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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
23 Mar 2021 - 28 May 2021
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference Type:
study report
Report date:

Materials and methods

Test guideline
according to guideline
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
June 2018
GLP compliance:
yes (incl. QA statement)

Test material

Constituent 1
Reference substance name:
Bis[C5-(linear and branched)-alkyl] benzene-1,4-dicarboxylate
EC Number:
Cas Number:
Molecular formula:
Bis[C5-(linear and branched)-alkyl] benzene-1,4-dicarboxylate
Test material form:

Test animals

New Zealand White
Details on test animals or test system and environmental conditions:
- Source: Envigo RMS (UK) Limited, Shaw’s Farm, Blackthorn, Bicester, Oxon, UK
- Age at study initiation: 4-5 mo
- Weight at study initiation: 2.7 - 4.1 kg
- Housing: single
- Diet: ad libitum
- Water: ad libitum

- Temperature (°C): 17-20
- Humidity (%): 35-65
- Air changes (per hr): ten or more air changes per hour
- Photoperiod (hrs dark / hrs light): 12h dark/12h light

IN-LIFE DATES: From: 29 Mar 2021 To: 30 Apr 2021

Administration / exposure

Route of administration:
oral: gavage
corn oil
Details on exposure:
- Test item dose formulations were prepared at least weekly. Dosing formulations were prepared based on a method established at the Test Facility.

- Justification for use and choice of vehicle (if other than water):
- Concentration in vehicle: 30mg/ml, 100 mg/ml, 300 mg/ml
- Dose volume: 1 ml/kg
Analytical verification of doses or concentrations:
Details on analytical verification of doses or concentrations:
Dose formulation samples were collected for concentration and homogeneity analysis. Formulation analyses confirmed that formulations of test item in corn oil were prepared accurately and homogenously.
Duration of treatment / exposure:
GD 6 to 28
Frequency of treatment:
once daily
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Group 1 / control
Dose / conc.:
30 mg/kg bw/day (nominal)
Group 2
Dose / conc.:
100 mg/kg bw/day (nominal)
Group 3
Dose / conc.:
300 mg/kg bw/day (nominal)
Group 4
No. of animals per sex per dose:
Control animals:
yes, concurrent vehicle
Details on study design:
The oral route of exposure was selected because this is a possible route of human exposure.
The dose levels for this study were selected based on the dose range finding developmental toxicity study in the rabbit (2020-0012-DGR_DRF, 490922). In the dose range finding study pregnant rabbits were dosed once daily by oral gavage at 250, 500 and 1000 mg/kg/day. Rabbits dosed at 500 and 1000 mg/kg/day were euthanised prematurely. The 1000 mg/kg/day dose caused, in the pregnant rabbits, a disruption of food consumption in the first 6 days of treatment, rabbits consumed only about 1-4 g of food per day and had continuous body weight loss throughout dosing. The 500 mg/kg/day dose showed a low food consumption, in the first 8 days of treatment, rabbits consumed only about 1-37 g of food per day and lost body weight. At 250 mg/kg/day, findings of lower implants, higher pre-implantation loss and higher post-implantation loss were present. As this dose of 250 mg/kg/day did not induce sufficient maternal toxicity, a marginally higher dose of 300 mg/kg/day was selected as the high dose for the main study with low and mid dose levels of 100 and 30 mg/kg/day.


Maternal examinations:
- Time schedule: At least once daily; from at least GD 4.

- Time schedule: Pretreatment – Once (GD 5); Dosing Period – Weekly from GD 6

- Time schedule for examinations: Pretreatment – Once; Dosing Period – Once on GD 6, 9, 13, 16, 20, 24, and 29.

- Daily from GD 6 (first weighed quantity offered on GD 5)

- Sacrifice on gestation day 29
- Organs examined: Adult animals were subjected to a complete necropsy examination
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Placenta size, colour, shape (only abnormalities were recorded)
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: half per litter
Parametric/non-parametric: one-way ANOVA F-test, Levene’s test or Kruskal-Wallis test; Dunnett’s or Dunn’s test
Incidence: Fisher's exact test
Pregnancy Rate % = No. of animals pregnant x 100/ No. of animals in cohabitation
Pre-Implantation Loss % = (No. of corpora lutea – no. of implants x 100)/ No. of corpora lutea
Post-Implantation Loss % = (No. of implants – no. of live fetuses x 100)/ No. of implants
Sex Ratio (% males) = No. male fetuses x 100/ Total no. of fetuses
Litter % of Fetuses with Abnormalities = No. of fetuses in litter with a given finding x 100/ No. of fetuses in litter examined
Historical control data:
Comparison with historical control data.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
mortality observed, treatment-related
Description (incidence):
At 300 mg/kg/day on Gestation Day (GD) 20, Animal 4508 was prematurely euthanised due to continued bodyweight loss and low food consumption. From GD6-20 there was a bodyweight loss of -771 g (20%). From GD6-8 food consumption dropped from 133 g to 65 g, then from GD8 20 food consumption ranged from 0 to 4 g. On GD20 there were clinical observations of cold to touch and the animal appeared thin. At necropsy there were no findings and it was confirmed that the animal was pregnant.
At 100 mg/kg/day on Gestation Day 27, Animal 3517 was found dead during the morning check. It was noted that there was red staining around the anus and in the cage and on the tray paper. Food consumption dropped to 0 g during the first few days of dosing and recovered with repeated dosing. However, it was noted that food consumption dropped to 13 g on GD25-26. At necropsy there were no findings to indicate a cause of death and the animal was noted to be pregnant but had 2 early and 4 late resorptions.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
At 300 mg/kg/day there was an initial transient weight loss from GD6-9. After this period there was a slightly lower body weight gain from GD9-13 of -15% (95.5 g) and GD13-16 of 52% (46.4 g) when compared with the control during those periods of 112.8 g and 97.2 g respectively.
At 30, 100 mg/kg/day there were no test item-related effects on body weight or body weight gain.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
At 300 mg/kg/day there was statistically significant mean lower food consumption during GD9-10, 10-11 and 16-17 of up to 40% when compared with the control. Food consumption was also lower in the control during the first few days of dosing, however picked up after GD8-9. Food consumption fluctuated throughout dosing and within the first few days of dosing (GD6-11) it was noted that many animals throughout this dose group had low food consumption ranging from 0-141 g. Many animals had continuous low food consumption throughout these days however, food consumption did pick up after the first few days for most of the animals with a few still showing lower food consumption throughout the dosing period. Food consumption remained lower than the control until GD21-22.
At 30 or 100 mg/kg/day there were a few incidences of lower food consumption when compared with the control. This lower food consumption considered to be transient in nature and a similar variability was seen in both the control and treatment groups.
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Endocrine findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
There were no test item-related effects on gravid uterine weights or corrected body weights.
Gross pathological findings:
no effects observed
Description (incidence and severity):
There were no test item-related effects on gross pathology.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in number of pregnant:
no effects observed

Effect levels (maternal animals)

Dose descriptor:
Effect level:
100 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
body weight and weight gain

Results (fetuses)

Fetal body weight changes:
no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Description (incidence and severity):
There were no test item-related malformations or variations at 30, 100 or 300 mg/kg/day. All malformation and variations were considered to be within the normal biological variation for this species therefore were considered not to be related to the test item.

Effect levels (fetuses)

Dose descriptor:
Effect level:
> 300 mg/kg bw/day (nominal)
Based on:
test mat.
Remarks on result:
not determinable due to absence of adverse toxic effects

Fetal abnormalities

no effects observed

Overall developmental toxicity

Developmental effects observed:

Applicant's summary and conclusion

In conclusion, administration of Di-(iso)-pentyl terephthalate (DPT) by once daily oral gavage in pregnant rabbits at levels of 300 mg/kg/day caused body weight loss and lower mean food consumption. In addition, at 300 mg/kg/day one animal was found dead following low food consumption which was considered to be test-item related. Based on these results, the maternal no-observed-adverse-effect level (NOAEL) was considered to be 100 mg/kg/day and the fetal no-observed-adverse-effect level (NOAEL) was considered to be up to 300 mg/kg/day.