start of the test, and at one, two and ~three months using fasted blood samples taken from a minimum of 5 males and 5 females in the groups selected. Parameters measured were: haemoglobin concentration, haematocrit value, erythrocyte count, total and differential leukocyte count.
Clinical chemistry analysis was carried out after ~3 months in a minimum of 5 males and 5 males in the groups selected. Parameters measured were: serum urea nitrogen concentration, serum alkaline phosphatase activity, serum glutamic-pyruvate transaminase activity and serum calcium concentration.
Urinalysis was carried out using samples collected at the same time as the blood samples. Pooled samples from 2 males and 2 females in each group were analysed. Parameters measured were: ketones, glucose, protein, pH, occult blood, microscopic elements.
Terephthalic acid content in the blood and urine was also determined.
Sacrifice and pathology:
All animals were subject to gross necropsy, including any that died during the study.
3 males and 3 females from each group were sacrificed at 30, 60 and 90 days for interim pathology. Special attention was given to examination for urinary calculi. Sections of the following tissues and organs were preserved in 10% formalin: heart, lungs, trachea, liver, pancreas, oesophagus, testes, ovaries, seminal vesicles, prostate, uterus, salivary glands, stomach, small intestine, caecum, colon, spleen, lymph nodes, kidneys, ureters, urinary bladder, adrenal glands, thyroid gland, pituitary gland, parathyroid gland, brain, bone marrow, skeletal muscle and any abnormal tissue.
After 105 days testing, the remaining animals were sacrificed and subject to gross necropsy as above.
Organ weights were determined for the liver, kidneys, spleen, heart, brain, gonads and lungs.
Microscopic evaluations were conducted on all tissues taken from the rats sacrificed at 30 and 60 days. In addition, kidney and bladder sections of animals from the two highest dose groups sacrificed at 90 days were included. At the final sacrifice, complete microscopic examinations were made on tissues from 10 males and 10 females in the highest dose group and in one control group. In addition, sections of kidney and bladder were examined from the remaining 7 high dose males as well as from 10 males and 10 females in other groups. Tissues were stained with Haematoxylin-Eosin, and kidney sections were also treated with Von Kossa's stain for calcium.
Other examinations:
None reported
Statistics:
ANOVA and Duncan tests
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
The only sign of toxicity observed was haematuria, occurring on a sporadic basis amongst most high-dose males during the last 2 months of the study.
Mortality:
mortality observed, treatment-related
Description (incidence):
One male in the 0.5% group died on day 56. Three females in the 5% group died on days 54, 87 and 90. No specific cause of death was attributed.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
The high dose groups gained less weight that the controls.
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
The only finding following urinalysis was occult blood in the urine of males from dose groups 0.16, 0.5, 1.6 and 5.0%, and in females from all treated groups.
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Some small differences in organ weights noted between groups, but the differences were not dose-dependent and were thought to be indirect effects of reduced weight gain.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Gross pathology findings were limited to the urinary bladder. High dose males exhibited distention of the bladder, and the bladders were found to contain one or more stones or concretions. The stones varied in size from <1 mm in length and diameter to approximately 3-4 mm in length and 1-1.5 mm in diameter. Stones were found in 3/3 rats sacrificed at 30 days, 2/3 rats sacrificed at 60 days, 2/3 rats sacrificed at 90 days and 9/17 rats sacrificed at study termination. No stones were seen in females of any group, or males in the other dose groups.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Mild focal non-specific inflammatory changes were seen in almost all sections of lung, however the changes are frequently observed in normal rats and were therefore considered to be related to naturally occurring disease.
"Vague impressions" of proliferative changes were observed in urinary bladder and occasionally in kidney pelvis epithelium in all animals including controls. The changes were markedly increased, both in severity and in the number of animals affected, in high dose males. In this group the epithelium of the bladder was piled up in high fronds and in large irregular nests of cells. Also, the lumen of the bladder was narrow in several rats. Evidence of proliferative change in high dose females, and males and females of lower dose groups was inconclusive.
Histopathological findings: neoplastic:
not examined
Description (incidence and severity):
It appeared that the majority of the test substance was excreted in the urine.
Dose descriptor:
NOAEL
Effect level:
1.6 other: % (1220 mg/kg bw males, 1456 mg/kg bw females)
Sex:
male/female
Basis for effect level:
gross pathology
Critical effects observed:
yes
Organ:
bladder

Calculation of the NOAEL of 1.6% terephthalic acid in the diet to 1220 mg/kg bw in male rats, and 1456 mg/kg in female rats is reported in OECD SIDS, SIDS Initial Assessment Report for the 12th SIAM, Paris, France, June 2001,Terephthalic Acid (TPA) CAS No: 100 -21 -0 (http://www.chem.unep.ch/irptc/sids/OECDSIDS/100-21-0.pdf ).

Blood and urine samples were assayed for terephthalic acid. The sensitivity of the assay was considered to be 5 µg/ml blood and 10 µg/ml urine. The results are summarised below.

Dietary Dose Level of Terephthalic acid (%, w/w)

Mean Terephthalic Acid Concentration (µg/ml)

Blood

Urine

4 weeks

14 weeks

15 weeks

0

<5

<5

<10

0.05

-

-

20

0.16

<5

<5

49

0.50

6

<5

353

1.6

22

22*

2457

5.0

38

18

5400

* Represents blood levels for females only; no acid was detected in males.

Conclusions:
The NOAEL can be considered as 1.6% test substance in diet (w/w) (1220 mg/kg/day).
Executive summary:

The test substance 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 the test substance was excreted 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. The 15 week dietary NOAEL can be considered as 1.6% (1220 mg/kg/day).

Endpoint conclusion
Dose descriptor:
NOAEL
1 220 mg/kg bw/day
Study duration:
subchronic
Species:
rat

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

Oral

This study was used for derivation of the long term systemic DNEL.

The substance rapidly hydrolyses to terephthalic acid (TPA). Therefore, the repeated dose oral toxicity study for TPA is being used to support meeting this data requirement. The test substance 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). 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 the test substance was excreted 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 characterized 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. The 15 week dietary NOAEL can be considered as 1.6% (1220 mg/kg/day).

 

Inhalation

Six male rats were exposed whole body to 0.087 mg/L of the test substance for four hours per day for ten days. Six control rats were exposed to air for the same period of time. Gross and histopathologic examinations were performed on three rats from each group after the last exposure and 14 days post-exposure. In rats exposed by inhalation to 0.087 mg/L for four hours for ten days, weight gain suppression was observed during exposure and was normal during recovery. No significant treatment related histophathological changes were found.

Justification for classification or non-classification

Based on results of repeated oral studies, the substance does not need to be classified for repeated dose toxicity according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.