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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1995
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study, well documented.
Cross-reference
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
publication
Title:
Assessment of the developmental toxicity and placental transfer of 1,2-dichloroethane in rats
Author:
Payan JP, Saillenfait AM, Bonnet P, Fabry JP, Lagonne I & Sabate JP
Year:
1995
Bibliographic source:
Fundam. Appl. Toxicol. 28: 187-198

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
not specified
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material: 1,2-dichloroethane
- Purity >99%, from Merck (Darmstadt, Germany)

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: IFFA CREDO Breeding Laboratories (St.-Germain-sur-l'Arbresle, France)
- Age at study initiation: young adult
- Weight at study initiation: 350 (males); 200-220 g (females)
- Diet: Commercial food pellets (UAR Alimentation, Villemoison, Epinay-sur-Orge, France), ad libitum
- Water (e.g. ad libitum): Filtered tap water, ad libitum
- Acclimation period: 1-2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 1 degree C
- Humidity: 55 ± 5 %
- Photoperiod: 12 hours dark / 12 hours light

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
In the oral administration study, groups of 25-26 bred rats were given daily doses of 1.2, 1.6, 2.0 or 2.4 mmol/kg bw by gastric intubation on Gestational days 6 to 20. The substance was dissolved in corn oil. The actual volume administered (2 mL/kg bw) was based on body weight taken on Gestational day 6. Corrections in dosage based on change in body weight during gestation would have contributed minimally (no more than 13 %) to differences between actual exposure and calculated exposure. A seperate control group of 26 females received an equivalent volume of corn oil and was treated in the same manner.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
no data on analytical verification of doses
Details on mating procedure:
Female rats were placed with males (one male: three females) overnight and were examined by vaginal smear for the presence of sperm the following morning. Sperm-positive females were considered at day 0 of gestation.
Duration of treatment / exposure:
days 6-20 of gestation
Frequency of treatment:
daily
Duration of test:
Animals were killed on day 21 of gestation.
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 1.2, 1.6, 2.0, 2.4 mmol/kg bw/d (= 0, 118, 158, 198, 238 mg/kg bw/d)
Basis:
actual ingested
No. of animals per sex per dose:
26 female rats
Control animals:
yes, concurrent vehicle
Details on study design:
no further details

Examinations

Maternal examinations:
Maternal body weights were recorded on day 0, and every 3 days from days 6 to 21 of gestation.
Ovaries and uterine content:
On day 21 of gestation, the females were killed by an intrapulmonary injection of T61( an euthanasia coctail consisting of embutramine, mebezonuin iodite, tetracaine hydrochlorite and dimethylformamide; Hoechst, Frankfurt, Germany), and the uterus was removed and weighed. The uterus horns were than opened, and the number of implantation and resorption sites and live and dead fetuses were recorded.
Fetal examinations:
Live fetuses were weighed and examined for external anomalies including those of the oral cavity, and the sex was determined by external examination. Half of the live fetuses from each litter were randomly selected, fixed in Bouin's solution, and examined microscopically as described by Barrow and Taylor (1969). The remaining half of fetuses were fixed in 70 % ethanol and subsequently eviscated, macerated in 1 % KOH, stained in alizarin red S, and examined microscopically for skeletal anomalies.
Statistics:
Whenever possible, the data were presented as mean ± SD. The number of implantation sites and live fetuses and various body weights were analyzed by one way analysis of variance, followed by Dunnett's test if differences were found. The frequency of nonsurviving implants, resorptions and anomalies among litters was evaluated by using the Wilcoxon test after an arc-sine-square root transformation. Rates of pregnancy and fetal sex ratio were analyzed using Fisher's test. Where applicable, least-square analysis was carried out. The reported level of statistical significance was p< 0.05. The litter was used as the basis for analysis of fetal variables.
Indices:
Implantation sites, live fetuses, nonsurviving implants, resorptions, anomalies among litters, rates of pregnancy and fetal sex ratio
Historical control data:
no data

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
26 female rats were used per group with 23 to 16 litters delivered. No deaths occurred. Maternal toxicity was indicated by decreased absolute weight gain at the two highest oral dose levels. Pregnancy rates were similar in all groups.

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
158 mg/kg bw/day
Basis for effect level:
other: maternal toxicity

Results (fetuses)

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

Details on embryotoxic / teratogenic effects:
At 240 mg/kg bw/d, 3 dams delivered pre-term on day 20. All fetuses of these litters were dead and were excluded from further final analysis of reproductive parameters due to possibility of cannibalism. No significant effect was noted on the mean number of implantation sites and live fetuses, fetal sex ratio, and fetal body weights. No embryo- or fetotoxicity, changes in fetal growth or teratological effects were induced at any dose. All malformations and variations seen were scattered among all groups with no indication of treatment-related effect. There was only some embryolethal effects (increase in non-viable implants and resorption sites per litter), significant at 200 mg/kg bw/d and higher (p<0.05).

Effect levels (fetuses)

open allclose all
Dose descriptor:
NOAEL
Effect level:
238 mg/kg bw/day
Basis for effect level:
other: teratogenicity
Dose descriptor:
NOAEL
Effect level:
158 mg/kg bw/day
Basis for effect level:
other: embryotoxicity
Dose descriptor:
NOAEL
Effect level:
238 mg/kg bw/day
Basis for effect level:
other: fetotoxicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
No embryo- or fetotoxicity or teratogenicity was noted at concentrations which caused maternal toxicity.
Executive summary:

In a developmental toxicity study, 1,2 -dichloroethane (> 99 %) was administered to 26 female Sprague-Dawley rats/dose in corn oil by gavage at dose levels of 0, 1.2, 1.6, 2.0 or 2.4 mmol/kg bw/d (= 0, 118, 158, 198 or 238 mg/kg bw/d) from days 6 through 20 of gestation. 26 female rats were used per group with 23 to 16 litters delivered. No deaths occurred. Maternal toxicity was indicated by decreased absolute body weight gain at the two highest oral dose levels. Pregnancy rates were similar in all groups. The maternal LOAEL was 198 mg/kg bw/d, based on changes in body weight. The maternal NOAEL was 158 mg/kg bw/d.

At 238 mg/kg bw/d, 3 dams delivered pre-term on day 20. All fetuses of these litters were dead and were excluded from further final analysis of reproductive parameters due to the possibility of cannibalism. No significant effect was noted on the mean number of implantation sites and live fetuses, fetal sex ratio, and fetal body weights. No embryo- or fetotoxicity, changes in fetal growth or teratological effects were induced at any dose. All malformations and variations seen were scattered among all groups with no indication of treatment-related effect. There was only some embryolethal effects (increase in non- viable implants and resorption sites per litter), significant at 198 mg/kg bw/d and higher (p<0.05). The developmental LOAEL was 198 mg/kg bw/d, based on embryotoxicity. The developmental NOAEL was 158 mg/kg bw/d.

The developmental toxicity study in the rat was classified acceptable and was conducted equivalent or similar to the guideline requirement for a developmental toxicity study (OECD 414) in rats.