Registration Dossier

Toxicological information

Developmental toxicity / teratogenicity

Currently viewing:

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1985-03-25 to 1985-06-04
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study performed under GLP.

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1986
Report Date:
1986
Reference Type:
review article or handbook
Title:
Terephthalsäuredimethylester CAS No. 120-61-6
Author:
BG Chemie
Year:
2005
Bibliographic source:
Toxikologische Bewertung Nr. 50, Ausgabe 02/05

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
(- according to the former OECD 414 rats were exposed from gd 7 - 16)
GLP compliance:
yes
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
Name as cited in the report: Terephthalsaeuredimethylester
Analytical purity: no data
Stability: After preparation in vehicle, the test substance was stable for at least 3 h

Test animals

Species:
rat
Strain:
Wistar
Details on test animals and environmental conditions:
TEST ANIMALS
- Source:
- Age at study initiation: 65-70d
- Weight at study initiation: 193 +/- 10g
- Fasting period before study:
- Housing: singly
- Diet (e.g. ad libitum): Altromin 1310
- Water (e.g. ad libitum):tap water
- Acclimation period:


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.5 - 23
- Humidity (%): 44 - 64
- Air changes (per hr): 16 - 20
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: To:

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: starch mucilage
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The substance was prepared freshly on a daily basis in starch mucilage (200 g potato starch in 1l bidest water)

DOSING VOLUME : 5 ml/kg bw
Analytical verification of doses or concentrations:
yes
Details on mating procedure:
- Impregnation procedure: cohoused
- Length of cohabitation: 14 h(15:30 p.m - 7:30 a.m)
- Proof of pregnancy: sperm in vaginal smear referred to as day 1 of pregnancy


Duration of treatment / exposure:
day 7 - 16 post copulation
Frequency of treatment:
daily

Duration of test:
till day 21 of gestation

No. of animals per sex per dose:
21 - 22 female animals
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Because of its low toxicity in both short term (LD50 > 6,590 mg/kg bw ) and long term (103 weeks, F 344 rats) trials, a limit test in line with guideline directives was performed.
- Standardly, the results were simultaneously analysed by comparison of the effects in the test group with those in the control group and also by comparing both groups with the normal range. The morphological findings were analysed individually according to fetuses and litters.
- The control animals were administered 5 ml/kg bw of the vehicle.

Examinations

Maternal examinations:

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily

BODY WEIGHT: Yes
- Time schedule for examinations: Once weekly and one day after application of last dose

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
-Time schedule for examinations: Continuous

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 21
- Organs examined: Brain, kidneys (macroscopic examinations)

Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes / No / No data
Examinations included:
- Gravid uterus weight: Yes / No / No data
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other:Upon sacrifice of the dams, following parameters were ascertained: number of fetuses in uterus, number of live and dead fetuses, number and stage (early or late) of resorptions, number of corpora lutea, the sex, body weight and crown-rump length of the fetuses and placental weight
Fetal examinations:
- External examinations: Yes: half per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: half per litter
Statistics:
The evaluation of the cesarian section parameters was based on the values relating to dams which were pregnant on day 21. The values of the remaining parameters were obtained from dams which additionally had at least one live fetus

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
Generally, no changes in the behaviour or general conditions of the test animals were observed. On day 14 of gestation, one animal developed a wound at the base of its neck which was scabbed over. Alopecia on the rump and adbomen was noted in another animal on day 17 of pregnancy. A red discolouration of the urine of one female in the control group was observed on day 21 of gestation. The body weight gain of the dams were comparable between the dosed animals (129 g) and the control group (132 g). The food consumption of the dams were comparable between the dosed animals (87 g/kg bw) and the control group (89 g/kg bw). With the exception of one dam in the control group, all animals carried live fetuses. One dam in the exposed group had a dead fetus (1.98g) alongside live fetuses. The amount of corpora lutea as well as the number of implantations and live fetuses were comparable between the dosed group and the control group. Macroscopic examination of the organs from exposed animals revealed no perculiar alterations.

Effect levels (maternal animals)

Key result
Dose descriptor:
NOEL
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: other:
Remarks on result:
not determinable due to absence of adverse toxic effects

Maternal abnormalities

Key result
Abnormalities:
no effects observed
Description (incidence and severity):
no effects observed

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
Fetal body measurements (weights and length) for exposed animals were comparable to that of controls. The sex ratio was relatively balanced between the control and exposed groups. In both the control and exposed groups, the weights of the male fetuses were higher. The number of early resorptions were similar in both dosed and control groups. The early resorption sites had a circumference of up to 0.62 cm. No perculiarities were observed with respect to the weights placentas containing live fetuses in the control and exposed groups. Macroscopic examination of the placentas revealed no perculiarities. A twin placenta was seen in one animal in the control. The placenta of one other animal of the control group was anemic. Necropsy of the fetuses revealed hematoma in the brain and kidney of some fetuses in both the control and exposed group. Blood was also found in the abdominal cavity of animals in the dose group and control group. Moreover, some animals of the control group exhibited following symptoms: hematoma on the neck, left hind limbs, right kidney, and the surroundings of the kidney. Distension of renal pelvis was seen in 2 animals of the control group. Skeletons were in the same stage of development for animals of the exposed and control group corresponding to day 21 of gestation. 2 fetuses of the exposed group exhibited a onesided shortened rib situated on 7th cervical vetebra. Each of the 2 fetuses had a shortened 13th rib, a 14th thoracic vetebra carrying an analogous pair of ribs. Many fetuses of both the exposed and control groups exhibited following morphological changes: An anlage of normal and/or short 14th rib on the 1st lumbar vertebra, thickened and/ or waved ribs or a fragmented longitudinal displaced sternebrae. The skeleton of the dead fetus (1 control animal)) was weakly ossified. No indication of a retardation in the skeletal ossification was observed in the fetuses from treated animals

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
changes in litter size and weights
skeletal malformations
visceral malformations
Remarks on result:
not determinable due to absence of adverse toxic effects

Fetal abnormalities

Key result
Abnormalities:
no effects observed
Localisation:
other:
Description (incidence and severity):
no effects observed

Overall developmental toxicity

open allclose all
Developmental effects observed:
not specified
Key result
Developmental effects observed:
no
Lowest effective dose / conc.:
1 000 mg/kg bw/day (actual dose received)
Treatment related:
no
Relation to maternal toxicity:
not specified
Dose response relationship:
no
Relevant for humans:
yes

Any other information on results incl. tables

No further remarks on results.

Applicant's summary and conclusion

Conclusions:
The test substance caused neither maternal toxicity nor is it embryotoxic or teratogenic to Wistar rats
Executive summary:

In a limited test, dimethyl terephthalate was administered to female Wistar rats via gavage, at a dose of 1000 mg/kg bw/d, on days 7 through 16 post-copulation. Controls received the vehicle alone. Dams were sacrificed on gestation day 21 for examination of uterine contents. There was no evidence of maternal toxicity. No embryotoxic or teratogenic effects were observed. The NOAEL for maternal and developmental toxicity is therefore the limit dose of 1000 mg/kg bw/d.