Tetradec-1-ene, dimers, hydrogenated

Developmental toxicity / teratogenicity

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

Test material information

Constituent 1

Reference substance name:

Reference substance 001

Cas Number:

1000172-11-1

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 Pentadecane, 7-methylene mixed with 1-tetradecene, dimers and trimers, hydrogenated 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 / concentrations

Doses / concentrations 1

Dose / conc.:

100 mg/kg bw/day (nominal)

Doses / concentrations 2

Dose / conc.:

300 mg/kg bw/day (nominal)

Doses / concentrations 3

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 13^thrib(s)	1	1	1.0	0	0	0.0	2	2	1.1	0	0	0.0
Y – bilateral/unilateral 13^thrib(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 Pentadecane, 7-methylene mixed with 1-tetradecene, dimers and trimers, hydrogenated 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 Pentadecane, 7-methylene mixed with 1-tetradecene, dimers and trimers, hydrogenated 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.