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Description of key information

The acute oral LD50 of the substance was found to be >15380 mg/kg bw in the rat.  The acute inhalation toxicity is also low, with a 2-hour LC50 of >2.02 mg/L.  Low acute dermal toxicity indicated in a limit test in rabbits.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
No information; study reported in 1975
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Older, proprietary and guideline-comparable study pre-dating the introduction of GLP
Qualifier:
no guideline followed
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Principles of method if other than guideline:
Standard acute oral toxicity study method comparable to OECD 401, but performed prior to the adoption of this guideline
GLP compliance:
not specified
Remarks:
: older study, pre-dates GLP
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
not specified
Sex:
male/female
Details on test animals or test system and environmental conditions:
Male and female albino rats
Route of administration:
oral: unspecified
Vehicle:
corn oil
Details on oral exposure:
Terephthalic acid was administered orally to rats as a 40% (w/v) homogenous suspension in corn oil
Doses:
6834, 10250, and 15380 mg/kg bw.
No. of animals per sex per dose:
5 rats per sex per dose
Control animals:
no
Details on study design:
The test substance was administered orally at three dose levels to groups of 5 male and 5 female albino rats. Rats were observed for clinical signs and mortality for 14 days post administration. Necropsy was performed on all rats that died during the test, and on all surviving rats at the end of the 14 day observation period. Body weights were recorded on test days 0 and 14.
Statistics:
Not applicable - not required
Preliminary study:
Not applicable
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 15 380 mg/kg bw
Based on:
test mat.
Remarks on result:
other: No deaths at the highest dose level
Mortality:
The only deaths that occurred were in the mid dose group (10250 mg/kg); 1 female died within 22 hours of administration, and 1 male died on day 3.
Clinical signs:
Clinical signs observed at all dose levels included hypoactivity, ruffled fur, diarrhoea, muscular weakness and rhinitis
Body weight:
1 female rat in the high dose group lost 4 g bodyweight during the test, all other rats in this group and the two lower doses gained weight during the 14 day observation period.
Gross pathology:
The two rats that died before the end of the study were found to have pale discoloured kidneys at necropsy. Examination of the rats surviving to the end of the 14 day observation period did not reveal any gross pathologic alterations.
Other findings:
No other findings reported.

The onset and recovery of clinical signs observed in rats following oral administration with terephthalic acid is shown below.

Clinical signs

Dose level of terephthalic acid (mg/kg bw)

6834

10250

15380

Onset

Recovery

Onset

Recovery

Onset

Recovery

Hypoactivity

6-22 h

3 d

30 m

6 d

30 m

7 d

Ruffled fur

6-22 h

3 d

30 m

6 d

30 m

6 d

Diarrhoea

6-22 h

2 d

6-22 h

4 d

1 h

5 d

Muscular weakness

6-22 h

2 d

6-22 h

5 d

6-22 h

5 d

Rhinitis

-

-

2 d

6 d

6-22 h

6 d

d =days, h =hours, m =minutes

Interpretation of results:
not classified
Remarks:
Migrated informationCriteria used for interpretation of results: EU
Conclusions:
The acute oral LD50 of terephthalic acid in rats is greater than 15380 mg/kg bw.
Executive summary:

Terephthalic acid in corn oil was administered orally by gavage to male and female rats at dose levels of 6834, 10250 and 15380 mg/kg bw. Rats were observed for 14 days following administration. The only deaths that occurred were in the mid dose group (10250 mg/kg bw); 1 female died within 22 hours of administration, and 1 male died on day 3. Gross necropsy revealed that these rats had pale discoloured kidneys. Clinical signs observed at all dose levels included hypoactivity, piloerection, diarrhoea, muscular weakness and rhinitis. Minimal transient weight loss was observed in individual animals; however there were no effects on body weight gain over the 14-day study period. Gross necropsy of all animals surviving to the end of the 14-day observation period did not reveal any abnormalities. The acute oral LD50 of terephthalic acid in the rat is therefore shown to be >15380 mg/kg bw under the conditions of this study.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
15 380 mg/kg bw
Quality of whole database:
One proprietary study is available for acute oral toxicity. The study pre-dates GLP and the OECD guideline, but is comparable to OECD 401 and considered to be sufficiently reliable for the purposes of hazard classification.

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
No information available: study reported in 1987
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Proprietary non-GLP study, similar to OECD guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
yes
Remarks:
: target exposure time of 4 hours was not achieved due to technical difficulties
Principles of method if other than guideline:
The methodology was similar to OECD 403 (limit test), the test concentration was 2 mg/l and the exposure period was 2 hours (the target concentration had been 5 mg/l and target exposure time 4 hours).
GLP compliance:
no
Remarks:
: study pre-dates mandatory GLP
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
Male and female Sprague-Dawley rats weighing approximately 135 g on arrival. The rats were purchased from Charles River Breeding Laboratories, Inc. MI. All rats were acclimatised for approximately 1 week and examined carefully to ensure their health and suitability as test subjects. Individuals were identified by metal ear tags.Purina Rodent Chow 5001 (Ralston Purina Co.) and reverse-osmosis purified water were available ad libitum, except during the exposure period.During acclimatisation and the post-exposure observation periods, the rats were housed individually in suspended stainless steel cages with deotized animal cage boards beneath the cages (except during exposure). Air conditioned animal rooms were maintained at approximately 22°C and 40% relative humidity. Fluorescent lighting was provided on a 12 hour light/dark cycle. Rats were randomly selected for testing and assigned to a single group.
Route of administration:
inhalation: dust
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
The rats were exposed for 2 hours to a particulate aerosol, generated from a single batch of the test article. The target concentration was 5 mg/L and the target exposure duration was 4 hours. The generator was a dry materials feeder. The test article was transported from a reservoir, by a rotating helix, to the generator outlet where it was blown by a Transvector Jet into the exposure chamber. The 68.2 litre chamber was made of glass, with a removable Plexiglass lid. The test article aerosol entered the chamber through a port near the top of one end of the chamber and exited through a pipe placed near the bottom of the chamber on the opposite side. The chamber exhaust was vented through a charcoal filter. A California-type fume hood enclosed the entire generation and exposure system. An attempt to determine the particle size, using a Mercer Cascade Impactor was made during the exposure. However, the quantity and nature of test article produced in the chamber contributed to a malfunction of the of the Mercer Cascade Impactor, therefore particle size could not be determined. The test article accumulated in the chamber during exposure such that the exposure was terminated after 2 hours.The average chamber temperature was 21°C, with a relative humidity of 40%.
Analytical verification of test atmosphere concentrations:
yes
Remarks:
The achieved concentration was measured gravimetrically by drawing a known volume of the test atmosphere across an open-face filter and dividing the weight of the test article collected by the sample volume.
Duration of exposure:
2 h
Remarks on duration:
Exposure was terminated prematurely due to technical difficulties
Concentrations:
The gravimetric time weighted average concentration was 2.02 mg/L, uncorrected for respirable particle size.
No. of animals per sex per dose:
5 males and 5 females
Control animals:
no
Details on study design:
Rats were observed during exposure, approximately 1-1/4 and 4 hours after exposure, and at least once per day for the remainder of the 14 day observation period. All rats were weighed prior to the exposure, weekly thereafter, and immediately prior to necropsy. All rats were sacrificed and necropsied at the end of the 14 day observation period.
Statistics:
Formal statistical analysis was not required.
Preliminary study:
No preliminary results available.
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 2.02 mg/L air (analytical)
Based on:
test mat.
Exp. duration:
2 h
Remarks on result:
other: Time Weighted Average concentration
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 1.01 mg/L air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Remarks on result:
other: Extrapolated from 2-hour exposure
Mortality:
There were no mortalities.
Clinical signs:
other: Diarrhoea, redness around the nose, wet/discoloured inguinal and abdominal fur and hairloss were observed during the study.
Body weight:
The mean initial body weights of the male and female rats were 198 g and 167 g, respectively. All rats gained weight progressively during the study.
Gross pathology:
All tissues examined in seven of the rats were within normal limits. Gross necropsy findings in the remaining three animals consisted of dark lungs in one male and enlarged mandibular lymph nodes in another male and female.
Other findings:
The test article accumulated on and around the rats during the exposure. All rats were covered with the test article when removed from the chamber, therefore each rat was rinsed with warm water following exposure.
Interpretation of results:
not classified
Remarks:
Migrated informationCriteria used for interpretation of results: EU
Conclusions:
Based on the results of the study, it was concluded that the LC50 in male and female rats was greater than 2.02 mg/L.
Executive summary:

Purified terephthalic acid was administered as a particulate aerosol by inhalation to a group of 5 male and 5 female Sprague-Dawley rats (whole-body exposure). The rats were exposed to an achieved concentration of 2.02 mg/L for 2 hours; exposure was terminated prematurely due to an accumulation of the test material in the exposure equipment. No deaths occurred. Signs of toxicity (diarrhoea, redness around the nose, wet/discoloured inguinal and abdominal fur and hairloss) were observed during the study. Weight gain was unaffected by treatment. Gross necropsy revealed dark lungs in three rats. The acute (2 -hour) inhalation LC50 of terephthalic acid was found to be >2.02 mg/L. By extrapolation, the 4 -hour LC50 is estimated to be >1.01 mg/L.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
Value:
2 020 mg/m³
Quality of whole database:
A guideline-comparable study is supported by less reliable data.

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
19 April to 4 May 1990
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Proprietary study, methodology similar to OECD guidelines
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Qualifier:
according to guideline
Guideline:
other: "Method of Testing Toxic Substances", Federal Register, Part 191 (1961)
GLP compliance:
not specified
Remarks:
no certificate/statement of compliance included in report
Test type:
standard acute method
Limit test:
yes
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals or test system and environmental conditions:
Male and female New Zealand albino rabbits, approximately 2 months of age, purchased from Johnson Rabbit Ranch (Wilkinson, IN). The rabbits weighed 1.6-2.4 kg on arrival, and were acclimatised for approximately 4 weeks during which time they were examined to ensure their health and suitability as test subjects. Selected rabbits were identified by metal ear tags and corresponding cage cards.Each rabbit was provided with approximately 150 g of Purina Lab Rabbit Chow HF #5326 (Ralston Purina Co., MO) daily. Reverse osmosis-purified water was supplied ad libitum by means of an automatic watering system.The rabbits were housed individually in stainless steel cages. Poly pads were placed in the below the stainless steel mesh floor. The air-conditioned animal room was maintained at an average temperature and relative humidity of 23.7°C and 32%, respectively. Flurorescent lighting was provided on a 12 hour light/dark cycle.
Type of coverage:
occlusive
Vehicle:
water
Remarks:
test site pre-moistened with water
Details on dermal exposure:
The test article was applied undiluted. Individual doses were dispensed in glass vials.Approximately 24 hours prior to study initiation, the fur was clipped from an area of approximately 240 cm² on the back of each rabbit and the skin was examined for abnormalities. Care was taken to avoid abrading the animal's backs.The shaved application site was pre-moistened with water prior to application of the test substance. The test substance was covered with a 12.8 x 23.0 cm surgical dressing (Surgipad). The dressing was then covered by plastic film and secured by lint-free cloth and Elastoplast. The wrappings were removed after 24 hours and the skin was wiped gently with gauze and 0.9% saline to remove residual test article.
Duration of exposure:
24 hours
Doses:
2000 mg/kg bw.
No. of animals per sex per dose:
5 rabbits/sex
Control animals:
not required
Details on study design:
Rabbits used in the study were selected at random and assigned to a single group of 5 males and 5 females. Prior to selection, the rabbits received a thorough physical examination to ensure their suitability for use.All rabbits were observed aproximately 3/4, 3-1/4, 4-1/4 and 5-1/4 hours after dosing and at least once per day for 14 days after removal of the wrappings. All test animals were weighed immediately prior to dosing and the weights used for dosage calculations. The rabbits were weighed 7 days after application and at study termination.All rabbits were euthanised at the end of the observation period by anaesthetic overdose. A limited gross necropsy was performed on all test animals.
Statistics:
Formal statistical analysis was not required.
Preliminary study:
A preliminary study was not conducted.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: No mortality at the limit dose
Mortality:
No deaths occurred during the study.
Clinical signs:
Minor signs of dermal irritation (i.e. erythema) were observed within the appplication site of two male and four female rabbits immediately following unwrapping. The application site of all test animals was partially or completely masked by hair growth throughout the observation period.
Body weight:
The initial mean body weights of the male and female was rabbits were 2.59 and 2.45 kg, respectively. Mean body weights increased during the study.
Gross pathology:
No abnormalities were detected at necropsy.
Other findings:
No other findings were reported.
Interpretation of results:
not classified
Remarks:
Migrated informationCriteria used for interpretation of results: EU
Conclusions:
The acute dermal LD50 of terephthalic acid was found to be greater than 2000 mg/kg bw under the conditions of this study.
Executive summary:

The acute dermal toxicity of terephthalic acid was determined in a limit test, with five male and five female New Zealand White rabbits. The test material was placed in contact with the shaved pre-moistened skin of the rabbits, under an occlusive dressing, for 24 hours. The rabbits were observed during this time and for 14 days thereafter. No deaths occurred during the study. Mild dermal irritation (erythema) was observed within the application site of six rabbits immediately following unwrapping. Otherwise, no adverse treatment-related clinical signs were observed in any rabbits during the study. Mean body weights increased during the study. No gross pathological lesions attributable to treatment were evident in any of the rabbits at necropsy. The acute dermal LD50 of terephthalic acid was found to be greater than 2000 mg/kg bw under the conditions of this study.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
Reliable, guideline-compliant study

Additional information

Acute oral toxicity

A guideline-comparable study (Harrison, 1975) is available, in which terephthalic acid in corn oil was administered orally by gavage to male and female rats at dose levels of 6834, 10250 and 15380 mg/kg bw. Rats were observed for 14 days following administration. The only deaths that occurred were in the mid dose group (10250 mg/kg bw); 1 female died within 22 hours of administration, and 1 male died on day 3. Gross necropsy revealed that these rats had pale discoloured kidneys. Clinical signs observed at all dose levels included hypoactivity, piloerection, diarrhoea, muscular weakness and rhinitis. Minimal transient weight loss was observed in individual animals; however there were no effects on body weight gain over the 14-day study period. Gross necropsy of all animals surviving to the end of the 14-day observation period did not reveal any abnormalities. The acute oral LD50 of terephthalic acid in the rat is therefore shown to be >15380 mg/kg bw under the conditions of this study. Terepthalic acid is therefore of very low acute oral toxicity.

Acute inhalation toxicity

In the key study (Leach et al, 1987), purified terephthalic acid was administered as a particulate aerosol by inhalation to a group of 5 male and 5 female Sprague-Dawley rats. The rats were exposed (whole body) to an aerosol concentration of 2.02 mg/L for two hours; the exposure period was terminated due to an accumulation of the test material. No rats died during the study. Therefore, the 2 hour acute inhalation LC50 of purified terephthalic acid was estimated to be greater than 2.02 mg/L. Gross necropsy revealed 1 male rat with dark lungs, and 1 male and 1 female rat with enlarged mandibular lymph nodes. No other abnormalities were detected. The 2-hour LC50 was therefore >2.02 mg/L; a time-adjusted 4 -hour LC50 of >1.01 mg/L can therefore be derived.

In a further study, investigating toxicity from pyrotechnic dissemination Thomson et al (1988), male F344 rats were exposed to pyrotechnically disseminated terephthalic acid in nose-only exposure chambers for 30 minutes. Nominal terephthalic acid concentrations were 100, 200 and 400 mg/m3. Two control groups were exposed to either air alone, or the fuse/fuel mix alone. Rats underwent pulmonary function tests and bronchoalveolar lavage immediately prior to sacrifice, at 24 hours or 14 days post exposure. There were no compound-related mortalities. There were no adverse changes in pulmonary function, lavage or histopathology. The only adverse reaction observed was a dose-related rhinorrhea that disapeared within 1 hour post exposure. There was no toxic effects of the combustion byproducts (CO, CO2, NO2 and SO2), which remained below the threshold limit value. Under the conditions of this study, the acute LC50 of TPA was greater than 235 mg/m3 (analytical concentration).

A further study (ICI, 1987) is available only as a secondary source but reports no treatmnet-related effects in groups of 10 male rats exposed to terephthalic acid at target concentrations of 30, 100 or 1000 mg/m3; these findings are consistent with the results of the other studies.

While the studies of acute inhalation toxicity available for terephthalic acid have some deficiencies, they are consistent in demonstrating low toxicity by this route of exposure.

Acute dermal toxicity

The acute dermal toxicity of the substance in the rabbit was investigated by Lord (1990) in a limit test, with five male and five female New Zealand White rabbits. The test material was placed in contact with the shaved pre-moistened skin of the rabbits, under an occlusive dressing, for 24 hours. The rabbits were observed during this time and for 14 days thereafter. No deaths occurred during the study. Mild dermal irritation (erythema) was observed within the application site of six rabbits immediately following unwrapping. Otherwise, no adverse treatment-related clinical signs were observed in any rabbits during the study. Mean body weights increased during the study. No gross pathological lesions attributable to treatment were evident in any of the rabbits at necropsy. The acute dermal LD50 of terephthalic acid was found to be greater than 2000 mg/kg bw under the conditions of this study.


Justification for selection of acute toxicity – oral endpoint
Only study available for this endpoint

Justification for selection of acute toxicity – inhalation endpoint
Guideline-comparable study

Justification for selection of acute toxicity – dermal endpoint
Only study available for this endpoint

Justification for classification or non-classification

No classification for acute toxicity is proposed on the basis of the acute oral and dermal toxicity studies. The available data also demonstrate low acute inhalation toxicity and indicate that the substance would not be classified for acute inhalation toxicity. Although the available inhalation toxicity studies use exposure periods shorter than the standard 4 hours and/or lower maximum exposure concentrations than the limits for classification, no further inhalation toxicity testing is proposed. It can be reliably assumed, based on the available lack of effects at exposure concentration of approximately 1 and 2 mg/L that the inhalation LC50 of the substance will be below the limit for classification of 5 mg/L. Additional testing is not considered to be appropriate on scientific grounds and for reasons of animal welfare.

No classification for acute toxicity is therefore proposed, according to the CLP Regulation.