Registration Dossier

Administrative data

Description of key information

One repeated dose toxicity study (28 days) according to OECD guideline 422 was conducted with DiPT and revealed no test-item related signs of toxicity. The NOAEL for systematic toxicity is above the highest administered dose 1000 mg test item/kg b.w./day, p.o..

A 90-day Study according to OECD TG 408 was conducted with 100, 300 or 1000 mgDi-(iso)-pentyl terephthalate (DPT)/kg b.w./day. The no-observed-adverse-effect level (NOAEL) was 1000 mg Di-(iso)-pentyl terephthalate (DPT)/kg b.w./day by oral administration for 90 days. The no-observed-effect level (NOEL) was 300 mg (iso)-pentyl terephthalate (DPT)/kg b.w./day by oral administration for 90 days.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
repeated dose toxicity: oral, other
Remarks:
COMBINED REPEATED DOSE TOXICITY STUDY WITH THE REPRODUCTION / DEVELOPMENTAL TOXICITY SCREENING TEST OF DI-(ISO)-PENTYL TEREPHTHALATE (DPT) IN RATS BY ORAL ADMINISTRATION
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
2015-04-22 to 2016-03-02
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Species:
rat
Strain:
other: CD / Crl:CD(SD)
Sex:
male/female
Details on test animals and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH
Sandhofer Weg 7
97633 Sulzfeld
Germany
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: Males (MS, RC)+ Females (MS, RC): 71 days
- Weight at study initiation:
Males (MS): 345.9 - 390.5 g
Males (RC): 350.6 - 372.8 g
Females (MS): 219.7 - 261.1 g
Females (RC): 229.5 - 255.9 g
- Housing:
With the exception of the mating period (see Section 3.9 'Mating procedure'), the
males and females (F0-Generation) were kept singly in MAKROLON cages (type III
plus) with a basal surface of approx. 39 cm x 23 cm and a height of approx.
18 cm.
- Diet : ad libitum
- Water: ad libitum
- Acclimation period: 6 days

DETAILS OF FOOD AND WATER QUALITY:

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22°C ± 3°C
- Humidity (%): 55% ± 15%
- Photoperiod (hrs dark / hrs light): The rooms were alternately lit (about 150 lux at approx. 1.5 m room height) and
darkened for periods of 12 hours.

IN-LIFE DATES:
First administration March 18, 2015
End of the in-life period Males: MS: April 16, 2015
RC: May 12, 2015
Females: MS: May 02, 2015
RC: May 12, 2015
Route of administration:
oral: gavage
Details on route of administration:
Frequency of administration: Once daily
Administration volume: 2 mL/kg b.w./day
Vehicle:
corn oil
Details on oral exposure:
Dose levels: Group 1: Control (vehicle)
Group 2: 100 mg/kg b.w./day
Group 3: 300 mg/kg b.w./day
Group 4: 1000 mg/kg b.w./day
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
At study initiation:
Analysis of stability and concentration
Immediately after preparation of the administration
formulation as well as after 8 and 24 hours
storage of the test item preparations at room
temperature:
(3 samples/dose level group).
Number of samples: 3 x 3 = 9

At termination of the administration period at a time point when the majority of animals was dosed:
Analysis of concentration
During treatment with the test item always before
administration to the last animal/dose level
group:
(1 sample per dose level group).
Number of samples: 1 x 3 = 3
Duration of treatment / exposure:
6 adaptation days
- 45 test days (Main study)
- 56 test days (Recovery study, including 14 days of recovery)
Frequency of treatment:
Once daily
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
300 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
Main study animals (MS): 96 animals (48 males and 48 females); 12 animals per sex and group
Recovery study animals (RC): 20 animals (10 males and 10 females); 5 animals per sex/each in groups 1 and 4
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale:
The dose levels were selected by the Sponsor based on available toxicological data and a 14-day dose range finding study.
In the 14-day dose range finding study doses of 100, 300 and 1000 mg Di-(iso)-pentyl terephthalate (DPT)/kg b.w./day were used.
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once daily

BODY WEIGHT: Yes
- Time schedule for examinations:
Males and females were weighed on the first day of dosing, weekly thereafter and
at termination. During gestation, females were weighed on days 0, 7, 14 and 20
and within 24 hours of parturition (day 1 post-partum) and day 4 post-partum.
Body weights were recorded individually for each adult animal.
The pups were weighed within 24 hours of parturition (lactation day 1) and on day
4 post-partum (lactation day 4).

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: Drinking water consumption was monitored daily by visual appraisal throughout
the study.

OPHTHALMOSCOPIC EXAMINATION: No


HAEMATOLOGY: Yes
- Time schedule for collection of blood:
At the end of the pre-mating period: (TD 15) 5 male and 5 female F0-animals randomly selected from each main study group.
At the end of the recovery period: (TD 56) All recovery animals.
- Anaesthetic used for blood collection: Yes
- Animals fasted: Yes

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood:
At the end of the pre-mating period: (TD 15) 5 male and 5 female F0-animals andomly selected from each main study group.
At the end of the recovery period: (TD 56) All recovery animals.
- Animals fasted: Yes

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations:
5 male F0-animals per group (randomly selected main study animals)7:
Between test days 27 and 28 (3 or 2 days before sacrifice on TD 30).

5 female F0-animals per group (randomly selected main study animals)6:
During the lactation period (3 to 5 days before sacrifice on TD 46).

All recovery animals: At the end of the recovery period on test day 55 (one day before sacrifice).

- Battery of functions tested: sensory activity, grip strength, motor activity

IMMUNOLOGY: No

OTHER: Reproductive performance (please see 7.8 Toxicity to reproduction)
Sacrifice and pathology:
GROSS PATHOLOGY: Yes

HISTOPATHOLOGY: Yes
Statistics:
Statistical analyses of the parametrical values, captured or calculated by Provantis
(i.e. clinical signs, parental body weight, body weight gain, food consumption,
haematological and biochemical parameters), were done by Provantis using the
following settings:
SHAPIRO-WILKS test and BARTLETT test
One-way analysis of variance (ANOVA)
KRUSKAL-WALLIS test
DUNNETT test
STUDENT's t-test
FISHERs exact test
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
No test item-related signs of clinical toxicity (changes in external appearance, behaviour or the faeces) were noted during the routine daily observations and the detailed weekly observations.
Mortality:
no mortality observed
Description (incidence):
No premature deaths were noted in the main study (100, 300 or 1000 mg test item/kg b.w./day) and the recovery study (1000 mg test item/kg b.w./day)
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
Males and females (MS + RC)
No test item-related influence on the body weight
and body weight gain was noted.
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
Males and females (MS + RC)
No test item-related differences were noted.
Food efficiency:
effects observed, non-treatment-related
Water consumption and compound intake (if drinking water study):
effects observed, non-treatment-related
Description (incidence and severity):
Males and females (MS + RC)
No test-item related changes were noted.
Ophthalmological findings:
not examined
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
Males and females (MS + RC)
No test-item related changes were noted.
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
Males and females (MS + RC)
No test-item related changes were noted.
Urinalysis findings:
not examined
Behaviour (functional findings):
effects observed, non-treatment-related
Description (incidence and severity):
Functional screening
Grip strength No test item-related influence was noted.
Spontaneous motility No test item-related influence was noted.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
Males and females (MS + RC)
No test item-related differences were noted.
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
Macroscopic post mortem
findings
Males and females (MS + RC)
No test item-related changes were noted.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
Males and females (MS + RC), control and high dose group
No test item-related changes were noted.
Histopathological findings: neoplastic:
effects observed, non-treatment-related
Other effects:
effects observed, non-treatment-related
Description (incidence and severity):
fertility and reproduction parameters: No test item-related influences were noted.
Key result
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects
Critical effects observed:
no
Conclusions:
Conclusion:
The aim of the study was to obtain information on possible effects of the test item on general toxicity, reproduction and/or development according to OECD guideline 422.
The test item Di-(iso)-pentyl terephthalate (DPT) was administered orally to rats at dose levels of 100, 300 or 1000 mg test item/kg b.w./day.
The administration of the main study rats started two weeks before mating on test day one and ended one day before sacrifice. Day of sacrifice was on test day 30
for all parental male rats and on lactation day 4 for all parental female rats. For the recovery study, additional - non-mated - males and females were used and
treated with the vehicle alone (control) or with 1000 mg test item/kg b.w./day. The treatment period of the male and female animals of the recovery study lasted
until test day 40 (the earliest test day on which the treatment period of the female animals of the main study was completed). Thereafter a recovery period followed
until sacrifice on test day 56.

General toxicity:
No premature death, no test item-related signs of clinical toxicity and no test itemrelated influence on the neurological function were noted for animals of the main
and the recovery study. Body weight, food consumption and the haematological and biochemical parameters were not influenced by the test item.
Necropsy revealed no test item related changes during the macroscopic and microscopic examinations and on the weights of the examined organs.
NOAEL for systematic toxicity: above 1000 mg test item/kg b.w./day, p.o.

Reproductive toxicity:
No influence was noted on the fertility and the reproductive parameters of the parental generation (F0-Generation) with respect to fertility, pre-coital time, gestation
length, gestation index, number of stillbirths, birth and live birth index and the preand post-implantation loss for any of the examined dose levels.
No adverse effects were noted on the development of the pups (F1-Generation) with respect to survival index, body weight, and gross abnormalities.

a) adverse effects on fertility and reproduction parameters
NOAEL: above 1000 mg test item/kg b.w./day, p.o.
b) adverse effects on the development of the pups
NOAEL: above 1000 mg test item/kg b.w./day, p.o.
Endpoint:
sub-chronic toxicity: oral
Remarks:
REPEATED DOSE 90-DAY ORAL TOXICITY STUDY
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Version / remarks:
June 2018
Deviations:
no
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Wistar
Details on species / strain selection:
CD® rats
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories Germany GmbH
Sandhofer Weg 7
97633 Sulzfeld
Germany
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: Young adults; 8-10 weeks at 1st dosing*
- Weight at study initiation:
- Fasting period before study:
- Housing: The animals are kept singly in MAKROLON cages (type III plus) with a basal surface of approximately 39 cm x 23 cm and a height of approximately 18 cm
- Diet: ad libitum
- Water: ad libitum
- Acclimation period:

DETAILS OF FOOD AND WATER QUALITY:
Commercial diet ssniff® R/M-H V1534 (ssniff Spezialdiäten GmbH, 59494 Soest, Germany, the composition of the diet will be stated in the report) serves as food. This food is offered ad libitum. Food residue is removed and weighed.
Periodic analysis of the food for contaminants based on EPA/USA2 is conducted by LUFA-ITL3 (see section 9.1 Limitation for contaminants in the diet). Certificates of analysis of the composition and for contaminants are provided by the manufacturer and are QAU archived.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22°C ± 3°C
- Humidity (%): 55% ± 10%
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 12 h each

IN-LIFE DATES: From: May 9, 2019 To: September 4, 2019
Route of administration:
oral: gavage
Vehicle:
corn oil
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
Once daily for 90 days
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
control
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
300 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
10
Control animals:
yes
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: The dose levels for this study will be selected in agreement with the Sponsor based on the available toxiciological data of an OECD 422 study. The dose of 1000 mg/kg b.w. was considered to be a maximum tolerated dose.
- Rationale for animal assignment (if not random):
- Fasting period before blood sampling for clinical biochemistry:
- Rationale for selecting satellite groups:
- Post-exposure recovery period in satellite groups:
- Section schedule rationale (if not random):
- Other:
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: one daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once before the first exposure (to allow for within-subject comparisons) and once a week thereafter, detailed clinical observations will be made in all animals

BODY WEIGHT: Yes
- Time schedule for examinations: The weight of each rat will be recorded at the time of group allocation, daily from the day of commencement of treatment up to and including test week 6 for dose adjustment, thereafter weekly throughout the experimental period.

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes / No / Not specified
- Time schedule for examinations: Water consumption will be recorded weekly by weighing the water bottles when filled and the residues upon removal at the end of the test week. The residue will be discarded.

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Examinations will be performed on all animals before first dosing, at main study termination and at the end of the recovery period.


HAEMATOLOGY: Yes
- Time schedule for collection of blood:
At the end of test week 13 (before necropsy):All main study animals
At the end of the recovery period: All recovery animals
- Anaesthetic used for blood collection: Yes
- Animals fasted: Yes
- Parameters checked were examined.:
Differential blood count10 (relative)
Differential blood count (absolute)
Erythrocytes (RBC)
Leucocytes (WBC)
Haematocrit value
Haemoglobin content
Platelets
Reticulocytes
Mean corpuscular volume (MCV)
Mean corpuscular haemoglobin (MCH)
Mean corpuscular haemoglobin concentration (MCHC)
Prothrombin time (PT)
Activated partial thromboplastin time (aPTT)

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Examinations will be performed on all animals before first dosing, at main study termination and at the end of the recovery period.
- Animals fasted: Yes
- Parameters were examined.:
Sodium
Potassium
Calcium
Chloride
Albumin
Total bilirubin
Total cholesterol
High density lipoprotein (HDL)
Low density lipoprotein (LDL)
Glucose
Total protein
Blood urea nitrogen (BUN)
Creatinine
Aspartate aminotransferase (ASAT/GOT)
Alanine amino-transferase (ALAT/GPT)
Alkaline phosphatase (aP)
Lactate dehydrogenase (LDH)

URINALYSIS: Yes
- Time schedule for collection of urine:
- Metabolism cages used for collection of urine: Yes / No / Not specified
- Animals fasted: Yes / No / Not specified
- Parameters checked in table [No.?] were examined.

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations:
In test week 13 (before any blood sampling for laboratory examinations): All animals
At the end of the recovery period: All recovery animals
- Battery of functions tested: sensory activity / grip strength / motor activity /

IMMUNOLOGY: No


OTHER: Thyroid hormone (T3, T4, TSH) determination: In order to obtain approximately 2x150 μL serum for each endocrine endpoint (T3, T4, TSH), a sufficient volume of blood will be taken from the retrobulbar venous plexus under isoflurane anaesthesia from animals fasted overnight.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes

HISTOPATHOLOGY: Yes
Statistics:
Toxicology and Pathology data will be captured, whenever possible, using the departmental computerized systems (Provantis®12 Integrated preclinical software, Instem LSS Ltd.). Raw data not fully compatible with the computerized systems will be maintained on paper according to appropriate SOPs.
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
Slight salivation starting up to 5 minutes p.a.
lasting 20 to 60 minutes was observed for 1 of
10 males treated with 300 mg Di-(iso)-pentyl
terephalate (DPT)/kg b.w./day on test days 59
and 60.
Slight to moderate salivation starting up to 5 minutes p.a. lasting 20 to 60 minutes was observed for 8 of 10 males and for 7 of 10 females treated with 1000 mg Di-(iso)-pentyl terephthalate (DPT)/kg b.w./day on 1 to 31 days starting on test day 55 (males) or 59 (females).
These changes are regarded to be test item-related, but not adverse.

A haemorrhagic left canthus was observed for
male no. 85 treated with 1000 mg Di-(iso)-pentyl
terephalate (DPT)/kg b.w./day on 19 test days
starting on test day 2.
This change is not regarded to be test item-related but to be related to the blood withdrawal.

Recovery period (restricted to groups 1 and 4)
No changes in behaviour, external appearance, or consistency of faeces were noted for the previously high-dosed male and female animals during the 28-day treatment-free recovery period.

Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
The body weight of the male animals treated with 1000 mg Di-(iso)-pentyl terephalate
(DPT)/kg b.w./day was slightly decreased by 5% to 9% starting on test day 22 compared to the
control animals (statistically significant at p ≤ 0.05 or 0.01 on test days 22, 29, 71, 78, 85 and 90).
The body weight of the female animals treated with 1000 mg Di-(iso)-pentyl terephalate
(DPT)/kg b.w./day was slightly decreased by 5% on test day 78 compared to the control animals
(statistically significant at p ≤ 0.05 on test day 78). The body weight gain and the body weight
at autopsy of the high dose animals were slightly reduced accordingly.
These changes were only slight (< 10% difference to control) and are considered not to be adverse.

Recovery period (restricted to groups 1 and 4)
The body weight of the male animals previously treated with 1000 mg Di-(iso)-pentyl terephthalate (DPT)/kg b.w./day was still reduced by 17% to 18% (statistically significant at p ≤ 0.05 on test days 97, 104, 111 and 118). The percentage difference in comparison to the control group during the recovery period was higher than that during the treatment period due to the comparably high or low body weight of the high dose group and the control group, respectively. This effect was mainly due to the animal constellation of the groups. Coincidentally, the control recovery animals were the heaviest while the high dose recovery animals were the lightest animals of the respective group.
The body weight at autopsy was reduced accordingly. However, the body weight gain of the previously high dosed males was above that of the control group indicating a trend towards recovery.
The body weight, the body weight gain and the body weight at autopsy of the female animals previously treated with 1000 mg Di-(iso)-pentyl terephthalate (DPT)/kg b.w./day were within the range of the control group.
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):
effects observed, treatment-related
Description (incidence and severity):
The drinking water consumption of the male and female animals treated with 1000 mg Di-(iso)- pentyl terephalate (DPT)/kg b.w./day by oral
administration was slightly increased by up to 17% for the males and by up to 19% for the females starting in test week 2 (males) or 3
(females) compared to the control animals, evaluated by weekly quantitative assessment (statistically significant at p ≤ 0.05 or 0.01 in
test week 2 for the males and in test week 2 and 4 for the males and females).
This finding is considered to be test item-related but not adverse, and might be due to the irritating properties of the test item.

Recovery period (restricted to groups 1 and 4)
The drinking water consumption of the male animals previously treated with 1000 mg Di-(iso)-pentyl terephthalate (DPT)/kg b.w./day was still slightly increased by up to 13% during the recovery period (statistically significant at p ≤ 0.05 in test week 14). The drinking water consumption of the female animals previously treated with 1000 mg Di-(iso)-pentyl terephthalate (DPT)/kg b.w./day was within the range of the control group during the 28-day treatment-free recovery period.
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Immunological findings:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
The macroscopic inspection at necropsy did not reveal any test item-related changes in the organs and tissues of the animals treated with 100, 300 or 1000 mg Di-(iso)-pentyl terephthalate (DPT)/kg b.w./day by repeated oral administration after terminal sacrifice at the end of the treatment period.
Changes in the tissue enlargement, enlarged lymph node, dilated uterus partly filled
with clear liquid, hairless abdomen and forepaws.
These changes are not regarded to be test item-related but spontaneous.
Neuropathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed
Description (incidence and severity):
Thyroid hormone (T3, T4, TSH) levels:
No test item-related influence was observed on the thyroid hormone levels of T3, T4 and TSH of the male and female animals treated with 100, 300 or 1000 mg
(DPT)/kg b.w./day by oral administration for 90 days compared to the control animals at the end of the treatment period (test day 91) and at the end of the recovery period (test day 119). All data are within the limits of normal biological variability.
Key result
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects
Dose descriptor:
NOEL
Effect level:
300 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
clinical signs
water consumption and compound intake
Dose descriptor:
NOEL
Effect level:
300 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
clinical signs
water consumption and compound intake
Key result
Critical effects observed:
no
Conclusions:
The no-observed-adverse-effect level (NOAEL) was 1000 mg Di-(iso)-pentyl terephthalate (DPT)/kg b.w./day by oral administration for 90 days. The no-observed-effect level (NOEL) was 300 mg (iso)-pentyl terephthalate (DPT)/kg b.w./day by oral administration for 90 days.
Executive summary:

The aim of the study was to obtain information on the toxicity of DPT when given to rats by daily oral administration via gavage for 90 days and to assess the reversibility of any effects after a treatment-free recovery period.

The rats were treated with 100, 300 or 1000 mg Di-(iso)-pentyl terephthalate (DPT)/kg b.w./day for 90 days.

None of the animals died or had to be sacrificed prematurely.

Slight salivation was observed for 1 of 10 males treated with 300 mg Di-(iso)-pentyl terephthalate (DPT)/kg b.w./day on test days 59 and 60. Slight to moderate salivation was observed for 8 of 10 males and for 7 of 10 females treated with 1000 mg Di-(iso)-pentyl terephthalate (DPT)/kg b.w./day on 1 to 31 days starting on test day 55 (males) or 59 (females).These slight changes are regarded to be test item-related, but not adverse.

The body weight of the male and female animals treated with 1000 mg Di-(iso)-pentyl terephthalate (DPT)/kg b.w./day was slightly decreased (<10%) during the treatment period compared to the control animals. The body weight gain and the body weight at autopsy were slightly reduced accordingly.These changes are considered not to be adverse.

The drinking water consumption of the male and female animals treated with 1000 mg Di-(iso)-pentyl terephthalate (DPT)/kg b.w./day by oral administration was slightly increased compared to the control animals, evaluated by weekly quantitative assessment. This findingis considered to be test item-related but not adverse, andmight be due to the irritating properties of the test item.

No test item-related changes were observed during the detailed clinical observations, food consumption, for any of the parameters of the neurological screening, for any of the haematological, coagulation, and clinical chemistry parameters, the thyroid hormone levels, the eyes or optic region, the auditory acuity, at macroscopic inspection at necropsy, the organ weights,the oestrus cycle, the sperm viability and morphologyand at histopathological examination at any dose level.

At the end of the recovery period, the body weight and body weight at autopsy of the male animals were still reduceddue to the animal constellation of the groups.Body weight gain indicated a slight trend to recovery. The drinking water consumption of the male animals was still slightly increased during the recovery period. The body weight and the drinking water consumption of the female animals had normalized during the 28-day treatment-free recovery period. All other changes had subsided during or at the end of the 28-day treatment-free recovery period.

Based on the above results, the no-observed-adverse-effect level (NOAEL) was 1000 mg Di-(iso)-pentyl terephthalate (DPT)/kg b.w./day by oral administration for 90 days. The no-observed-effect level (NOEL) was 300 mg (iso)-pentyl terephthalate (DPT)/kg b.w./day by oral administration for 90 days.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 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

Justification for classification or non-classification

No classification for repeated dose toxicity is indicated according to the classification, labeling, and packaging (CLP) regulation (EC) No 1272/2008.