Registration Dossier

Toxicological information

Developmental toxicity / teratogenicity

Currently viewing:

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
other information
Study period:
No data
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Insufficient number of female tested, concentrations tested were too high and substance was not administered until the day prior to scheduled caesarean section. Lack of details on test procedure and test results. This study can be used for assessment.
Cross-referenceopen allclose all
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
publication
Title:
Effects of aliphatic nitriles in micromass cultures of rat embryo limb bud cells
Author:
Saillenfait A.-M., Sabaté J.P., Gaspard C.
Year:
2004
Bibliographic source:
Toxicology in vitro, 18:311-318

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
Insufficient number of female, substance not administered until the day prior to scheduled caesarean section
Principles of method if other than guideline:
Not applicable
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): cis-2-pentenenitrile
- Analytical purity: > 98 %
- Impurities (identity and concentrations): no data

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: IFFA CREDO breeding laboratories (Saint Germain sur l'Arbresle, France)
- Age at study initiation: no data
- Weight at study initiation: no data
- Fasting period before study: no data
- Housing: mated females were singly housed in clear polycarbonate with stainless steel wire lids and corncob granules as bedding
- Diet: fodd pellets (UAR Alimentation, Villemoisson, France) ad libitum
- Water: filtered tap water ad libitum
- Acclimation period: no data


ENVIRONMENTAL CONDITIONS
- Temperature: 21 +/- 2 °C
- Humidity: 50 +/- 5 %
- Air changes (per hr): no data
- Photoperiod: 12 hrs dark / 12 hrs light


IN-LIFE DATES: no data

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
paraffin oil
Details on exposure:
VEHICLE
- Justification for use and choice of vehicle (if other than water): no data
- Amount of vehicle (if gavage): 5 mL/kg
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
No data
Details on mating procedure:
- Impregnation procedure: cohoused
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
From GD 6 to GD 17
Frequency of treatment:
Daily
Duration of test:
Until GD 21
Doses / concentrations
Remarks:
Doses / Concentrations:
8, 16, 28, 42 and 56 mg/kg bw/day
Basis:
other: gavage study
No. of animals per sex per dose:
5 to 8 females per dose
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: no data
- Rationale for animal assignment (if not random): random

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: GD 0, 6, 9, 12, 15 ,18 and 21.

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 21 (intrapulmonary ingestion of T61)
- Organs examined: uterus
Ovaries and uterine content:
Examinations included:
- Number of implantations: Yes
- Number of resorptions: Yes
Fetal examinations:
- External examinations: Yes: live fetuses
Statistics:
Quantitative parameters were presented as mean +/- SD. All parameters were evaluated by the Kruskall-Wallis test, followed by the Mann-Whitney test where appropriate. The reported level of statistical significance was P < 0.05.
Indices:
No data
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:
No test dam died. The maternal weight gain was significantly depressed at all doses, and the corrected weight gain at 42 and 56 mg/kg bw.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
LOAEL
Effect level:
8 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
LOAEL
Effect level:
28 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Dose descriptor:
NOAEL
Effect level:
16 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

Details on embryotoxic / teratogenic effects:
There was an increased incidence of resorptions from 28 mg/kg bw, which rose up 49.6 % at 56 mg/kg bw. The number of live fetuses was significantly reduced at 45 mg/kg bw. Cis-2-pentenenitrile induced a dose-related decrease in fetal body weight, which achieved statistical significance at 28 mg/kg bw. External examination revealed malformations in the treated-groups. Omphalocele was observed in three fetuses from two different litters at 42 mg/kg bw, and in 27 fetuses from six different litters at 56 mg/kg bw. Meningocele or domed head (five fetuses from 2 litters) and ectrodactyly (four fetuses form two litters) were also detected at 56 mg/kg bw.

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Table 7.8.2/1: Effects on cis-2 -pentenenitrile given to Sprague-Dawley rats by gavage on GD 6 -17

Dose (mg/kg bw/day

 

0

8

16

28

42

56

Dams

No. pregnant/treated

8/9

8/9

8/9

7/8

5/5

6/6

Body weight on GD6 (g)

266 ± 17

268 ± 16

266 ± 15

270 ± 11

282 ± 12

277 ± 18

Body weight gain on GD6-18 (g)

99 ± 7

88 ± 12*

82 ± 10**

74 ± 8**

44 ± 18**

10 ± 24**

Body weight gain on GD18-21 (g)

51 ± 8

48 ± 10

46 ± 13

45 ± 6

43 ± 10

32 ± 1**

Corrected weight gain (g)#

37 ± 7

37 ± 11

33 ± 15

28 ± 9

16 ± 14*

3 ± 15 *

Litters

Mean no. of implantation sites per litter

14.9 ± 1.1

13.3 ± 3.5

13.8 ± 3.6

14.1 ± 2.3

13.8 ± 3.4

15.3 ± 1.0

Mean no. of live fetuses per litter

14.6 ± 1.1

13.0 ± 3.3

13.1 ± 3.3

13.0 ± 2.1

11.8 ± 3.1

7.7 ± 4.0**

Mean % post-implantation loss per litter

1.6 ± 3.0

1.7 ± 3.1

4.1 ± 3.4

7.9 ± 6.6*

14.1 ± 11.6*

49.6 ± 27.4**

Mean % resorptions per litter

1.6 ± 3.0

0.8 ± 2.2

4.1 ± 3.4

7.9 ± 6.6*

11.6 ± 9.9

49.6 ± 27.4**

Mean % males fetuses per litter

54.4 ± 14.6

49.0 ± 9.9

50.4 ± 13.5

45.4 ± 8.9

52.8 ± 12.2

72.9 ± 16.8

Fetal body weight (g)

5.75 ± 0.22

5.80 ± 0.39

5.58 ± 0.27

5.39 ± 0.15**

4.61 ± 0.62**

3.08 ± 0.57**

Total no. fetuses with external malformations/no. examined

0/117

0/104

0/105

0/91

3/59

28/46

Total no. litters with external malformations/no. examined

0/8

0/8

0/8

0/7

2/5

6/6

* and ** indicated significant difference from the vehicle control, P < 0.05 and P < 0.01, respectively

# Body weight gain during GD 6 -21 minus gravid uterine weight

Applicant's summary and conclusion

Executive summary:

In a developmental toxicity study (Saillenfait et al., 2004) cis-2-pentenenitrile (> 98 % pure) was administered to 5-8 females Sprague-Dawley rats/dose by gavage at dose levels of 0, 8, 16, 28, 42 and 56 mg/kg bw/day from days 6 through 17 of gestation.

No test dam died. The maternal weight gain was significantly depressed at all doses, and the corrected weight gain was depressed at 42 and 56 mg/kg bw. The maternal LOAEL is 8 mg/kg bw/d, based on these findings.

There was an increased incidence of resorptions from 28 mg/kg bw, which rose up 49.6 % at 56 mg/kg bw. The number of live fetuses was significantly reduced at 45 mg/kg bw. Cis-2-pentenenitrile induced a dose-related decrease in fetal body weight, which achieved statistical significance at 28 mg/kg bw. External examination revealed malformations in the treated-groups. Omphalocele was observed in three fetuses from two different litters at 42 mg/kg bw, and in 27 fetuses from six different litters at 56 mg/kg bw. Meningocele or domed head (five fetuses from 2 litters) and ectrodactyly (four fetuses form two litters) were also detected at 56 mg/kg bw.

Previously reported study (Lewis, 2005 and MacKenzie, 2001), showed that important compound-related reductions in body weights and nutritional parameters were observed at doses as low as 10 mg/kg bw/d. Therefore the effects observed on fetuses in this study at doses above 16 mg/kg bw/d are probably related to the maternal effects and not to developmental effects. By consequence this study can't be used for health hazard assessment .