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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
15 Sep - 16 Oct 1987
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
GLP - Guideline study. According to the ECHA guidance document "Practical guide 6: How to report read-across and categories (March 2010)", the reliability was changed from RL1 to RL2 to reflect the fact that this study was conducted on a read-across substance.

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1988
Report Date:
1988
Reference Type:
secondary source
Title:
Diesters Category of the Aliphatic Esters Chemicals (Test Plan and Robust Summaries for Substances in the HPV Test Plan)
Author:
US-EPA (American Chemistry Council's Aliphatic Esters Panel)
Year:
2010
Bibliographic source:
High Production Volume (HPV) Chemical Challenge Program (201-16837A and 201-16837B)
Reference Type:
secondary source
Title:
Bis(2-ethylhexyl)adipate (DEHA) CAS N°: 103-23-1
Author:
OECD
Year:
2000
Bibliographic source:
SIDS Initial Assessment Report for SIAM 10; Tokyo, Japan, 15-17 March 2000

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Di(2-Ethylhexyl) Adipate
- Supplier: ICI France, Department Baleycourt
- Physical state: colourless liquid
- Batch: Y02259/003/003-4
- Analytical purity: 99.2% w/w
- Impurities (identity and concentrations): Phthalate (as DOP) 0.08% w/w

Test animals

Species:
rat
Strain:
other: Alpk:APfSD (Wistar derived)
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: SPF colony maintained at the Animal Breeding Unit, ICI Pharmaceuticals, Alderley Park, Cheshire, UK.
- Age at study initiation: 12 weeks
- Weight at study initiation: 218-278 g
- Housing: individually in stainless steel cages with absorbent paper over collecting trays.
- Diet (e.g. ad libitum): CTI diet, Special Diets Services Ltd., Essex, UK.
- Water (e.g. ad libitum): yes

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-24
- Humidity (%): 44-70
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light):12/12

IN-LIFE DATES: From: 15 Sept - 16 Oct 1987.

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The experimental diets were prepared in 30 kg batches from premixes.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Chemical stability was observed at 300 ppm up to at least 32 days. This interval was in excess of the maximum period of use of the first batch of diet (21 days from preparation). The achieved concentration was within 8% of target and the doses received by the test groups were approximately 28, 170 and 1080 mg/kg bw/day.
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: not reported
- Length of cohabitation: overnight
- Proof of pregnancy: sperm in vaginal smear referred to as day 1 of pregnancy

Successfully mated females were delivered to the experimental unit.
A total of 96 mated females was supplied over a two week period.
Duration of treatment / exposure:
days 1-22 of gestation.
Frequency of treatment:
Continuous feeding
Duration of test:
22 days
No. of animals per sex per dose:
24
Control animals:
yes, plain diet

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: on arrival and daily

BODY WEIGHT: Yes
- Time schedule for examinations: daily during days 1-22 of gestation

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 22
- Organs examined: uterus, ovaries, liver, spleen, kidney, stomach, rectum, abdominal cavity, pelvic cavity,
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, in each ovary.
- Number of implantations: Yes
- Number of early resorptions: Yes (early intra-uterine deaths)
- Number of late resorptions: Yes (late intra-uterine deaths)
- Other: Each foetus was weighed and individually identified within the litter by means of a cardboard tag. After weighing the foetuses were killed with an intra-cardiac injection of pentobarbitone.
Fetal examinations:
- External examinations and cleft palate: Yes, each foetus
- Soft tissue examinations: Yes, all
- Skeletal examinations: Yes, all
- Head examinations: Yes, the head of each foetus was cut along the fronto-parietal suture line and the brain was examined for macroscopic abnormalities.
Statistics:
Analysis of variance, Student's t-test, Fisher's Exact Test
Indices:
- Pre-implantation loss (No. of corpora lutea / No. of implantations)
- Post implantation loss (No. of implantations / No. of live foetuses)
Historical control data:
Yes, data on variants and frequency of occurence in rats of this strain were given.
Defects like bipartite 5th sternebrae, slightly dilated ureters and kinked ureters were seen in historical controls of this strain.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
At 12000 ppm a small but statistically significant reduction in maternal bodyweight gain was observed.
There was also a small but statistically significant reduction in food consumption at this dose level from days 2-18 inclusive of gestation.
There was no evidence of maternal toxicity at 300 or 1800 ppm.

Effect levels (maternal animals)

open allclose all
Key result
Dose descriptor:
NOAEL
Effect level:
ca. 170 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Key result
Dose descriptor:
LOAEL
Effect level:
ca. 1 080 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 080 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Key result
Dose descriptor:
NOEL
Effect level:
ca. 28 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Key result
Dose descriptor:
LOEL
Effect level:
ca. 170 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes. Remark: (non-adverse)

Details on embryotoxic / teratogenic effects:
There was no effect at any dose on foetal weight, litter weight, gravid uterus weight, numbers of intra-uterine deaths or numbers of external abnormalities. At 12000 ppm there was a minimal increase of pre-implantation loss with an associated decrease in litter size.
Six major abnormalities (in five foetuses) were seen in the treated groups and eight in the control group (of which seven consisted of multiple minor skull defects in one litter). There was no evidence that the type or distribution of these abnormalities was related to treatment with the test substance.
Overall, minor skeletal defects were increased in a dose-related manner at 1800 and 12000 ppm of the test substance, while skeletal variants (as a percentage of foetuses affected) were increased at the top dose only. These findings indicated slightly poorer ossification at dose levels of 1800 and 12000 ppm, which were considered to be the result of slight fetotoxicity. However, the slightly poorer ossification is not considered as adverse effect.

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Remarks on result:
not measured/tested

Fetal abnormalities

Key result
Abnormalities:
not specified

Overall developmental toxicity

Key result
Developmental effects observed:
not specified

Any other information on results incl. tables

Table 1: Foetal defects and variants - Intergroup comparison of foetal defects and variants

 

Dietary conc. of DEHA (ppm)

0

300

1800

12000

No. of litters examined

24

23

24

23

External and visceral defects

No. of foetuses examined

282

263

278

243

No. of foetuses showing major defects

1

2

0

2

No. of foetuses showing minor defects only

7

8

9

3

Variants

No. of foetuses showing variants

69

69

81

78*

Skeletal defects

No. of foetuses examined

282

263

278

243

No. of foetuses showing major defects

7

0

1

1

No. of foetuses showing minor defects only

70

78

97**

120**

Variants

No. of foetuses showing variants

270

257

268

243**

 

Table 2: Summary of the type and incidence of major defects

 

Dietary conc. of DEHA (ppm)

0

300

1800

12000

External/Visceral

Situs inversus totalis

0

0

0

1

Left adrenal, kidney and ureter absent

1

0

0

0

Cysts attached to liver

0

1

0

0

Small right kidney

0

1

0

0

Umbilical hernia

0

0

0

1

Skeletal

Skull: Multiple minor defects

7

0

0

0

3rdand 7thribs (left) not ossified0

0

0

0

1

1strib (right) partially ossified

0

0

1

0

 There was no evidence that the test substance is teratogenic to the rat at any of the dose levels tested (up to 12000 ppm -approximately 1000 mg/kg/day). Administration of 12000 ppm DEHA resulted in slight maternal toxicity and slight foetotoxicity.

At 1800 ppm, there was no evidence of maternal toxicity although minimal foetotoxicity was observed. A dietary level of 300 ppm DEHA was a clear no-effect level for embryonic development. 

Applicant's summary and conclusion