Bis(hydroxyethyl) terephthalate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Reference Type:

publication

Title:

Distribution of Terephthalic Acid in Tissues

Author:

Hoshi, A., & Kuretani, K.

Year:

1968

Bibliographic source:

Chemical and Pharmaceutical Bulletin 16(1): 131-135

Materials and methods

Objective of study:

distribution

Principles of method if other than guideline:

The distribution of terephthalic acid in rat tissues was determined using radio-labelling.

GLP compliance:

no

Remarks:

predates GLP

Test material

Test material information

Constituent 1

Reference substance name:

Terephthalic acid

EC Number:

202-830-0

EC Name:

Terephthalic acid

Cas Number:

100-21-0

Molecular formula:

C8H6O4

IUPAC Name:

terephthalic acid

Radiolabelling:

yes

Test animals

Species:

rat

Strain:

Wistar

Sex:

female

Administration / exposure

Details on exposure:

Feed experiments: groups of rats were fed 0.5% TPA in the basal diet.
Gavage experiments: rats were given a single oral administration of 2% TPA in 0.5% sodium carboxymethylcellulose solution prepared with a glass homogeniser.

Duration and frequency of treatment / exposure:

Feed experiments: Group a were fed the test diet for 1 day; Group B were fed the test diet for 3 days; Group C was fed the test diet for 3 days followed by the basal diet alone for 1 day.
Gavage experiments: Single oral administration

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

85 mg/kg bw (total dose)

Remarks:

Gavage experiments

Doses / concentrations 2

Dose / conc.:

0.5 other: % in diet

Remarks:

Feed experiments

No. of animals per sex per dose / concentration:

Feed experiments: 5 female rats/group.
Gavage experiments: 5 females rats/time point (six time points in total).

Control animals:

no

Details on study design:

Feed experiments: each group of rats was sacrificed following completion of their respective feeding periods.
Gavage experiments: 5 rats per time point were sacrificed at 2, 4, 6, 8, 24 and 48 h after administration.

Details on dosing and sampling:

In both experiments, 4 ml blood was drawn from the vena cava with a heparinized syringe under light ether anesthesia, and tissues were excised after the animals were sacrificed by bleeding from the carotid artery.

Treatment of samples: 0.1 ml whole blood was taken in a screw cap vial, washed twice with 5 ml of 0.9% NaCl solution and centrifuged. Plasma was separated by centrifuging 0.2 ml of whole blood.
Tissues were cut finely with scissors, an aliquot of which was weighed as follows: 100 mg of liver, spleen, bone (femur) and salivary gland, and 200 mg of kidney, lung, heart, brain, muscle (thigh), pancreas, uterus, adipose (white) tissue and skin. For the rest of the tissues, whole organs were used because of their small quantities available, such as 30-50 mg of ovary, 9-13 mg of thyroid land and 8-15 mg of pituitary gland.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Not measured

Details on distribution in tissues:

Feed experiments: In group A, the content of TPA in the kidney and liver was considerably higher than other tissues. A moderate amount of TPA was detected in the plasma, and in all other tissues that levels were low. In group B, the content of TPA in the plasma was comparable to that found in group A, and the content in the other tissues followed the same distribution pattern as that seen in group A. In group C, TPA content had decreased rapidly in the tissues compared to groups A and B, with no TPA detected at all in many of the tissues.

Gavage experiments: The highest content of TPA was found 2 hours after administration in the plasma, kidney and liver. Overall a similar distribution pattern was observed following gavage administration compared to dietary administration.

Toxicokinetic parameters

Toxicokinetic parameters 1

Toxicokinetic parameters:

half-life 1st: 1.2-3.3 h, tissues, gavage administration

Toxicokinetic parameters 2

Toxicokinetic parameters:

half-life 1st: 2.43 h (95% CI: 1.99-3.1 h), plasma, gavage administration

Metabolite characterisation studies

Metabolites identified:

not measured

Any other information on results incl. tables

Distribution of TPA in tissues of rats fed a diet containing 0.5% radio-labelled TPA

 

Tissue	TPA content (µg/g tissue; µg/ml plasma)^a
	Group A^c	Group B	Group C
Plasma	9.77±1.59	8.43±5.22	0.04±0.02
Kidney	49.35±12.99	40.31±22.46	0.31±0.05
Liver	22.67±8.78	15.77±7.45	0.09±0.05
Brain	2.10±0.31	1.87±0.42	0.07±0.03
Skin	3.85±1.45	4.75±2.97	1.20±0.51
Lung	3.98±1.95	3.88±2.23	0
Pancreas	2.22±0.85	4.64±3.90	0.22±0.08
Spleen	1.36±0.73	1.29±0.69	0
Adipose tissue (white)	1.05±0.68	2.28±20.9	0
Heart	2.18±1.07	1.77±1.07	0
Muscle (thigh)	0.39±0.12	0.84±0.44	0
Bone (femur)	0.42±0.27	0.51±0.32	0
Blood cell^b	0.66±0.43	0.95±0.84	0
Uterus	3.69±1.45	3.66±2.05	0.07±0.05
Ovary	2.70±0.50	1.40±1.00	0
Salivary gland	2.28±0.74	1.36±0.66	0.06±0.06
Thyroid gland	2.90±0.80	2.80±0.80	0
Pituitary gland	3.10±1.50	3.00±1.60	0
Adrenal gland	1.80±0.60	1.30±0.80	0

a  mean value ± SE; 5 rats per group

b  corresponding to 1 ml of whole blood

c  Group A: fed 0.5% TPA diet for 1 day; Group B: fed 0.5% TPA diet for 3 days; Group C: fed 0.5% TPA for 3 days followed by 1 day treatment-free recovery period.

 

Distribution of TPA in rat tissues following a single oral administration of 85 mg/kg bw

 

Tissue	TPA content (µg/g tissue; µg/ml plasma)^aat hours post-administration
	2 h	4 h	6 h	8 h	24 h	48 h
Plasma	10.38±1.74	6.75±2.05	2.96±0.32	2.38±0.37	0	0
Kidney	58.52±10.71	25.71±4.60	15.74±3.03	8.54±1.67	0.41±0.04	0
Liver	31.25±2.88	12.96±2.18	8.14±1.40	5.13±0.56	0.13±0.04	0
Brain	0.98±0.05	1.22±0.07	1.17±0.11	1.32±0.08	0.07±0.01	0
Skin	6.04±1.33	2.91±0.45	2.14±0.42	1.90±0.29	0.06±0.04	0
Lung	4.19±0.34	1.72±0.40	1.34±0.40	0.63±0.13	0	0
Pancreas	3.11±0.37	1.06±0.09	0.63±0.16	0.38±0.05	0	0
Spleen	1.30±0.16	0.47±0.09	0.34±0.11	0.22±0.04	0	0
Adipose tissue (white)	0.87±0.22	0.45±0.05	0.36±0.09	0.16±0.02	0	0
Heart	2.53±0.41	0.84±0.19	0.61±0.19	0.29±0.05	0	0
Muscle (thigh)	0.72±0.11	0.31±0.05	0.24±0.10	0.09±0.01	0	0
Bone (femur)	0.41±0.14	0.12±0.04	0.10±0.04	0	0	0
Blood cell^b	0.43±0.07	0.32±0.13	0.18±0.06	0	0	0
Uterus	5.67±1.31	2.15±0.68	1.70±0.54	0.70±0.17	0	0
Ovary	4.40±0.80	1.50±0.10	1.10±0.40	0.70±0.20	0	0
Salivary gland	3.16±0.68	1.58±0.33	1.00±0.08	0.81±0.22	0	0
Thyroid gland	3.00±0.30	2.00±0.30	1.40±0.30	1.00±0.40	0	0
Pituitary gland	3.10±0.40	2.20±0.60	1.10±0.30	0.90±0.10	0	0
Adrenal gland	2.10±0.20	0.90±0.20	0.50±0.10	0.20±0.10	0	0

a  mean value ± SE; 5 rats per group

b  corresponding to 1 ml of whole blood

Applicant's summary and conclusion

Conclusions:

Low bioaccumulation potential based on study results
Terephthalic acid was eliminated rapidly from tissues and plasma, and did not accumulate in any tissues.

Executive summary:

The distribution of terephthalic acid (TPA) in the tissues of rats was determined using radio-labelling; terephthalic carboxyl-14C acid. Female Wistar King-A rats were fed a diet containing 0.5% TPA for 1 day (group A), 3 days (group B), or 3 days followed by a 1 day recovery period (group C). Rats were sacrificed at the end of the respective feeding periods and the tissues assayed for radioactivity to determine the TPA content. Another group of female rats was administered a single oral dose by gavage of 85 mg/kg bw radio-labelled TPA, and sacrificed at various intervals post-administration for determination of TPA content in the tissues.

 

In the rats fed TPA-diets, TPA content was highest in the kidney (40 -50 µg/g), liver (16 -23 µg/g) and plasma (8 -10 µg/ml). Content in the other tissues was low. A single administered dose was distributed rapidly in the tissues within 2 hours of administration, and the distribution pattern in the tissues was similar to that seen in the feeding study. The maximum content of TPA in the tissues was seen within 2 hours of administration, whereas in the brain the maximum content was seen 8 hours after adminstration.

Only small amounts of TPA remained in the tissues 24 hours after single administration, and 24 hours after completion of a 3 day feeding period.

 

The biological half life was calculated following the single gavage administration and found to be 1.2 - 3.3 hours in tissues, and 2.43 hours in plasma. It was concluded that terephthalic acid was eliminated rapidly from tissues and plasma, and did not accumulate in any of the tissues examined.