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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:
17/01/2012 - 14/09/2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2012
Report date:
2012

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
Principles of method if other than guideline:
Clinical Observations

On Day 18 of the study the five hour observations for animal numbers 85 to 90 were not recorded in error.

Post Mortem Studies

The macroscopic observations for the litter from female number 36 were not recorded due to a technician error.

These deviations do not affect the purpose or integrity of the study.
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Reference substance name:
Tetradec-1-ene, dimers, hydrogenated
Molecular formula:
C28H58
IUPAC Name:
Tetradec-1-ene, dimers, hydrogenated
Test material form:
liquid

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Details on test animals or test system and environmental conditions:
A total of ninety-six time-mated female Sprague-Dawley Crl:CD(SD) IGS BR strain rats obtained from Charles River (UK) Limited, Margate, Kent
At the start of the study the females weighted 186 to 291 g and were approximately ten to twelve weeks old

The animals were housed individually in solid-floor polypropylene cages with stainless steel lids furnished with softwood flakes in a single air-conditioned room within the Harlan Laboratories
The rate of air exchange was at least 15 air changes per hour and low intensity fluorescent lighting was controlled to give 12 hours continuous light and 12 hours darkness
The temperature and relative humidity were set to achieve target values of 21 ± 2ºC
and 55 ± 15% respectively.
A pelleted diet was used
Main drinking water supplied from polycarbonated bottles attached to the cage
The diet and drinking water did not contain any contaminant at a level that might have affected the purpose or integrity of the study

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
arachis oil
Details on exposure:
The animals were randomly allocated to treatment groups using a randomisation procedure based on stratified body weight to ensure similarity between the treatment groups. The animals were uniquely identified within the study by an ear punching system routinely used in these laboratories.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The concentration of Hydrogenated oligomerisation product, including dimers and trimers, of tetradec-1-ene and alkene in the test item formulations was determined by gas chromatography (GC) using an external standard technique.

The standard and sample solutions were analysed by GC using the following conditions:
GC system: Agilent Technologies 5890, incorporating autosampler and workstation
Column: DB-5 (30 m x 0.25 mm id x 0.25 µm film)
Oven temperature program: initial 200 ºC for 1 mins (rate 15ºC/min; final 325 ºC for 10 mins)
Injection temperature: 300 ºC
Flame ionisation detector temperature: 300 ºC
Injection volume: 1 µl
Retention time: Profile of peaks from ~ 7 to 8.5 mins
Duration of treatment / exposure:
Treatment was administered for 14 days, from Day 5 to Day 19.
Frequency of treatment:
Once daily
Doses / concentrationsopen allclose all
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
300 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
12
Control animals:
yes, concurrent vehicle
Details on study design:
The foetuses were killed by subcutaneous injection of a suitable barbiturate agent. Foetuses from each litter were divided into two groups and examined for skeletal alterations and soft tissue alterations. Alternate foetuses were identified using an indelible marker and placed in Bouin’s fixative. Foetuses were transferred to 90% industrial methylated spirits (IMS) in distilled water and examined for visceral anomalies under a low power binocular microscope. The remaining foetuses were identified using colour coded wires and placed in 70% IMS in distilled water. The foetuses were eviscerated, processed and the skeletons stained with alizarin red. The foetuses were examined for skeletal development and anomalies. Following examination foetuses that were examined for skeletal development were placed in 100% glycerol.

Examinations

Ovaries and uterine content:
The ovaries and uteri of pregnant females were removed, examined and the following data recorded:
i) Number of corpora lutea
ii) Number, position and type of intrauterine implantation
iii) Foetal sex
iv) External foetal appearance
v) Foetal weight
vi) Placental weight
vii) Gravid uterus weight
Fetal examinations:
Implantation types were divided into:

Early Death: No visible distinction between placental/decidual tissue and embryonic tissue
Late Death: Separate embryonic/foetal and placental tissue visible
Dead Foetus: A foetus that had died shortly before necropsy. These were included as late deaths for reporting purposes

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
There were no toxicologically significant clinical observations detected in any treated females.
One female treated with 1000 mg/kg bw/day had generalised fur loss between Days 11 and 20. In isolation this observation is considered not to be of toxicological significance.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry 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
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
One female treated with 1000 mg/kg bw/day had generalised fur loss at necropsy. This was an isolated incident and is considered not to be of toxicological significance. One female treated with 300 mg/kg bw/day had a mass in the left mammary gland. As similar observations were not apparent in animals treated with 1000 mg/kg bw/day, this was considered to be an isolated finding and is considered not to be of toxicological significance.#

Animals treated with 300 mg/kg bw/day showed a statistically significant (p<0.01) increase in total corpora lutea when compared to control animals. In the absence of a true dose related response or any associated effects in the uterine parameters examined the intergroup difference is considered not to be of toxicological significance.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed

Maternal developmental toxicity

Number of abortions:
not examined
Pre- and post-implantation loss:
not examined
Total litter losses by resorption:
not examined
Early or late resorptions:
not examined
Dead fetuses:
not examined
Changes in pregnancy duration:
not examined
Changes in number of pregnant:
not examined
Other effects:
not examined

Effect levels (maternal animals)

Key result
Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: No effects observed.

Maternal abnormalities

Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Reduction in number of live offspring:
not examined
Changes in sex ratio:
not examined
Changes in litter size and weights:
not examined
Changes in postnatal survival:
not examined
External malformations:
not examined
Skeletal malformations:
not examined
Visceral malformations:
not examined
Other effects:
not examined

Effect levels (fetuses)

Key result
Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects

Fetal abnormalities

Key result
Abnormalities:
no effects observed

Overall developmental toxicity

Key result
Developmental effects observed:
no

Any other information on results incl. tables

Key to tables

M – Male

F – Female

sd – standard deviation

n – number of animals/litters

NF – number of foetuses

NL – number of litters

† - group mean per litter

%† - group mean percent

N/A – not applicable

● - no data available

Table 1 summary of female performance

Category

Number of female at dose level (mg/kg bw/day)

0

100

300

1000

Initial Group Size

24

24

24

24

Pregnant

24

24

24

24


Table 2 clinical observations – group incidences

 

Dose level

Number of animals

Clinical observations

Number showing effect(days post coitum affected)

0 (control)

24

No abnormalities detected

-

100

24

No abnormalities detected

-

300

24

No abnormalities detected

-

1000

24

No abnormalities detected

1 (days 11-20)

 

Table 3 body weight during gestation – group mean values

Dose level (mg/kg bw/day)

Number of animals

Body weight (g) at daypost coitum

 

3

5

6

7

8

11

14

17

20

0 (control)

24

Mean

241

250

251

256

261

281

300

330

370

sd

26

26

25

26

26

28

28

32

37

100

24

Mean

243

252

255

259

264

285

304

332

371

sd

20

19

19

19

20

22

24

27

31

300

24

Mean

241

250

252

256

261

280

300

329

369

sd

18

19

18

18

18

20

21

25

30

1000

24

Mean

240

250

251

256

260

279

297

324

363

sd

20

20

19

19

19

19

21

24

28

 

Table 4 body weight change during gestation – group mean values

Dose level (mg/kg bw/day)

Number of animals

Body weight change (g) during days post coitum

 

3 to 5

5 to 6

6 to 7

7 to 8

8 to 11

11 to 14

14 to 17

17 to 20

0 (control)

24

Mean

10

1

5

5

20

20

30

40

sd

6

4

4

3

5

5

7

8

100

24

Mean

9

3

4

5

20

19

29

39

sd

5

5

3

3

4

4

6

8

300

24

Mean

9

3

3

5

19

19

30

40

sd

4

5

3

3

4

5

6

8

1000

24

Mean

9

2

5

4

19

18

27

39

sd

3

2

3

3

6

5

5

7

Dose level (mg/kg bw/day)

Number of animals

Body weight change (g) from day 5post coitum

 

6

7

8

11

14

17

20

0 (control)

24

Mean

1

6

11

31

50

80

120

sd

4

5

6

8

10

15

20

100

24

Mean

3

7

12

33

52

80

119

sd

5

6

7

9

11

15

19

300

24

Mean

3

6

11

30

50

79

119

sd

5

5

6

7

10

15

21

1000

24

Mean

2

7

11

30

47

74

113

sd

2

4

5

7

10

13

17

Table 5 - Gravid Uterus weight and adjusted body weight and body weight change during gestation – group mean values

Dose level (mg/kg bw/day)

Number of animals

 

Body weight (g) on dayspost coitum

Body weight change (g) during dayspost coitum

Gravid Ulterus weight (g)

Adjusted body weight (g) day 20

Adjusted body weight (g) change 5-20

5

20

5-20

0 (control)

24

Mean

250

370

120

73.99

296

46

sd

26

37

20

12.94

31

14

100

24

Mean

252

371

119

72.93

298

46

sd

19

31

19

11.68

24

13

300

24

Mean

250

369

119

78.00

291

41

sd

19

30

21

13.71

23

15

1000

24

Mean

250

363

113

75.08

287

38

sd

20

28

17

9.66

22

12

Table 6 – Food consumption during gestation – group mean values

Dose level (mg/kg bw/day)

Number of animals

Food consumption (g/rat/day) between dayspost coitum

 

3 to 5

5 to 8

8 to 11

11 to 14

14 to 17

17 to 20

0 (control)

24    

Mean

23

21

22

23

24

25

sd

3

3

3

3

3

3

100

24

Mean

23

21

22

23

24

24

sd

2

3

2

3

3

3

300

24

Mean

23

21

22

23

24

24

sd

2

2

2

2

2

3

1000

24

Mean

23

21

22

23

24

23

sd

2

2

2

3

3

3

 

● = n-23 Days 5 to 8

∆ = n=23 Days 14 to 17

□ = n=23 Days 3 to 5

Table 7 – Necropsy Findings – group incidences

 

 

Dose Level (mg/kg bw/day)

0 (control)

100

300

1000

Number of animals examined

24

24

24

24

Generalised fur loss

0

0

0

1

Mass om left mammary gland (20mm x 20mm)

0

0

1

0

No abnormalities detected

0

24

23

23

 


Table 8 – Litter data – Group mean values

Dose level (mg/kg bw/day)

Number of litter

 

Number of Corpora Lutea

Number Implants

Number of Embryonic Deaths

Implantation Loss %

Number of Live Implants

% Male Foetuses

Mean Male Foetal Weight (g)

Mean Female Foetal Weight (g)

Mean Foetal Weight (g)

Mean Placental Weight (g)

Litter Weight (g)

Total Placental Weight (g)

Early

Late

Total

Pre

Post

Male

Female

Total

0 (control)

24

Mean

13.7

12.3

0.2

0.3

0.5

10.2

3.9

6.5

5.3

11.8

54.7

4.22

4.04

4.13

0.52

48.22

6.15

sd

2.2

2.3

0.6

0.7

0.8

9.9

7.2

2.2

2.0

2.5

14.0

0.26

0.30

0.27

0.03

8.30

1.22

100

24

Mean

14.4

12.7

0.3

0.4

0.7

11.4

5.8

6.0

6.0

12.0

49.3

4.07

3.88

3.97

0.51

47.47

6.11

sd

2.3

1.8

0.6

0.7

0.9

7.9

7.4

2.1

1.7

2.1

13.4

0.29

0.29

0.28

0.05

7.79

1.06

300

24

Mean

15.5**

13.0

0.2

0.2

0.3

16.4

2.9

6.5

6.1

12.6

52.8

4.22

3.98

4.11

0.51

51.75

6.48

sd

1.4

1.9

0.4

0.6

0.9

11.9

8.1

2.0

2.5

2.3

17.0

0.19

0.17

0.18

0.05

9.49

1.35

1000

24

Mean

15.0

12.5

0.3

0.2

0.4

16.3

3.2

5.9

6.2

12.0

48.7

4.14

3.97

4.06

0.52

48.87

6.31

sd

1.8

1.5

0.7

0.4

0.7

10.4

5.5

1.9

1.8

1.5

13.9

0.30

0.20

0.21

0.05

6.01

0.92

Table 9 – Foetal External Findings – Group Incidences

 

 

Dose level (mg/kg bw/day)

0 (control)

100

300

1000

Number of foetuses (litters) examined

284 (24)

288 (24)

303 (24)

289 (24)

NF

NL

%†

NF

NL

%†

NF

NL

%†

NF

NL

%†

Total Number Affected

1

1

0.4

4

3

1.3

1

1

0.2

6

6

2.4

Small

1

1

0.4

3

2

1.0

0

0

0.0

6

6

2.0

Subcutaneous Haemorrhage to back of head

0

0

0.0

0

0

0.0

1

1

0.2

0

0

0.0

Damaged tail

0

0

0.0

0

0

0.0

0

0

0.0

1

1

0.3

Atretic tail

0

0

0.0

1

1

0.3□

0

0

0.0

0

0

0.0

 

□= observations not recorded for one litter in error

Table 10 – Foetal Visceral Findings – Group Incidences

 

 

Dose level (mg/kg bw/day)

0 (control)

100

300

1000

Number of foetuses (litters) examined

149 (24)

150 (24)

157 (24)

149 (24)

NF

NL

%†

NF

NL

%†

NF

NL

%†

NF

NL

%†

HEAD

A – eye lens – ovoid

1

1

0.6

0

0

0.0

0

0

0.0

2

2

1.5

B – subcutaneous haemorrhage on head (including/excluding snout)

1

1

0.7

1

1

0.7

0

0

0.0

1

1

0.8

C – small cleft at front of palate

1

1

0.7

0

0

0.0

0

0

0.0

0

0

0.0

D – dilated brain ventricle (s)

1

1

0.7

2

2

1.4

0

0

0.0

4

4

2.7

E – bilateral brain ventricle (s)

0

0

0.0

0

0

0.0

0

0

0.0

1

1

0.5

F – small pituitary

0

0

0.0

0

0

0.0

0

0

0.0

1

1

0.5

NECK/THORAX

G – pericardial haemorrhage

1

1

0.5

0

0

0.0

0

0

0.0

1

1

0.7

H – undescended lobe (s) of thymus

9

8

6.0

9

3

5.7

3

3

1.8

4

4

2.9

I – subcutaneous oedema – neck region

1

1

0.5

0

0

0.0

0

0

0.0

0

0

0.0

J – small lobe of thyroid

1

1

0.7

0

0

0.0

0

0

0.0

0

0

0.0

K – persistent truncus arteriosus

0

0

0.0

0

0

0.0

0

0

0.0

1

1

0.5

L – enlarged right atrium

0

0

0.0

0

0

0.0

0

0

0.0

1

1

0.5

M – interventricular septal defect

0

0

0.0

0

0

0.0

0

0

0.0

1

1

0.5

N – no brachiocephalic trunk

0

0

0.0

0

0

0.0

0

0

0.0

1

1

0.5

ABDOMEN

O – small/no development of renal papilla(e)

20

10

12.6

26

15

18.0

29

11

18.0

21

11

14.6

P – kinked and/or dilated ureter (s)

13

7

8.2

18

12

12.3

26

9

16.3

16

9

11.2

Q – blood in abdomen

1

1

0.6

2

2

1.5

2

2

1.2

1

1

0.6

R – extralobulation of one liver lobe

2

2

1.3

3

3

2.3

1

1

0.6

0

0

0.0

S – increased renal pelvic cavitation

0

0

0.0

2

2

1.3

5

3

3.2

5

4

3.5

GENERAL

T – small foetus

0

0

0.0

0

0

0.0

0

0

0.0

2

2

1.5

U – vestigial tall

0

0

0.0

0

0

0.0

0

0

0.0

1

1

0.7

Total

35

18

23.4

39

19

27.0

34

13

21.0

28

14

19.3

 

NOTE: a foetus may appear in more than one category

 

Table 11 – Foetal Skeletal Development – Group Incidence

 

 

Dose level (mg/kg bw/day)

0 (control)

100

300

1000

Number of foetuses (litters) examined

135 (24)

138 (24)

146 (24)

140 (24)

NF

NL

%†

NF

NL

%†

NF

NL

%†

NF

NL

%†

Number of ribs

13/*

0

0

0.0

0

0

0.0

1

1

0.6

0

0

0.0

13/13

135

24

100.0

138

24

100.0

145

23

99.4

140

24

100.0

Number of ossified sternebrae

<4

1

1

0.8

1

1

0.7

0

0

0.0

3

3

1.8

4

31

11

20.7

26

9

17.9

21

10

13.0

9

7

6.6

>4

103

24

78.5

111

24

81.4

125

24

87.0

128

24

91.6

Number of post lumber vertebral centra

<7

1

1

0.5

4

4

2.8

3

2

2.0

4

3

3.0

≥7

134

24

99.5

134

24

97.2

143

24

98.0

136

24

97.0

Number of post lumber vertebral arches

<5

8

4

5.1

11

7

8.0

0

0

0.0

4

4

2.8

≥5

127

24

94.9

127

23

92.0

146

24

100.0

136

24

97.2

Number of metacarpals

<6

0

0

0.0

0

0

0.0

0

0

0.0

1

1

0.6

6

18

8

10.4

24

10

17.6124

11

5

7.2

13

8

9.4

≥6

117

24

89.6

114

23

82.4

135

24

92.8

126

24

90.0

Number if forelimb phalanges

≤2

120

24

88.0

129

24

93.6

130

24

89.0

124

24

88.2

>2

15

9

12.0

9

6

6.4

16

9

11.0

16

9

11.8

Number of hindlimb phalanges

≤2

135

24

100.0

138

24

100.0

145

24

99.3

139

24

99.3

≥2

0

0

0.0

0

0

0.0

1

1

0.7

1

1

0.7

Number of metatarsals

<6

0

0

0.0

0

0

0.0

0

0

0.0

1

1

0.6

6

1

1

0.5

1

1

0.7

0

0

0.0

1

1

0.7

>6

134

24

99.5

136

24

98.6

146

24

100.0

138

24

98.7

Fontanelle size

Small

10

4

6.2

15

4

9.0

13

2

7.7

11

4

6.6

Medium

123

24

92.8

116

22

85.4

127

23

88.7

124

24

89.7

Large

2

2

1.1

7

3

5.6

6

4

3.6

5

4

3.7

NOTE: a foetus may appear in more than one category

*= Rib damaged at evisceration

 

Table 12 – Foetal Skeletal Findings – Group Incidence

 

 

Dose level (mg/kg bw/day)

0 (control)

100

300

1000

Number of foetuses (litters) examined

135 (24)

138 (24)

146 (24)

140 (24)

NF

NL

%†

NF

NL

%†

NF

NL

%†

NF

NL

%†

HEAD/NECK

A – incomplete ossification of one cranial bone (variant)

51

22

38.1

46

21

33.0

65

22

44.7

60

23

44.0

B – incomplete ossification of more than one cranial bone (variant)

38

15

25.7

47

18

36.8

36

16

25.1

38

18

28.7

C – irregular ossification of one cranial bone (variant)

29

14

23.4

25

15

17.7

31

14

20.6

29

16

21.0

D – incomplete ossification of more than one cranial bone

5

4

3.7

2

2

1.4

1

1

1.0

3

3

2.0

xx – incomplete ossification of one facial bone

3

3

2.7

6

5

4.7

4

4

2.5

2

2

1.7

E – incomplete ossification of more than one facial bone

1

1

0.8

3

1

2.5

1

1

0.6

1

1

0.7

F – irregular ossification of one facial bone

1

1

0.5

2

2

1.3

0

0

0.0

0

0

0.0

AA – irregular ossification of more than one facial bone

0

0

0.0

0

0

0.0

0

0

0.0

1

1

0.6

G – no ossification of hyoid

8

5

4.7

12

6

9.7

11

6

6.8

9

6

4.7

H – incomplete ossification of hyoid

4

2

2.6

5

2

3.7

3

3

1.7

0

0

0.0

I – extra area of ossification between left parietal and inter parietal

0

0

0.0

0

0

0.0

1

1

0.6

0

0

0.0

J – hyoid - small

0

0

0.0

1

1

0.7

1

1

0.6

2

1

1.4

K – hyoid - bipartite

0

0

0.0

0

0

0.0

1

1

0.6

1

1

0.7

STERNEBRAE (1-4)

DD – no ossification of one sternebra

0

0

0.0

1

1

0.7

0

0

0.0

0

0

0.0

L – no ossification of more than one sternebra

1

1

0.8

0

0

0.0

0

0

0.0

1

1

0.7

M – incomplete ossification of one sternebra

2

2

1.4

5

2

4.0

4

3

2.6

4

4

2.8

yy – incomplete ossification of more than one sternebra

0

0

0.0

0

0

0.0

1

1

0.5

0

0

0.0

N – one sternebra – small

4

2

2.4

3

2

1.8

1

1

0.6

0

0

0.0

O – one sternebra – bipartite

3

2

1.8

0

0

0.0

0

0

0.0

0

0

0.0

P – more than one sternebra – semi bipartite

0

0

0.0

1

1

0.7

0

0

0.0

0

0

0.0

Q – more than one sternebra – hemicentric

1

1

0.5

0

0

0.0

0

0

0.0

0

0

0.0

R – one sternebra – hemicentric

0

0

0.0

0

0

0.0

1

1

0.6

0

0

0.0

S – one sternebra – asymmetric ossification

5

5

4.0

1

1

0.7

5

5

3.6

1

1

0.6

T – more than one sternebra – asymmetric ossification

1

1

0.7

0

0

0.0

2

2

1.2

1

1

0.7

U – more than one sternebra – small

1

1

0.5

1

1

0.7

0

0

0.0

0

0

0.0

V – one sternebra – semi bipartite

1

1

0.5

3

2

1.9

0

0

0.0

0

0

0.0

RIBS

W – bilateral/unilateral wavy rib(s)

0

0

0.0

1

1

0.5

0

0

0.0

1

1

0.8

X – bilateral/unilateral rudimentary 13thrib(s)

1

1

1.0

0

0

0.0

2

2

1.1

0

0

0.0

Y – bilateral/unilateral 13thrib(s) short

9

6

7.6

8

7

6.1

7

4

4.1

7

4

5.1

Z – extra area of ossification in cartilage of rib 3 right side

1

1

0.6

0

0

0.0

0

0

0.0

0

0

0.0

aa – more than one rib - thickened

0

0

0.0

1

1

0.6

0

0

0.0

1

1

0.8

VERTERBRAE

bb – one thoracic vertebral centre semi-bipartite (variant)

25

16

18.3

24

14

17.9

24

14

15.9

36

20

26.2

cc – more than one thoracic vertebral centrum semi-bipartite (variant)

18

7

13.0

18

11

15.1

17

11

12.5

20

12

14.1

dd – one thoracic vertebral bipartite

4

3

2.5

4

4

2.9

7

6

4.7

6

6

4.2

ee – more than one thoracic vertebral centrum bipartite

1

1

0.7

2

2

1.5

0

0

0.0

0

0

0.0

ff – one lumbar centre not ossified

1

1

0.8

1

1

0.8

0

0

0.0

1

1

0.7

gg – thoracic vertebral centre not ossified

0

0

0.0

1

1

0.6

0

0

0.0

1

1

0.7

hh – lumbar centre not ossified

0

0

0.0

1

1

0.6

0

0

0.0

0

0

0.0

ii – one thoracic vertebral centre – small

1

1

0.5

0

0

0.0

0

0

0.0

0

0

0.0

jj – one thoracic vertebral centre – asymmetric

0

0

0.0

0

0

0.0

1

1

0.6

0

0

0.0

ll – precocious ossification of more than one cervical centrum

4

1

3.3

1

1

0.6

5

4

3.7

3

1

2.5

mm – one lumbar vertebral centre – small

0

0

0.0

1

1

0.7

0

0

0.0

0

0

0.0

nn - one lumbar vertebral centre – bipartite

0

0

0.0

1

1

0.7

0

0

0.0

0

0

0.0

oo – more than one lumbar vertebral centre – semi bipartite

0

0

0.0

1

1

0.7

0

0

0.0

0

0

0.0

zz – more than one one lumbar vertebral centre – small

0

0

0.0

0

0

0.0

0

0

0.0

1

1

0.7

Other

qq – incomplete ossification of schia

0

0

0.0

0

0

0.0

0

0

0.0

1

1

0.6

rr – pubis (es) – small

1

1

0.5

0

0

0.0

0

0

0.0

1

1

0.6

ss - incomplete ossification of pubis (es)

1

1

0.8

5

2

3.7

0

0

0.0

2

2

1.3

tt - incomplete ossification of ischrum/ischia

1

1

0.8

2

1

1.7

0

0

0.0

0

0

0.0

uu – precocious ossification in tail region distal to sacrum

0

0

0.0

0

0

0.0

1

1

0.6

0

0

0.0

vv – no ossification – pubes

0

0

0.0

0

0

0.0

0

0

0.0

1

1

0.6

EE – incomplete ossification of ilia

0

0

0.0

0

0

0.0

0

0

0.0

1

1

0.6

Total

117

24

87.2

120

24

88.2

129

24

88.5

121

24

87.7

 

NOTE: a foetus may appear in more than one category

 

 


Applicant's summary and conclusion

Conclusions:
The oral administration of Hydrogenated oligomerisation product, including dimers and trimers, of tetradec-1-ene and alkene to pregnant rats by oral gavage during organogenesis at dose levels of 100, 300 and 1000 mg/kg bw/day did not result in any toxicologically significant effects at any dose level. No significant changes were detected in the offspring parameters measured the ‘No Observed Effect Level’ (NOEL) was therefore, considered to be 1000 mg/kg bw/day. The ‘No Observed Effect Level’ (NOEL) for reproductive and developmental toxicity was therefore considered to be 1000 mg/kg bw/day.
Executive summary:

The study was designated to investigate the effects of the test item on embryonic and foetal development following repeated administration by gavage to the pregnant female during the period of organogenesis.

The test item was administered by gavage to three groups each of twenty-four time mated Sprague-Dawley Crl:CD (SD) IGS BR strain rats, between Days 5 and 19 of gestation inclusive at dose levels 100, 300, and 1000 mg/kg bw/day. A further group of twenty-four time mated females was exposed to the vehicle only (Arachis oil BP) to serve as a control.

Clinical signs, body weight change and food consumptions were monitored during the study.

 

All surviving females were terminated on Day 20 of gestation and subjected to gross necropsy including examination of the uterine contents. The number of corpora lutea, number, position and type of implantation, placental weights, foetal weight, sex and external and internal macroscopic appearance were recorded. Half of each litter were preserved in Industrial Methylated Spirit (IMS) and then transferred into 100% glycerol and examined for skeletal development. The remaining half were preserved in Bouin’s solution and examined viscerally.

 

The results are as follows,

 

Mortality. There were no unscheduled deaths.

 

Clinical Observations. There were no toxicologically significant clinical observations detected in any treated females.

 

Body Weight. No treatment-related effects in body weight development were detected.

 

Food Consumption. No adverse effects were detected in food consumption.

 

Post Mortem Studies. No toxicologically significant macroscopic abnormalities were detected in treated females at terminal kill. No treatment-related effects were detected in the uterine parameters examined, in foetal viability or in growth and development.

 

Foetal Evaluation. No treatment-related effects were detected on skeletal development or in the type and incidence of skeletal or visceral findings.

 

The oral administration of Hydrogenated oligomerisation product, including dimers and trimers, of tetradec-1-ene and alkene to pregnant rats by oral gavage during organogenesis at dose levels of 100, 300 and 1000 mg/kg bw/day did not result in any toxicologically significant effects at any dose level. No significant changes were detected in the offspring parameters measured the ‘No Observed Effect Level’ (NOEL) was therefore, considered to be 1000 mg/kg bw/day. The ‘No Observed Effect Level’ (NOEL) for reproductive and developmental toxicity was therefore considered to be 1000 mg/kg bw/day.