Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available

Effects on developmental toxicity

Description of key information

The reproductive effects of behenyl alcohol were investigated in an embryonic development study in rabbits (similar to OECD 414). No evidence of maternal or fetal toxicity was observed. The substance had no developmental effects on rabbits treated with doses up to 2000 mg/kg body weight. The observation of pale feces was the only compound-related effect reported, limited to rabbits treated with 2000 mg behenyl alcohol/kg body weight. Based on these findings, there is no evidence to suggest that behenyl alcohol is a developmental toxicant (Iglesias, 2002).

The effects of behenyl alcohol on fertility, reproduction and development were investigated in rats exposed to 0, 10, 100 and 1000 mg/kg bw by gavage during pre-mating, mating and postmating (females until day 19 of gestation). No evidence of parental or fetal toxicity was observed. Behenyl alcohol demonstrated no effects on the fertility or reproduction of rats dosed up to 1000 mg/kg bw and no effects on fetal devlopment up to 1000 mg/kg bw. Based on these findings, there is no evidence to suggest that behenyl alcohol is reproductive toxic, teratogenic or embryotoxic. The NOAEL is 1000 mg/kg bw (Iglesias 2002).

In a test according to OECD 414, the oral administration of Lanolin Alcohols to rats by gavage, at dose levels of 100, 300 and 1000 mg/kg bw/day, did not result in any toxicologically significant adverse effects. The NOAEL was therefore considered to be >= 1000 mg/kg bw/day for maternal toxicity and developmental toxicity (Croda 2014).

For acetic acid pregnant adult female albino CD-1 mice were dosed daily by oral intubation beginning on day 6 of gestation at concentrations of 0 (control), 16, 74, 345, and 1600 mg/kg bw/day. Animals were observed daily and body weights recorded for 10 days. On day 17, Caesarian sections were performed on all dams and the numbers of implantation sites, resorption sites, and live and dead fetuses was recorded. General external and internal examinations were also made of the dams. No effects on nidation or on maternal or fetal survival were observed at doses up to 1600 mg/kg bw/day. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring in the controls (HSDB).

Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
15 Aug - 11 Nov 2013
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
(adopted 22 January 2001)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
Deviations:
no
Qualifier:
according to
Guideline:
other: Japenese Ministry of Agriculture, Forestry and Fisheries Testing guidelines for Toxicology studies, 12 NohSan No 8147, (24 November, 2000)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Remarks:
The Department of Health of the Government of the United Kingdom
Limit test:
no
Species:
rat
Strain:
other: Sprague-Dawley Crl:CD (SD) IGS BR
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Limited, Margate, Kent, UK
- Weight at study initiation: 214 to 299 g
- Housing: The animals were housed individually in solid-floor polypropylene cages with stainless steel lids furnished with softwood flakes (Datesand Ltd., Cheshire, UK)
- Diet: pelleted diet (Rodent 2018C Teklad Global Certified Diet, Harlan UK, Oxon, UK); ad libitum
- Water: drinking water; ad libitum


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±3
- Humidity (%): 50±20
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 18 Aug 2013 To: 05 Sept 2013
Route of administration:
oral: gavage
Vehicle:
other: Arachis oil BP
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: The test item was prepared at the appropriate concentrations as a solution in Arachis oil BP. The stability and homogeneity of the test item formulations were previously determined by Harlan Laboratories Ltd., Shardlow, UK Analytical Services (Harlan Laboratories Ltd., Project Number 41301173). Results showed the formulations to be stable for at least twenty days. Formulations were therefore prepared once and stored at approximately +4°C in the dark.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples were taken of each test item formulation and were analyzed for concentration of Lanolin Alcohols at Harlan Analytical Laboratory, Shardlow. The test item concentration in the test samples was determined by HPLC with UV detection using an external standard technique. The results indicate that the prepared formulations were within ± 2% of the nominal concentration.
Details on mating procedure:
- Impregnation procedure: purchased timed pregnant
- The day that positive evidence of mating was observed was designated Day 0 of gestation.
Duration of treatment / exposure:
Day 5 - 19 of gestation
Frequency of treatment:
daily
Duration of test:
15 days
No. of animals per sex per dose:
24 (except for the intermediate treatment group: Only 23 animals were used in the intermediate treatment group as upon delivery of the animals, one female was found to have a damaged eye. This female was unsuitable to be used on the study and was humanely killed.)
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The dose levels were chosen based on previous toxicity data.
- Other: The oral route was selected as the most appropriate route of exposure, based on the physical properties of the test item, and the results of the study are delieved to be of value in predicting the likely toxicity of the test item to man.
Maternal examinations:
CLINICAL OBSERVATIONS: Yes
- Time schedule: Following arrival, all animals were examined for overt signs of toxicity, ill-health or behavioral changes once daily during the gestation period. Additionally, during the dosing period, observations were recorded immediately before and soon after dosing and one hour post dosing.

BODY WEIGHT: Yes
- Time schedule for examinations: on Day 3 of gestation (before the start of treatment) and on Days 5, 6, 7, 8, 11, 14 and 17 of gestation. Body weights were also recorded for animals at terminal kill (Day 20).

FOOD CONSUMPTION: Yes
- Time schedule for examinations: for each individual animal at Day 3, 5, 8, 11, 14, 17 and 20 of gestation.

WATER CONSUMPTION: Yes
- Time schedule for examinations: daily by visual inspection of the water bottles for any overt changes

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation Day 20
- All animals were subjected to a full external and internal examination and any macroscopic abnormalities were recorded.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number, position and type of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Placental weight: Yes
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: half per litter
- Visceral examinations: Yes: half per litter
Statistics:
Female body weight change, food consumption and gravid uterus weight: Bartlett’s test for homogeneity of variance and one way analysis of variance, followed by Dunnett’s multiple comparison test or, if unequal variances were observed, on alternative multiple comparison test.
All caesarean necropsy parameters and fetal parameters: Kruskal-Wallis non-parametric analysis of variance; and a subsequent pairwise analysis of control values against treated values using the Mann-Whitney ‘U’ test, where significance was seen.
Fetal evaluation parameters, including skeletal or visceral findings: Kruskal-Wallis nonparametric analysis of variance and Mann-Whitney ‘U’ test.
Probability values (p) are presented as follows:
p<0.001 ***
p<0.01 **
p<0.05 *
p≥0.05 (not significant)
Indices:
Pre- and post-implantation losses
Historical control data:
Historical control data from several former embryofetal development toxicity studies were provided, giving information on skeletal findings, visceral examination, and reproductive data.
Details on maternal toxic effects:
Maternal toxic effects:yes. Remark: Observed effects on body weight, food consumption, clinical signs, pre-implantation loss and number of corpora lutea. However, these effects were considered not to represent an adverse effect or to be incidental and unrelated to treatment.

Details on maternal toxic effects:
Mortality: There were no unscheduled deaths (table 3).

Clinical Observations: Females treated with 1000 and 300 mg/kg bw/day showed isolated incidences of increased salivation between Days 6 and 13 (table 2). No such effects were detected in females treated with 100 mg/kg bw/day. Observations of this nature are commonly observed following the oral administration of an unpalatable test item formulation and in isolation are considered not to be of toxicological significance. One female treated with 1000 mg/kg bw/day also showed fur loss between days 16 and 20 (table 2). Observations of this nature are commonly observed in isolation are not considered to be related to test item toxicity. Therefore, no treatment-related effects were found.

Body Weight: No adverse effects on body weight development were detected. Statistical analysis of the data did not reveal any significant intergroup differences (table 3).

Food Consumption: Females treated with 1000 mg/kg bw/day showed a statistically significant increase in food consumption between Days 14 and 17 (table 4). The increase in food consumption is not considered to represent an adverse effect of treatment. Furthermore, intergroup differences on body weight were considered of no toxicological significance.

Water Consumption: Daily visual inspection of water bottles did not reveal any overt intergroup differences.

Pathological examinations: No macroscopic abnormalities were detected.

Females treated with 1000 and 300 mg/kg bw/day showed a statistically significant reduction in the number of corpora lutea (table 5). This intergroup difference was not dose-related and was considered to be incidental and unrelated to treatment due to ovulation and mating occurring prior to the administration of the test item. Females treated with 1000 mg/kg bw/day also showed a statistically significant reduction in pre-implantation loss (table 5). A reduction in this parameter is considered not to represent an adverse effect of treatment therefore the intergroup difference was considered of no toxicological importance.
Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
Litter Data and Litter Placenta and Fetal Weights:
There were no treatment-related effects on in utero offspring survival, as assessed by the mean numbers of early or late resorptions, live litter size and post-implantation losses. There was also no adverse effect in sex ratio.
For all dose groups, there were no significant treatment-related trends in the proportion of fetuses (or litters) with evidence of external, visceral or skeletal anomalies (tables 6, 7 and 8). The type of external, visceral and skeletal anomalies, were those commonly observed for this type of study. There were no findings that were considered to represent any known malformations. Statistical analysis of the data did not reveal any significant differences.
Therefore, no treatment-related effects were detected in the uterine parameters examined, in fetal viability or in growth and development.
Key result
Remarks on result:
not determinable because of methodological limitations
Key result
Abnormalities:
not specified
Developmental effects observed:
not specified

Table 1: Summary of female performance

 

Control group

100 mg/kg bw/day

300 mg/kg bw/day

1000 mg/kg bw/day

Initial group size

24

24

23

24

Pregnant animals

22

24

20

24

 

Table 2: Summary incidence of daily clinical observations

Dose level [mg/kg bw/day]

Number of animals

Clinical observations

Number of animals showing effect (day of observation)

0

24

no abnormalities detected

-

100

24

no abnormalities detected

-

300

23

Increased salivation

3 (6, 9)

1000

24

Increased salivation

15 (6-13)

Generalized fur loss

1 (16-20)

 

Table 3: Group mean values on pregnant females

Parameter

Control group

100 mg/kg bw/day

300 mg/kg bw/day

1000 mg/kg bw/day

Number of dams examined

22

24

20

24

Mortality of dams [%]

0.0

0.0

0.0

0.0

Body weight gain [g]

Day 5–20 of gestation

121.3±15.5

125.6±15.6

124.4±16.4

126.8±14.7

Gravid uterus weight [g]

82.3±9.7#

80.3±14.6

80.3±9.3

81.2±11.2

#: n=21 for gravid uterus weight. Gravid uterus weight not recorded for one female in error.

 

 

Table 4: Group mean food consumption values

Dose level [mg/kg bw/day]

Number of dams examined

Food consumption (g/rat/day) between days of gestation

3-5

5-8

8-11

11-14

14-17

17-20

0

22

25.6±2.0

21.0±2.2

23.0±2.6

24.7±1.9

25.7±2.2

25.2±2.1

100

24

25.0±2.2

21.8±3.4

23.3±2.6

25.2±3.4

26.1±2.6

27.2±5.0

300

20

25.5±2.5

21.5±2.2

23.0±3.3

25.2±2.8

26.9±3.6

26.5±3.9

1000

24

25.4±3.1

22.0±2.0

24.7±2.3

26.2±2.0

27.9±2.6**

27.4±3.0

** Significantly different from control: p** < 0.01

 

Table 5: Group mean litter data values

Parameter

Control group

100 mg/kg bw/day

300 mg/kg bw/day

1000 mg/kg bw/day

Number of corpora lutea

14.9±1.5

14.4±1.8

13.0±1.5***

13.5±2.0**

Number of implants

13.5±1.7

12.8±2.6

12.5±1.2

13.1±1.8

Total number of live implants

12.8±2.4

12.6±2.7

12.2±1.4

12.5±2.0

Total number of embryonic/fetal deaths

1.0±1.6

0.3±0.5

0.3±0.4

0.6±1.6

Pre-implantation loss [%]

8.8±7.9

12.0±13.7

4.0±4.9

2.8±5.5**

Post-implantation loss [%]

5.8±12.0

1.0±2.7

2.1±3.7

4.0±10.4

Total number of litters

22

24

20

24

Mean fetal weight[g]

4.073±0.156

4.157±0.196

4.217±0.156

4.166±0.262

Mean placental weight[g]

0.559±0.049

0.553±0.067

0.577±0.037

0.582±0.056

** Significantly different from control: p** < 0.01

*** Significantly different from control: p*** < 0.001

Table 6: Summary incidence of fetal external findings

Parameter

0 (Control)

100 mg/kg bw/day

300 mg/kg bw/day

1000 mg/kg bw/day

Number of foetuses examined

281

303

244

301

Small fetus

0

1

1

1

Omphalocele

1

0

0

0

Pale

0

0

1

1

Total number of foetuses with fetal external findings (% of foetuses with fetal external findings)

1 (0.4)

1 (0.4)

2 (0.8)

2 (0.7)

 

Table 7: Summary incidence of fetal visceral findings

Parameter

0 (Control)

100 mg/kg bw/day

300 mg/kg bw/day

1000 mg/kg bw/day

Number of foetuses examined

146

157

128

157

Total number of foetuses with fetal visceral findings (% of foetuses with fetal external findings)

51 (33.5)

53 (34.3)

34 (26.5)

70 (45.1)

 

Table 8: Summary incidence of fetal skeletal findings

Parameter

0 (Control)

100 mg/kg bw/day

300 mg/kg bw/day

1000 mg/kg bw/day

Number of foetuses examined

135

146

117

144

Total number of foetuses with fetal skeletal findings (% of foetuses with fetal external findings)

117 (88.6)

123 (84.7)

96 (81.5)

114 (78.8)

 

NOTE: a fetus may appear in more than one category

 

Conclusions:
The NOAEL is considered to be >= 1000 mg/kg bw/day for maternal toxicity and developmental toxicity.
Executive summary:

In a test according to OECD 414, Lanolin alcoholswas administered by gavage to three dose groups each of twenty-four (twenty-three for the 300 mg/kg bw/day dose group) time mated rats, between Days 5 and 19 of gestation at dose levels of 100, 300 and 1000 mg/kg bw/day (Croda, 2014). A further group of twenty-four time mated females was exposed to the vehicle only (Arachis oil) to serve as a control.

Clinical signs, body weight change, food and water consumptions were monitored during the study. All 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, fetal weight, sex and external and internal macroscopic appearance were recorded. Half of each litter were examined for detailed skeletal development and the remaining half were subjected to detailed visceral examination.

There were no unscheduled deaths. Females treated with 1000 and 300 mg/kg bw/day showed isolated incidences of increased salivation between Days 6 and 13. No such effects were detected in females treated with 100 mg/kg bw/day. Observations of this nature are commonly observed following the oral administration of an unpalatable test item formulation and in isolation are considered not to be of toxicological significance. One female treated with 1000 mg/kg bw/day also showed fur loss between days 16 and 20. Observations of this nature are commonly observed and in isolation is not considered to be related to test item toxicity. No adverse effect on body weight development was detected and statistical analysis of the data did not reveal any significant intergroup differences. At necropsy, no macroscopic abnormalites were found.

There was no treatment related effects on in utero offspring survival, as assessed by the mean numbers of early or late resorptions, live litter size and post-implantation losses. There were also no adverse effects on pre-implantation losses or in sex ratio. Females treated with 1000 and 300 mg/kg bw/day showed a statistically significant reduction in the number of corpora lutea. This intergroup difference was not dose related and was considered to be incidental and unrelated to treatment due to ovulation and mating occurring prior to the administration of the test item. Females treated with 1000 mg/kg bw/day also showed a statistically significant reduction in pre-implantation loss. A reduction in this parameter is considered not to represent an adverse effect of treatment therefore the intergroup difference was considered of no toxicological importance.

For all dose groups, there were no significant treatment-related trends in the proportion of fetuses (or litters) with evidence of external, visceral or skeletal anomalies. The type of external, visceral and skeletal anomalies, were those commonly observed for this type of study. There were no findings that were considered to represent any known malformations. Statistical analysis of the data did not reveal any significant differences.

In conclusion, the oral administration of Lanolin Alcohols to rats by gavage, at dose levels of 100, 300 and 1000 mg/kg bw/day, did not result in any toxicologically significant adverse effects. The NOAEL was therefore considered to be >= 1000 mg/kg bw/day for maternal toxicity and developmental toxicity.

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
limited documentation
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes
Remarks:
stated in the article
Limit test:
no
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Froxfield SPF Rabbits Limited (Hampshire, England)
- Age at study initiation: 18-26 weeks
- Weight at study initiation: 3.29-4.98 kg
- Fasting period before study: none
- Housing: individually in suspended stainless-steel cages (type TR6)
- Diet: standard rabbit diet (Special Diets Services Ltd., Witham, Essex, England) ad libitum
- Water: tap water ad libitum
- Acclimation period: at least 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 °C
- Humidity (%): 55%
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12

Estrous cycles were synchronized by an intravenous injection of 25 IU luteinizing hormone two weeks before arrival and on day of mating with untreated New Zealand White males (insemination = day 0 of gestation)
Route of administration:
oral: gavage
Vehicle:
other: Tween 80
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The required amount of behenyl alcohol was weighed into a glass container and heated (approximately 80 °C until molten using an electric mantle. An appropriate volume of vehicle (1% Tween 80) was heated in a water bath to at least 75 °C and then combined with the molten behenyl alcohol under continuous magnetic stirring, to a concentration of 20% behenyl alcohol. The resulting suspension was slowly cooled, with homogenization to a temperature of below 60 °C, and then further cooled in a water bath to a temperature of 30 °C. Once the resulting suspension reached this temperature, it was again slowly homogenized for at least 2 min and allowed to cool to room temperature.

VEHICLE - Justification for use and choice of vehicle (if other than water): solubility of the substance
- Amount of vehicle (if gavage): maximum 10 mL/kg
- dose volume 10, 0.625, 2.5, and 10 ml/kg at 0, 125, 500 and 2000 mg/kgbw
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
no data provided
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused: with male New Zealand White rabbits
- M/F ratio per cage: no data
- Length of cohabitation: no data
- Proof of pregnancy: no data
Duration of treatment / exposure:
from day 6-19 of gestation
Frequency of treatment:
daily
Duration of test:
29 days
Dose / conc.:
125 mg/kg bw/day
Dose / conc.:
500 mg/kg bw/day
Dose / conc.:
2 000 mg/kg bw/day
No. of animals per sex per dose:
22 females/dose
Control animals:
yes, concurrent vehicle
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: daily

FOOD CONSUMPTION: Yes
- Time schedule for examinations: from day 1-6, 6-12, 23-19, 20-23 and 24-28

WATER CONSUMPTION: Yes
- Time schedule for examinations: daily

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 29
- Organs examined: macroscopy and examination of uterus and its contents
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Placental weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
OTHER
- Number of viable fetuses with distribution of fetuses in each uterine horn
- fetal sex
- fetal weight
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: all per litter
- Head examinations: Yes: 1/3 per litter
Statistics:
To test the statistical significance of suggestive intergroup differences, one-way analysis of variance and t test were performed on body weights, body weig t changes, and food and water consumption. Organ weights were evaluated by Dunnett’s or Behren’s Fisher’s tests. Nested analysis of variance and weighed t test were conducted on fetal and placental weights. Differences with an associated probability of P < 0.05 were deemed to be statistically significant.
Indices:
no data
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
pale faeces at 2000 mg/kg bw
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Water consumption and compound intake (if drinking water study):
no effects observed
Gross pathological findings:
no effects observed
Number of abortions:
effects observed, non-treatment-related
Description (incidence and severity):
total litter loss in 2 control females, 1 female at 125 mg/kg bw and 1 female at 500 mg/kg bw (not defined whether abortions or resorption)
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
Implantation loss (%)
Pre 10.4 14.2 13.9 and 13.5% at 0, 125, 500 and 2000 mg/kg bw
Post 12.1 12.0 15.2 and 14.7% at 0, 125, 500 and 2000 mg/kg bw
Total litter losses by resorption:
effects observed, non-treatment-related
Description (incidence and severity):
total litter loss in 2 control females, 1 female at 125 mg/kg bw and 1 female at 500 mg/kg bw (not defined whether abortions or resorption)
Early or late resorptions:
no effects observed
Description (incidence and severity):
Number of resorptions (SD)
Early 0.4(0.6) 0.3(0.5) 0.4(0.6) and 0.7(0.8) at 0, 125, 500 and 2000 mg/kg bw
Late 1.0(1.0) 1.1(1.0) 1.2(1.1) and 0.9(0.9) at 0, 125, 500 and 2000 mg/kg bw
Total 1.4(1.2) 1.3(1.2) 1.7(1.3) and 1.6(1.2) at 0, 125, 500 and 2000 mg/kg bw
Dead fetuses:
not examined
Description (incidence and severity):
Number of viable young (SD)
Male 4.6(2.6) 4.8(1.5) 3.8(1.5) and 4.7(2.2) at 0, 125, 500 and 2000 mg/kg bw
Female 5.5(2.4) 4.9(1.7) 5.5(2.1) and 4.3(2.5) at 0, 125, 500 and 2000 mg/kg bw
Total 10.1(3.7) 9.8(2.1) 9.3(2.6) and 9.0(3.8) at 0, 125, 500 and 2000 mg/kg bw
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
Pregnancy rate: 20/22, 19/22, 19/22 and 20/22 at 0, 125, 500 and 2000 mg/kg bw
Other effects:
no effects observed
Description (incidence and severity):
placental weights were not affected by treatment
Dose descriptor:
NOAEL
Effect level:
2 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: absence of adverse effects
Abnormalities:
no effects observed
Fetal body weight changes:
no effects observed
Description (incidence and severity):
fetal body weight was not affected by treatment
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
Number of viable young (SD)
Male 4.6(2.6) 4.8(1.5) 3.8(1.5) and 4.7(2.2) at 0, 125, 500 and 2000 mg/kg bw
Female 5.5(2.4) 4.9(1.7) 5.5(2.1) and 4.3(2.5) at 0, 125, 500 and 2000 mg/kg bw
Total 10.1(3.7) 9.8(2.1) 9.3(2.6) and 9.0(3.8) at 0, 125, 500 and 2000 mg/kg bw
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Description (incidence and severity):
not further specified
External malformations:
no effects observed
Description (incidence and severity):
no details
Skeletal malformations:
no effects observed
Description (incidence and severity):
no details
Visceral malformations:
no effects observed
Description (incidence and severity):
no details
Details on embryotoxic / teratogenic effects:
No treatment related adverse effects were observed
Dose descriptor:
NOAEL
Effect level:
2 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: absence of adverse effects
Abnormalities:
no effects observed
Developmental effects observed:
no

Reproductive and developmental parameters

Observation

Dose (mg/kg bw/day)

0

125

500

2000

Animals Assigned (Mated)

22

22

22

22

Animals Pregnant

Pregnancy Rate (%)a

20

91%

19

86%

19

86%

20

91%

Nonpregnant

2

3

3

2

Total litter loss

(%)a

1

10.0%

1

5.3%

1

5.3%

0

0.0%

Corpora Lutea/Dam (mean±SD)

12.8±3.1

12.9±2.2

12.6±3.0

12.2±3.9

Implantations/Dam (mean±SD)

11.4±3.9

11.1±2.6

11.0±3.3

10.6±4.3

Live Fetuses/Dam (mean±SD)

Male (mean±SD)

Female (mean±SD)

10.1±3.7

4.6±2.6

5.5±2.4

9.8±2.1

4.8±1.5

4.9±1.7

9.3b±2.6

3.8±1.5

5.5±2.1

9.0±3.8

4.7±2.2

4.3±2.5

Resorptions/Dam (mean±SD)

Early (mean±SD)
Late (mean±SD)

1.4±1.2

0.4±0.6

1.0±1.0

1.3±1.2

0.3±0.5

1.1±1.0

1.7±1.3

0.4±0.6

1.2±1.1

1.6±1.2

0.7±0.8

0.9±0.9

Preimplantation Loss (%)

10.4

14.2

13.9

13.5

Postimplantation Loss (%)

12.1

12.0

15.2

14.7

aCalculated for this table

bIncludes one foetus not sexed at necropsy

Conclusions:
The substance did not induce developmental toxicity in rabbits. The NOAEL is 2000 mg/kg bw
Executive summary:

The reproductive effects of behenyl alcohol were investigated in an embryonic development study in rabbits (similar to OECD 414)

No evidence of maternal or fetal toxicity was observed. The substance had no developmental effects on rabbits treated with doses up to 2000 mg/kg body weight. The observation of pale feces was the only compound-related effect reported, limited to rabbits treated with 2000 mg behenyl alcohol/kg body weight. Based on these findings, there is no evidence to suggest that behenyl alcohol is a developmental toxicant.

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Remarks:
limited documentation
Qualifier:
no guideline followed
Principles of method if other than guideline:
Males were treated with behenyl alcohol daily for 71 days prior to mating, during mating, and until termination. Females were treated with the test substance for 15 days prior to mating, during mating, and up to Day 17 of gestation
GLP compliance:
yes
Remarks:
stated in the article
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Limited (Margate, Kent, England)
- Age at study initiation: Males 6-7 weeks; Females 10-11-weeks
- Weight at study initiation: Males 193 - 240 g Females 208 -262 g
- Fasting period before study: no data
- Housing: Males: 5/TR18 stainless-steel cage during pre- and postmating period; Females 5/TR18 stainless-steel cage during premating and 5/RB3-modified high-grade polypropylene
cage with stainless-steel mesh lids and floors during post mating; during mating 1 male and 1 female/RB3-modified high-grade polypropylene cage with stainless-steel mesh lids and floors
- Diet: expanded rodent diet (Special Diets Services Ltd., Witham, Essex, England) ad libitum
- Water: tap water ad libitum
- Acclimation period: duration not indicated

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 °C
- Humidity (%): 55%
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
other: Tween 80
Details on exposure:
REPARATION OF DOSING SOLUTIONS:
The required amount of behenyl alcohol was weighed into a glass container and heated (approximately 80 °C until molten using an electric mantle. An appropriate volume of vehicle (1% Tween 80) was heated in a water bath to at least 75 °C and then combined with the molten behenyl alcohol under continuous magnetic stirring, to a concentration of 20% behenyl alcohol. The resulting suspension was slowly cooled, with homogenization to a tempeature of below 60 °C, and then further cooled in a water bath to a temperature of 30 °C. Once the resulting suspension reached this temperature, it was again slowly homogenized for at least 2 min and allowed to cool to room temperature.

VEHICLE - Justification for use and choice of vehicle (if other than water): solubility of the substance
- Amount of vehicle (if gavage): maximum 5 mL/kg bw
- dose volume 5 mL/kg bw
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
- Impregnation procedure: cohoused
- M/F ratio per cage: 1/1
- Length of cohabitation: no data
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
Males: prior to mating, during mating, and until termination (total 71 days).
Females 15 days prior to mating, during mating, and up to Day 17 of gestation.
Frequency of treatment:
daily
Duration of test:
Males 71 days;
Females > 45 days
Dose / conc.:
10 mg/kg bw/day
Dose / conc.:
100 mg/kg bw/day
Dose / conc.:
1 000 mg/kg bw/day
No. of animals per sex per dose:
22 males and 22 females
Control animals:
yes, concurrent vehicle
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes daily

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes (see below)

FOOD CONSUMPTION: Yes (see below)

WATER CONSUMPTION: Yes (see below)

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20 of gestation
- Organs examined: uterus contents was desected and the distribution of fetuses in each uterine horn was recorded

Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Placental weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
OTHER
- Number of viable fetuses with distribution of fetuses in each uterine horn
- fetal sex
- fetal weight
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes half per litter
- Head examinations: No
Statistics:
To test the statistical significance of suggestive intergroup differences, one-way analysis of variance and t test were performed on body weights, body weight changes, and food and water consumption. Organ weights were evaluated by Dunnett’s or Behren’s Fisher’s tests. Nested analysis of variance and weighed t test were conducted on fetal and placental weights. Differences with an associated probability of P < 0.05 were deemed to be statistically significant.
Indices:
none reported
Historical control data:
no data
Clinical signs:
no effects observed
Mortality:
mortality observed, non-treatment-related
Description (incidence):
No mortality in females
One male treated with 1000 mg/kg bw with demonstrating abdominal distension, pallor, ptosis, irregular respiration, and a decrease in body weight was killed during Week 6.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
in females and males
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
in females and males
Water consumption and compound intake (if drinking water study):
no effects observed
Description (incidence and severity):
in females and males
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
In the male that was killed; watery blood, enlargement of the liver with the lobular pattern accentuated, enlarged pale spleen, and reduced gastrointestinal tract content
Other effects:
no effects observed
Description (incidence and severity):
No significant macroscopic findings were reported in males. Absolute and relative weights of reproductive organs were similar between the treatment groups and the control group. Evaluation of sperm number and motility revealed no findings attributable to behenyl alcohol treatment.
Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
Implantation loss (%)
Pre 3.3, 8.3, 3.2 and 5.8 at 0,10,100 and 1000 mg/kg bw
Post 4.7, 6.4, 6.3 and 5.8 at 0,10,100 and 1000 mg/kg bw
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Description (incidence and severity):
Resorptions (SD)
Early 0.82 (0.90), 1.09 (1.04), 1.14 (1.07) and 1.05 (1.02) at 0,10,100 and 1000 mg/kg bw
Late 0.00 (0.00), 0.0(0.00), 0.00 (0.00) and 0.00 (0.00) at 0,10,100 and 1000 mg/kg bw
Total 0.82 (0.90), 1.09 (1.04), 1.14 (1.07) and 1.05 (1.02) at 0,10,100 and 1000 mg/kg bw
Dead fetuses:
no effects observed
Description (incidence and severity):
Viable young (SD)
Male 8.4(2.9), 8.4(2.3), 8.5(2.5) and 8.6(2.6) at 0,10,100 and 1000 mg/kg bw
Female 8.0(3.0), 7.5(2.6), 8.5(2.2) and 8.3(2.2) at 0,10,100 and 1000 mg/kg bw
Total 16.4(3.2), 15.9(3.5), 17.0(2.3) and 16.9(2.2) at 0,10,100 and 1000 mg/kg bw

Changes in pregnancy duration:
not examined
Changes in number of pregnant:
not examined
Description (incidence and severity):
pregnancy rate: 100% at all dose groups
Other effects:
no effects observed
Description (incidence and severity):
Corpora lutea count (SD) 17.8(2.7), 18.4(4.0), 18.7(2.3) and 18.9(2.4) at 0,10,100 and 1000 mg/kg bw
Implantations 17.2(2.6), 17.0(3.2), 18.1(1.8) and 18.0(2.3) at 0,10,100 and 1000 mg/kg bw
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: no treatment related adverse effects observed in both males and females
Abnormalities:
no effects observed
Fetal body weight changes:
no effects observed
Description (incidence and severity):
no details provided
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
Viable young (SD)
Male 8.4(2.9), 8.4(2.3), 8.5(2.5) and 8.6(2.6) at 0,10,100 and 1000 mg/kg bw
Female 8.0(3.0), 7.5(2.6), 8.5(2.2) and 8.3(2.2) at 0,10,100 and 1000 mg/kg bw
Total 16.4(3.2), 15.9(3.5), 17.0(2.3) and 16.9(2.2) at 0,10,100 and 1000 mg/kg bw
Changes in sex ratio:
no effects observed
Description (incidence and severity):
No details
Changes in litter size and weights:
no effects observed
Description (incidence and severity):
No details
External malformations:
no effects observed
Description (incidence and severity):
no details
Skeletal malformations:
no effects observed
Description (incidence and severity):
no details
Visceral malformations:
no effects observed
Description (incidence and severity):
no details
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no treatment related adverse effects observed
Abnormalities:
no effects observed
Developmental effects observed:
no
Conclusions:
No effects on the males and female reproductive performance was seen. No fetal toxicity was observed. The NOAEL for reproduction and development is 1000 mg/kg bw
Executive summary:

The effects of behenyl alcohol on fertility, reproduction and development were investigated in rats exposed to 0, 10, 100 and 1000 mg/kg bw by gavage during pre-mating, mating and postmating (females until day 19 of gestation).

No evidence of parental or fetal toxicity was observed. Behenyl alcohol demonstrated no effects on the fertility or reproduction of rats dosed up to 1000 mg/kg bw and no effects on fetal devlopment up to 1000 mg/kg bw. Based on these findings, there is no evidence to suggest that behenyl alcohol is reproductive toxic, teratogenic or embryotoxic. The NOAEL is 1000 mg/kg bw.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

Based on the available information and the expected hydrolysis, it is expected that Reaction mass of Acetic acid, esters with lanolin alcs. and hexadecyl acetate and octadecyl acetate and oleyl acetate does not induce effects on development. The NOAEL for developmental toxicity is therefore 1000 mg/kg bw.

Justification for classification or non-classification

Based on the information available the substance does not need to be classified for reproduction and developmental toxicity according to EC Regulation 1272/2008 (CLP).