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EC number: 917-709-4 | CAS number: 17438-89-0
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
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:
- 2 012
- 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
- Reference substance name:
- Reference substance 001
- Cas Number:
- 1000172-11-1
Constituent 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 / 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 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.
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