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Diss Factsheets

Administrative data

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Effects on fertility

Description of key information

No data available on the registered substance.

By analogy with octadecan-1-ol (see RAAF document), Combined repeated dose and reproduction / developmental screening (Comparable to OECD 422, GLP, Key, rel.2): NOAEL(fertility and developmental) = 2207 mg/kg bw/day in rats. No adverse effect reported at the highest dose level tested in this study.

By analogy with APG C10/16 (see RAAF document), reproduction / developmental study (OECD 421, GLP, Key, rel.1): NOAEL(fertility and developmental) = 850 mg/kg bw/day in rats. No adverse effect reported at the highest dose level tested in this study.

Link to relevant study records

Referenceopen allclose all

Endpoint:
screening for reproductive / developmental toxicity
Remarks:
combined repeated dose and reproduction / developmental screening (OECD 422)
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
18 August 1992
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
Comparable to OECD 422
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
Principles of method if other than guideline:
Conducted according to Draft OECD 422 combined repeated dose and reproductive/developmental toxicity screening test.
GLP compliance:
yes (incl. QA statement)
Limit test:
no
Species:
rat
Strain:
Wistar
Details on species / strain selection:
No data.
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Moellegard Breeding Centre
- Age at study initiation: 7-8 weeks
- Weight at study initiation: not specified
- Fasting period before study: not specified
- Housing: 2 rats per cage for acclimatization period the individually
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 8 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22± 2
- Humidity (%):55 ±10%
- Air changes (per hr): not specified
- Photoperiod (hrs dark / hrs light): fluorescente light was on from 8 pm to 8 am


IN-LIFE DATES: not specified
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on exposure:
DIET PREPARATION:
- Diet preparation involved first mixing the octadecanol with the barley component, the proportion of which varied for each dose level. The other components of the diet were then added.
- Rate of prepartion of diet (frequency) : not specified
- Mixing appropriate amounts with (Type of food) : IT chow 101 diet
- Storage temperature of food : not specified.
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: up to 22 days
- Proof of pregnancy: vaginal plug refered to as day 0 or, if the plug was recorded during the morning, day 1 of pregnancy.
- After 14 days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: no
- After successful mating each pregnant female was caged : individually in steel wire cages type 3 until day 20 in pregnancy where the pregnant females were placed in macrolon cages type 3.
- Any other deviations from standard protocol: none
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
Exposure period: males 45 days , females up to 54 days
Premating exposure period (males) : 14 days
Premating exposure period (females): 14 days
Duration of test : males 45 days, females up to 54 days
Frequency of treatment:
Continuous in diet
Details on study schedule:
- Age at mating of the mated animals in the study: 10 (males) and 9 (females ) weeks
Dose / conc.:
0 ppm
Remarks:
Control group
Dose / conc.:
1 500 ppm
Remarks:
Group 2 (Mid dose, 100 mg/kg bw/day nominal in diet)
Dose / conc.:
7 500 ppm
Remarks:
Group 3 (Low dose, 500 mg/kg bw/day nominal in diet)
Dose / conc.:
30 000 ppm
Remarks:
Group 4 (High dose, 2000 mg/kg bw/day nominal in diet)
No. of animals per sex per dose:
12 males and 12 females per group
Control animals:
yes, plain diet
Details on study design:
- Dose selection rationale: Doses chosen from the results of a preliminary test
- Rationale for animal assignment : Randomized into 4 groups with the same mean body weight

- The following design was used : 1-Octadecanol was mixed in the diet and given in the following concentrations .Group I: 0 ppm, group II : 1500 ppm , group III 7500 ppm , and group IV : 30000 ppm.
Positive control:
none
Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS:No

DETAILED CLINICAL OBSERVATIONS: No
- Time schedule: not specified

BODY WEIGHT: Yes / No / No data
- Time schedule for examinations: During the experiment the males were weighed once/week.
the female were weighed during the premating period and during pregnancy once/week.
Pup litter weight was determined on day 1 an 4 after birth.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes


OTHER: Haemotology and clinicla biochemistry was conducted in the males.
Oestrous cyclicity (parental animals):
Exposure was for 14 days premating covering at least 2 oestrous cycles. Ovaries were weighed and examined histopathologically at section (5 days after birth)
Sperm parameters (parental animals):
Macroscopic examinations were performed on each male animal
Exposure 14 days premaing , no specific sperm analyses was carried out, the testes and epididymus were weighed and examined histopathologically.
Litter observations:
STANDARDISATION OF LITTERS
- Performed on day 4 postpartum:no

PARAMETERS EXAMINED
The following parameters were examined in [F1 / F2 / F3] offspring:
number and sex of pups, postnatal mortality, presence of gross anomalies, weight gain,
Examination of the externel malformations incliding the heead (especially eyes and cleft palate) and thoracic cave for the study of sex and malformations of internal organs.

GROSS EXAMINATION OF DEAD PUPS: no

Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals sacrified after 45 days of dosing
- Maternal animals: All surviving animals sacrified on postnatal day 5
GROSS NECROPSY
- Gross necropsy consisted of full macroscopic examination.

HISTOPATHOLOGY / ORGAN WEIGHTS:
The liver , kidney , thymus, testes and epididymides were weighed;
The liver, kidneys, adrenals ,brain, heart , spleen , ovaries thymus , testes , epididimymides and any organs showing abnormality in macroscopic examination were fixed and the tissues from all controls and top dose treated rats (except the thymus) plus abnormalities were examined.
Postmortem examinations (offspring):
SACRIFICE
- The F1 offspring not selected as parental animals and all F2 offspring were sacrificed at 5 days of age.
- These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination) as follows:

GROSS NECROPSY
- Gross necropsy consisted of malformations including the head (especially eyes and cleft palate.) Animals were then opened to the abdomen and thoracic cavity for a study of the malformations of the internal organs.

HISTOPATHOLOGY / ORGAN WEIGTHS
No histopathology or organ weights measured
Statistics:
Statistical ananlysisi was made on all data using the SAS-stat program.The raw data were transferred to the SAA-program and an analysis of varience was performed.All statistically significant findings were further evaluated by means of Dunnett's t-test to assess possiblbe intergroup diferences. For pregnancy rate a Chi-squared test was carried out to confirm lack of significance.
Reproductive indices:
Pregnancy rate , lenght of gestation ,implantations, corpora lutea and resorption were recorded.
Offspring viability indices:
None
Clinical signs:
not examined
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
Food consumption was significantly increased in top dose males (p<0.001) and in mid dose females (p<0.05) at week 3. There were no other differences in food consumption.
Food efficiency:
no effects observed
Description (incidence and severity):
There were no differences in food conversion efficiency.
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Description (incidence and severity):
No statistically significant differences between treated and control groups (males only examined).
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
A statistically significant (p< 0.05) increase in plasma glucose was observed in groups 2 and 3 , whereas an equally large, but not significant increase was observed in group 4.A statistically significant (p< 0.01) reduction in plasma triglyceride was observed in group 2 and 4.A statistically signiificant (p<0.05) increase in plasma free cholesterol was observed in group 2, 3 and 4 . None of these changes were dose-related
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Histopathological findings: neoplastic:
not specified
Other effects:
no effects observed
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
not specified
Key result
Dose descriptor:
NOAEL
Effect level:
ca. 2 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects observed.
Key result
Critical effects observed:
no
Clinical signs:
not examined
Dermal irritation (if dermal study):
no effects observed
Mortality / viability:
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
Clinical biochemistry findings:
no effects observed
Sexual maturation:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed
No effect of treatement on litter size (mean litter size 11.73, 10.0, 13.6 and 13.38 for controls , low, mid and high dose respectively) and postnatal survival until day 5 was similar in the treated and control groups.
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
ca. 2 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
sexual maturation
mortality
body weight and weight gain
clinical biochemistry
organ weights and organ / body weight ratios
gross pathology
other: Litter size , litter sex ratio, survival index
Key result
Critical effects observed:
no
Key result
Reproductive effects observed:
no
Lowest effective dose / conc.:
2 000 mg/kg bw/day (nominal)
Conclusions:
Based on the results of this study it is concluded that the NOAEL of test item for systemic toxicity was 30000 ppm (equivalent to 2000 mg/kg bw/day). The NOAEL of test item for reproductive/developmental effects was concluded to be 30000 ppm (equivalent to 2000 mg/kg bw/day).
Executive summary:

In a Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test conducted similarly to OECD Guideline 422 and in compliance with GLP, octadecan-1-ol was administered to groups of Wistar rats at dietary concentrations of 1500, 7500 and 30000 ppm (100, 500 and 2000 mg/kg bw/day)

 

No mortality or cilnical signs were observed.The only systemic effects seen in this study were significant changes in plasma free cholesterol, triglycerides and glucose. These changes occurred at all dose levels but were not dose related. Although the reduction in plasma triglyceride levels may be indicative of mild effects in the liver, the differences in the composition of the test diets may have confounded these results.

Octadecan-1 administered to male and female rats via the diet at concentrations up to 30.000 ppm during pre-mating , mating and gestation.Pregnancy rates, uterine parameter, time to pregnancy and gestation length indicated that fertility was not affected by exposure to octadecan-1-ol. There were no microscopic changes observed in the reproductive organs.

Based on the results of this study it is concluded that the NOAEL of test item for systemic toxicity was 30000 ppm (equivalent to 2000 mg/kg bw/day). The NOAEL of test item for reproductive/developmental effects was concluded to be 30000 ppm (equivalent to 2000 mg/kg bw/day).

Therefore, the test substance should not be classified according to the criteria of the Regulation (EC) No.1272/2008 (CLP) and to the GHS.


Endpoint:
screening for reproductive / developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
See RAAF document.
Reason / purpose for cross-reference:
read-across source
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
Food consumption was significantly increased in top dose males (p<0.001) and in mid dose females (p<0.05) at week 3. There were no other differences in food consumption.
Food efficiency:
no effects observed
Description (incidence and severity):
There were no differences in food conversion efficiency.
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Description (incidence and severity):
No statistically significant differences between treated and control groups (males only examined).
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
A statistically significant (p< 0.05) increase in plasma glucose was observed in groups 2 and 3 , whereas an equally large, but not significant increase was observed in group 4.A statistically significant (p< 0.01) reduction in plasma triglyceride was observed in group 2 and 4.A statistically signiificant (p<0.05) increase in plasma free cholesterol was observed in group 2, 3 and 4 . None of these changes were dose-related
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Other effects:
no effects observed
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
not specified
Key result
Dose descriptor:
NOAEL
Effect level:
ca. 2 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects were observed.
Key result
Dose descriptor:
NOAEL
Effect level:
2 207 mg/kg bw/day
Based on:
other: apx 20P
Sex:
male/female
Basis for effect level:
other: No adverse effects were observed.
Key result
Critical effects observed:
no
Clinical signs:
not examined
Dermal irritation (if dermal study):
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Clinical biochemistry findings:
no effects observed
Sexual maturation:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed
No effect of treatement on litter size (mean litter size 11.73, 10.0, 13.6 and 13.38 for controls , low, mid and high dose respectively) and postnatal survival until day 5 was similar in the treated and control groups.
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
ca. 2 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
sexual maturation
mortality
body weight and weight gain
clinical biochemistry
organ weights and organ / body weight ratios
gross pathology
other: Litter size , litter sex ratio, survival index
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
2 207 mg/kg bw/day (nominal)
Based on:
other: apx 20P
Sex:
male/female
Basis for effect level:
other: Litter size , litter sex ratio, survival index
Key result
Reproductive effects observed:
no
Conclusions:
Based on the results of this study it is concluded that the NOAEL of test item for systemic toxicity was 30000 ppm (equivalent to 2000 mg/kg bw/day), which corresponds to 3184 mg/kg bw/day of the target registered substance. The NOAEL of test item for reproductive/developmental effects was concluded to be 30000 ppm (equivalent to 2000 mg/kg bw/day), which corresponds to 2207 mg/kg bw/day for the target registered substance.
Executive summary:

In a Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test conducted similarly to OECD Guideline 422 and in compliance with GLP, octadecan-1-ol was administered to groups of Wistar rats at dietary concentrations of 1500, 7500 and 30000 ppm (100, 500 and 2000 mg/kg bw/day)

 

No mortality or cilnical signs were observed.The only systemic effects seen in this study were significant changes in plasma free cholesterol, triglycerides and glucose. These changes occurred at all dose levels but were not dose related. Although the reduction in plasma triglyceride levels may be indicative of mild effects in the liver, the differences in the composition of the test diets may have confounded these results.

Octadecan-1-ol administered to male and female rats via the diet at concentrations up to 30000 ppm during pre-mating, mating and gestation. Pregnancy rates, uterine parameter, time to pregnancy and gestation length indicated that fertility was not affected by exposure to octadecan-1-ol. There were no microscopic changes observed in the reproductive organs.

 

Based on the results of this study it is concluded that the NOAEL of test item for systemic toxicity was 30000 ppm (equivalent to 2000 mg/kg bw/day), which corresponds to 3184 mg/kg bw/day of the target registered substance. The NOAEL of test item for reproductive/developmental effects was concluded to be 30000 ppm (equivalent to 2000 mg/kg bw/day), which corresponds to 2207 mg/kg bw/day for the target registered substance.

 

Therefore, the registered substance should not be classified according to the criteria of the Regulation (EC) No.1272/2008 (CLP) and to the GHS.

 

Endpoint:
screening for reproductive / developmental toxicity
Remarks:
OECD 421
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
2007
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
No data on vehicle for gavage, limited details on test substance and examinations.
Reason / purpose for cross-reference:
reference to same study
Qualifier:
according to guideline
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Deviations:
yes
Remarks:
No data on vehicle for gavage, limited details on test substance and examinations.
Principles of method if other than guideline:
Not applicable.
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Details on species / strain selection:
No data.
Sex:
male/female
Details on test animals or test system and environmental conditions:
According to Guideline.TEST ANIMALS
- Source: no data
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: (P) 12 wks
- Weight at study initiation: no data
- Fasting period before study: no data
- Housing: in groups of 5 per sex per cage.
- Diet (e.g. ad libitum): laboratory rodent diet (Altromin MT pelleted diet, A. Rieper, Bolzano, Italy), ad libitum.
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 7 days.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21+/- 2
- Humidity (%): 55 +/- 10
- Air changes (per hr): 15-20
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: To: no data.
Route of administration:
oral: gavage
Vehicle:
not specified
Details on exposure:
No data
Details on mating procedure:
- M/F ratio per cage: 1
- Length of cohabitation: 3 days (mean pre-coital period)
- Proof of pregnancy: vaginal plug
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
2 weeks before pairing and continuously thereafter, up to the day before sacrifice (study day 53, day 4 post partum).
Frequency of treatment:
Daily, 7 days/week.
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
Control (Group 1)
Dose / conc.:
100 mg/kg bw/day (nominal)
Remarks:
Low dose (Group 2)
Dose / conc.:
300 mg/kg bw/day (nominal)
Remarks:
Mid dose (Group 3)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
Remarks:
High dose (Group 4)
No. of animals per sex per dose:
10
Control animals:
yes
Positive control:
Not required.
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Clinical signs were recorded daily throughout the study.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: all animals were examined on arrival. Examinations of dams and litters took place on Day 4 post partum.

BODY WEIGHT: Yes
- Time schedule for examinations: body weigt gain was recorded during the study.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
Oestrous cyclicity (parental animals):
Vaginal smears are taken daily for 14 days prior to pairing and each morning during the pairing period to detect marked anomalies of the estrous cycle.
Sperm parameters (parental animals):
Parameters examined in P male parental generations:
testis weight, epididymis weight
Litter observations:
STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: no

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities, other: implantation per litter.

GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities; possible cause of death was not determined for pups born or found dead.

ASSESSMENT OF DEVELOPMENTAL NEUROTOXICITY: no

ASSESSMENT OF DEVELOPMENTAL IMMUNOTOXICITY: no
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals on Day 53 (On Day 4 post partum).
- Maternal animals: All surviving animals on Day 53 (on Day 4 post partum).
Postmortem examinations (offspring):
SACRIFICE
- The F1 offspring not selected as parental animals and all F2 offspring were sacrificed at 4 days of age.
- These animals were subjected to postmortem examinations (macroscopic examination)
Statistics:
Mean values and standard deviations of the following parameters were calculated:
- litter weights at birth and sacrifice
- absolute and relative organ weights of testes, epididymis, seminal vesicles and prostate
- pre-coital intervals
- total litter size, sex ratio (%)
- implantation/litter
- gestation period
- pre-birth loss/litter (number and %)
Reproductive indices:
- Female: copulation or fertility index.
- Males: fertility index.
Clinical signs:
no effects observed
Description (incidence and severity):
No clinical signs were observed during the whole study period.
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No effects on body weights were noted during the study.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No effects on food consumption were observed during the experimental period.
Food efficiency:
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Other effects:
not examined
Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
No effects on estrous cycle were reported.
Reproductive function: sperm measures:
no effects observed
Description (incidence and severity):
No treatment-related effects on absolute and relative weights of testis and epididymis were observed at any dose level.
Reproductive performance:
no effects observed
Description (incidence and severity):
In males and females, no substance-related effects on fertility index were observed. A slight, but not significant decrease in copulatory index was observed in females receiving the high dose (1000 mg/kg bw/d). One male in the mid dose dose group and two females in the high dose group did no mate until day 10 and were mated with another male afterwards. One female in the high dose group did not mate after a period of 20 days.
Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality
body weight and weight gain
food consumption and compound intake
food efficiency
organ weights and organ / body weight ratios
gross pathology
other: No treatment-related effects.
Remarks on result:
other: Systemic toxicity
Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reproductive function (oestrous cycle)
reproductive function (sperm measures)
reproductive performance
other: no adverse effects on male and female reproductive organs and performance.
Remarks on result:
other: Reproductive toxicity
Key result
Critical effects observed:
no
Clinical signs:
no effects observed
Description (incidence and severity):
No treatment-related clinical signs were observed in pre-weaning pups.
Mortality / viability:
no mortality observed
Description (incidence and severity):
No effects on mean litter weights and sex ratios were observed between the F1 generations of treated and control animals. Some slight, but not significant variations in pre-birth loss were seen in the high dose group compared to controls.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No differences in the mean litter weight on Day 0 (birth) and Day 4 (sacrifice) were noted in treated and controls group.
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Sexual maturation:
not examined
Anogenital distance (AGD):
not examined
Nipple retention in male pups:
not examined
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Description (incidence and severity):
Necropsy did not reveal any substance related effects in decedent or F1 pups.
Histopathological findings:
not specified
Other effects:
not specified
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
viability
clinical signs
body weight and weight gain
gross pathology
other: No treatment-related effects were observed at all tested doses.
Key result
Critical effects observed:
no
Reproductive effects observed:
no
Lowest effective dose / conc.:
1 000 mg/kg bw/day (nominal)
Conclusions:
Under the conditions of a state-of-the-art reproduction/developmental toxicity screening testing according to the OECD guideline 421, no adverse effects were observed regarding male and female reproductive organs even at the very high dose of 1000 mg/kg bw/day.
Executive summary:

In a Reproduction / Developmental Toxicity Screening Test conducted according to OECD Guideline 421, the test substance (APG C12 -C14 fatty alcohol from renewable sources, n= 1.43) was applied to 40 males and 40 females Sprague-Dawley rats prior to mating, throughout the gestation and lactation period until post partum day 3. Treatment by gavage with 0, 100, 300 and 1000 mg/kg bw/day began 7 days after allocation for both males and females. Treatment commenced when males and females were approximately 12 weeks of age, 2 weeks before pairing and continuously thereafter, up to the day before sacrifice (study day 53, day 4 post partum). Matings were monogamous.

 

During the study, parameters of general toxicity like clinical signs, food consumption and body weight gain were recorded in the parental generation and in the pups. Effects related to reproduction and hormone balance such as oestrous cycle, mating performance, pregnancy rates and the number of embryo resorptions were registered. Pup losses were recorded and the filial generation was examined for behavioural abnormalities and external growth abnormalities.

Under the conditions of a state-of-the-art reproduction/developmental toxicity screening testing according to the OECD guideline 421, no adverse effects were observed regarding male and female systemic toxicity and reproductive organs even at the very high dose of 1000 mg/kg bw/day. There is no indication for any impairment of reproduction, either with regard to the development of the progeny or to the effects on fertility both of the structural and functional level. Therefore, a hazard of reproductive toxicity for APG is not expected.

Based on the results of this study it is concluded that he NOAEL of test item for reproductive/developmental effects was concluded to be 1000 mg/kg bw/day.

Therefore, the test substance should not be classified according to the criteria of the Regulation (EC) No.1272/2008 (CLP) and to the GHS.

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
See RAAF document.
Reason / purpose for cross-reference:
read-across source
Clinical signs:
no effects observed
Description (incidence and severity):
No clinical signs were observed during the whole study period.
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No effects on body weights were noted during the study.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No effects on food consumption were observed during the experimental period.
Food efficiency:
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Other effects:
not examined
Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
No effects on estrous cycle were reported.
Reproductive function: sperm measures:
no effects observed
Description (incidence and severity):
No treatment-related effects on absolute and relative weights of testis and epididymis were observed at any dose level.
Reproductive performance:
no effects observed
Description (incidence and severity):
In males and females, no substance-related effects on fertility index were observed. A slight, but not significant decrease in copulatory index was observed in females receiving the high dose (1000 mg/kg bw/d). One male in the mid dose dose group and two females in the high dose group did no mate until day 10 and were mated with another male afterwards. One female in the high dose group did not mate after a period of 20 days.
Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality
body weight and weight gain
food consumption and compound intake
food efficiency
organ weights and organ / body weight ratios
gross pathology
other: No treatment-related effects.
Remarks on result:
other: Systemic toxicity
Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reproductive function (oestrous cycle)
reproductive function (sperm measures)
reproductive performance
other: no adverse effects on male and female reproductive organs and performance.
Remarks on result:
other: Reproductive toxicity
Key result
Dose descriptor:
NOAEL
Effect level:
850 mg/kg bw/day
Based on:
other: apx 20P
Sex:
male/female
Remarks on result:
other: No treatment-related effects.
Remarks:
Reproductive toxicity
Key result
Dose descriptor:
NOAEL
Effect level:
850 mg/kg bw/day
Based on:
other: apx 20P
Sex:
male/female
Remarks on result:
other: Systemic toxicity
Key result
Critical effects observed:
no
Clinical signs:
no effects observed
Description (incidence and severity):
No treatment-related clinical signs were observed in pre-weaning pups.
Mortality / viability:
no mortality observed
Description (incidence and severity):
No effects on mean litter weights and sex ratios were observed between the F1 generations of treated and control animals. Some slight, but not significant variations in pre-birth loss were seen in the high dose group compared to controls.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No differences in the mean litter weight on Day 0 (birth) and Day 4 (sacrifice) were noted in treated and controls group.
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Sexual maturation:
not examined
Anogenital distance (AGD):
not examined
Nipple retention in male pups:
not examined
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Description (incidence and severity):
Necropsy did not reveal any substance related effects in decedent or F1 pups.
Histopathological findings:
not specified
Other effects:
not specified
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
viability
clinical signs
body weight and weight gain
gross pathology
other: No treatment-related effects were observed at all tested doses.
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
850 mg/kg bw/day
Based on:
other: apx 20P
Sex:
male/female
Basis for effect level:
other: No treatment-related effects.
Key result
Critical effects observed:
no
Key result
Reproductive effects observed:
no
Conclusions:
Under the conditions of a state-of-the-art reproduction/developmental toxicity screening testing according to the OECD guideline 421, no adverse effects were observed regarding male and female reproductive organs even at the very high dose of 1000 mg/kg bw/day, which corresponds to 850 mg/kg bw/day for the target registered substance.
Executive summary:

In a Reproduction / Developmental Toxicity Screening Test conducted according to OECD Guideline 421 and in compliance with GLP, the test substance (APG C12 -C14 fatty alcohol from renewable sources, n= 1.43) was applied to 40 males and 40 females Sprague-Dawley rats prior to mating, throughout the gestation and lactation period until post partum day 3. Treatment by gavage with 0, 100, 300 and 1000 mg/kg bw/day began 7 days after allocation for both males and females. Treatment commenced when males and females were approximately 12 weeks of age, 2 weeks before pairing and continuously thereafter, up to the day before sacrifice (study day 53, day 4 post partum). Matings were monogamous.

 

During the study, parameters of general toxicity like clinical signs, food consumption and body weight gain were recorded in the parental generation and in the pups. Effects related to reproduction and hormone balance such as oestrous cycle, mating performance, pregnancy rates and the number of embryo resorptions were registered. Pup losses were recorded and the filial generation was examined for behavioural abnormalities and external growth abnormalities.

Under the conditions of a state-of-the-art reproduction/developmental toxicity screening testing according to the OECD guideline 421, no adverse effects were observed regarding male and female systemic toxicity and reproductive organs even at the very high dose of 1000 mg/kg bw/day. There is no indication for any impairment of reproduction, either with regard to the development of the progeny or to the effects on fertility both of the structural and functional level. Therefore, a hazard of reproductive toxicity for APG is not expected.

Based on the results of this study it is concluded that he NOAEL of test item for reproductive/developmental effects was concluded to be 1000 mg/kg bw/day, which corresponds to 850 mg/kg bw/day for the target registered substance.

Therefore, the test substance should not be classified according to the criteria of the Regulation (EC) No.1272/2008 (CLP) and to the GHS.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
850 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The key study is GLP-compliant (OECD 421, Klimisch score = 1).
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

No data available on the registered susbtance.

- By analogy with octadecan-1-ol, a key study was identified (Hansen, 1992b). In this study (Similar to OECD 422, GLP), octadecan-1-ol was administered to groups of Wistar rats at dietary concentrations of 1500, 7500 and 30000 ppm (100, 500 and 2000 mg/kg bw/day)

 

No mortality or cilnical signs were observed.The only systemic effects seen in this study were significant changes in plasma free cholesterol, triglycerides and glucose. These changes occurred at all dose levels but were not dose related. Although the reduction in plasma triglyceride levels may be indicative of mild effects in the liver, the differences in the composition of the test diets may have confounded these results.

Octadecan-1 administered to male and female rats via the diet at concentrations up to 30.000 ppm during pre-mating , mating and gestation.Pregnancy rates, uterine parameter, time to pregnancy and gestation length indicated that fertility was not affected by exposure to octadecan-1-ol. There were no microscopic changes observed in the reproductive organs.

Based on the results of this study it is concluded that the NOAEL of test item for systemic toxicity was 30000 ppm (equivalent to 2000 mg/kg bw/day), which corresponds to 3184 mg/kg bw/day of the target registered substance. The NOAEL of test item for reproductive/developmental effects was concluded to be 30000 ppm (equivalent to 2000 mg/kg bw/day), which corresponds to 2207 mg/kg bw/day of the target registered substance.

- In a Reproduction / Developmental Toxicity Screening Test conducted according to OECD Guideline 421 and in compliance with GLP, the test substance (APG C12 -C14 fatty alcohol from renewable sources, n= 1.43) was applied to 40 males and 40 females Sprague-Dawley rats prior to mating, throughout the gestation and lactation period until post partum day 3. Treatment by gavage with 0, 100, 300 and 1000 mg/kg bw/day began 7 days after allocation for both males and females. Treatment commenced when males and females were approximately 12 weeks of age, 2 weeks before pairing and continuously thereafter, up to the day before sacrifice (study day 53, day 4 post partum). Matings were monogamous.

 

During the study, parameters of general toxicity like clinical signs, food consumption and body weight gain were recorded in the parental generation and in the pups. Effects related to reproduction and hormone balance such as oestrous cycle, mating performance, pregnancy rates and the number of embryo resorptions were registered. Pup losses were recorded and the filial generation was examined for behavioural abnormalities and external growth abnormalities.

Under the conditions of a state-of-the-art reproduction/developmental toxicity screening testing according to the OECD guideline 421, no adverse effects were observed regarding male and female systemic toxicity and reproductive organs even at the very high dose of 1000 mg/kg bw/day.There is no indication for any impairment of reproduction, either with regard to the development of the progeny or to the effects on fertility both of the structural and functional level. Therefore, a hazard of reproductive toxicity for APG is not expected.

Based on the results of this study it is concluded that he NOAEL of test item for reproductive/developmental effects was concluded to be 1000 mg/kg bw/day, which corresponds to 850 mg/kg bw/day for the target registered substance.

These results are supported by two studies available on other analogues ( repeated dose toxicity study (2y rat), no test substance related-effects were observed in male or female reproductive organs.

Effects on developmental toxicity

Description of key information

No data available on the registered substance. By analogy with 2 -Octyldodecan-1 -ol (OECD 414, Rel.1), the NOAEL for maternal systemic toxicity and developmental toxicity was up to 1000 mg /kg bw/day, which corresponds to 1442 mg/kg bw/day of the registered substance.

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
August to November 1992
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
Principles of method if other than guideline:
Not applicable.
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
CD-1
Details on test animals or test system and environmental conditions:
According to guidelineTEST ANIMALS
- Source: Charles River, Sulzfeld, Germany
- Age at study initiation: 8-10 weeks
- Weight at study initiation: mean weight 196 g
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-23
- Humidity (%): 38-58
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: To: September 30 to November 4, 1992
Route of administration:
oral: gavage
Vehicle:
arachis oil
Details on exposure:
Test substance was administered orally by gavage once daily in the morning from day 6 up tp day 15 post coitum inclusive. All groups received a dose volume of 5ml/kg body weight, adjusted to the body weight of day 6 post coitum. Control animals were similarly dosed with the vehicle alone.
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
According to guideline.
Duration of treatment / exposure:
day 6 to day 15 of gestation.
Frequency of treatment:
daily
Duration of test:
until day 20 of gestation.
Dose / conc.:
0 mg/kg bw/day
Remarks:
Group 1 (Control group)
Dose / conc.:
100 mg/kg bw/day
Remarks:
Group 2 (Low dose, actual ingested)
Dose / conc.:
300 mg/kg bw/day
Remarks:
Group 3 (Mid dose, actual ingested)
Dose / conc.:
1 000 mg/kg bw/day
Remarks:
Group 4 (High dose, actual ingested)
No. of animals per sex per dose:
24
Control animals:
yes
Details on study design:
none
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
DETAILED CLINICAL OBSERVATIONS: Yes
BODY WEIGHT: Yes
POST-MORTEM EXAMINATIONS: Yes
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes :
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: half per litter
Statistics:
yes
Historical control data:
no
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Changes in number of pregnant:
no effects observed
Other effects:
no effects observed
Details on maternal toxic effects:
Maternal toxic effects:no effects
Dose descriptor:
NOEL
Effect level:
> 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Remarks on result:
other: No maternal toxicity was observed at all tested doses.
Key result
Abnormalities:
not specified
Fetal body weight changes:
no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Group 1: no variations
Group 2: ribs rudimentary unilateral/bilateral, significant decrease at level 1%, thoracic vertebrae, dumbbell shape, significant increase at level 5%
Group 3: no variations
Group 4: thoratic vertebrae, dumbell shape, significant increase at level 1%

The statistical significant differences were considered to be incidental. The findings in the ribs rudimentare are due to the increase of the control group. The other variation effects to the thoratic vertebrae, dumbell shape are also incidental and not dose-related. The incidental character of these variations is emphasized by the fact that the values were within the normal range of variations for this strain.
Visceral malformations:
no effects observed
Other effects:
no effects observed
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects
Key result
Dose descriptor:
NOEL
Effect level:
> 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: embryotoxicity
Remarks on result:
other: No effects were observed at all tested doses.
Key result
Dose descriptor:
NOEL
Effect level:
> 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: fetotoxicity
Remarks on result:
other: No effects were observed at all tested doses.
Key result
Abnormalities:
not specified
Key result
Developmental effects observed:
not specified
Conclusions:
Under the test conditions, the NOAEL for maternal systemic toxicity and developmental toxicity was up to 1000 mg /kg bw/day, as no effects were observed at all tested doses.
Executive summary:

In a developmental toxicity study conducted according to the OECD guideline No. 414 and in compliance with GLP, 2 -octyl-1 -dodecanol diluted in arachis oil was administered to 24 females rats/dose by gavage at dose levels of 0, 100, 300 or 1000 mg/kg bw/day from days 6 through 15 of gestation.

 

All animals were observed twice daily for appearance and behavior. The uteri and ovaries were examined, and the number of fetuses, early and late resorptions, total implantations and corpora lutea were recorded. Gravid uterine weights were recorded, and net body weights and net body weight changes were calculated. The fetuses were weighted, sexed and examined for external, visceral and skeletal malformations and developmental variation.

 

All animals survived to the scheduled necropsy. No maternal effects were observed in all tested doses.

There were no test article-related internal findings at the scheduled necropsy. For the effect on fetuses, no significant changes were observed in the number of live fetuses, embryo/fetal mortality, sex ratio, body weight of live fetuses, or in the external, visceral, or skeletal examination of fetuses, at all tested animals. No test article-related fetal malformations or developmental variations were noted at any dose level in this study. No other signs of developmental toxicity were noted.

Based on the results of this study, the dose level up to 1000 mg/kg bw/day was considered to be the NOAEL(systemic effects) for maternal toxicity and the NOAEL for developmental toxicity.

Under the test conditions, the test substanceis not classified according to Regulation (EC) No.1272/2008 (CLP) criteria.

This study is acceptable and satisfies the requirement for developmental toxicity endpoint.

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

No study available on the test substance, by analogy with 2 -Octyldodeca-1 -ol (see RAAF document), a key study was identified (BASF, 1992). In this study (OECD 414, GLP), 2 -octyl-1 -dodecanol diluted in arachis oil was administered to 24 femalesrats/dose by gavage at dose levels of 0, 100, 300 or 1000 mg/kg bw/day from days 6 through 15 of gestation.

 

All animals were observed twice daily for appearance and behavior. The uteri and ovaries were examined, and the number of fetuses, early and late resorptions, total implantations and corpora lutea were recorded. Gravid uterine weights were recorded, and net body weights and net body weight changes were calculated. The fetuses were weighted, sexed and examined for external, visceral and skeletal malformations and developmental variation.

 

All animals survived to the scheduled necropsy. No maternal effects were observed in all tested doses.

There were no test article-related internal findings at the scheduled necropsy. Forthe effect on fetuses, no significant changes were observed in the number of live fetuses, embryo/fetal mortality, sex ratio, body weight of live fetuses, or in the external, visceral, or skeletal examination of fetuses, at all tested animals. No test article-related fetal malformations or developmental variations were noted at any dose level in this study.No other signs of developmental toxicity were noted.

 

Based on the results of this study, the dose level up to 1000 mg/kg bw/day was considered to be the NOAEL(systemic effects) for maternal toxicity and the NOAEL for developmental toxicity, which corresponds to 1000 mg/kg bw/day of the registered substance.

Justification for classification or non-classification

 

Harmonized classification:

The substance has no harmonized classification according to the Regulation (EC) No 1272/2008.

 

Self-classification:

Based on the available data, no adverse effects were identified, therefore no additional classification is proposed according to the Regulation (EC) No 1272/2008 and to the GHS.

Additional information