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Administrative data

Description of key information

Various literature data were available in rats for the oral repeated dose toxicity of long chain alcohols (LCOH C16 and C18 chains), alkyl sulfates (AS C12 chain representing worst case situation for C14-C20) and sodium sulfate. When the NOAEL of the target substance was calculated by concentration addition based on the general equation as presented in the CLP regulation on mixtures (2008) from NOAEL values of the components (C16 and C18 LCOH, C12 AS as worst case, sodium sulfate), this resulted in an oral systemic NOAEL of 602 mg/kg bw in rats. It can therefore be concluded that the oral systemic NOAEL of the registered substance is 602 mg/kg bw. Target organ based on the subacute and subchronic rat toxicity study in rats of the major LCOH C16 fraction is the liver (reversible weight increase).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1987
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Remarks:
Guideline study
Qualifier:
according to guideline
Guideline:
other: Directive 79/831/EEC, Annex V, Part B
GLP compliance:
yes
Specific details on test material used for the study:
OTHER SPECIFICS:
> 90 % active substance
C12 > 98 %
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: ca 6 weeks
- Weight at study initiation: 58 - 79 g

Route of administration:
oral: gavage
Duration of treatment / exposure:
28 days / 23-24 applications in total
Frequency of treatment:
single dosing once per day on 5 days per week
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
30 mg/kg bw/day (nominal)
Remarks:
ca. 27 mg active substance/kg bw per day
Dose / conc.:
100 mg/kg bw/day (nominal)
Remarks:
ca. 90 mg active substance/kg bw per day
Dose / conc.:
300 other: mg/kg bw/day (nominal); high dose was changed from 300 to 600 mg/kg after 10 treatments
Remarks:
ca. 270 mg active substance/kg bw per day first 10 treatments high dose
Dose / conc.:
600 other: mg/kg bw/day (nominal); high dose was changed from 300 to 600 mg/kg after 10 treatments
Remarks:
ca.540 mg active substance/kg bw per day after 10 treatments at 300 mg/kg bw
No. of animals per sex per dose:
10
Satellite groups for recovery (0 or 300 / 600 mg/kg bw): 5 males and females over 29 days p.a.
Control animals:
yes, concurrent vehicle
Observations and examinations performed and frequency:
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION
- Yes, weekly.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: weekly

OPHTHALMOSCOPIC EXAMINATION: Yes

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at termination

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at termination

URINALYSIS: No data

Sacrifice and pathology:
GROSS PATHOLOGY: Yes. Macroscopic: brain, testes, heart, liver, spleen, adrenals, kidneys, thymus

HISTOPATHOLOGY: Yes. Microscopic: complete examination (all relevant organs)


Statistics:
t- and U-test
Clinical signs:
not specified
Mortality:
mortality observed, treatment-related
Description (incidence):
300 / 600 mg TS/kg bw: increased mortality (1 m / 1 f)
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Body weight gain was decreased inhigh dose males.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Feed intake was decreased in high dose males.
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
300 / 600 mg TS/kg bw: Increase in water intake
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
300 / 600 mg TS/kg bw: Decrease in haematocrit and MCV (mean corpuscular volume) levels, increase in number of leucocytes and neutrophile leucocytes.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
300 / 600 mg TS/kg bw: Decrease in ALT levels
Urinalysis findings:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
300 / 600 mg TS/kg bw: Increase in relative weights of adrenals, kidney, brain, gonads and liver. Decrease in relative thymus weights.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
300 / 600 mg TS/kg bw: Ulcerations and bleedings in the stomach; alterations of the tongue and myocard (fully reversible within 29 days p.a.) and fore stomach (partially reversible within 29 days p.a.)
Histopathological findings: non-neoplastic:
not specified
Dose descriptor:
NOAEL
Effect level:
ca. 90 mg/kg bw/day (nominal)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
body weight and weight gain
clinical biochemistry
gross pathology
haematology
mortality
organ weights and organ / body weight ratios
Dose descriptor:
LOAEL
Effect level:
ca. 270 - ca. 540 mg/kg bw/day (nominal)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
gross pathology
Dose descriptor:
NOAEL
Effect level:
<= 100 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
gross pathology
Critical effects observed:
no
Conclusions:
NOAEL is <= 100 mg/kg bw based on test material and ca. 90 mg/kg bw based on active substance.
LOAEL is ca. 270 - 540 mg /kg bw based on active substance.
Executive summary:

The IUCLID dataset of C12-Alkylsulfate (CAS 151-21-3) in the OECD SIDS Initial Assessment Profile on Sodium dodecyl sulfate (SDS) describes the following Klimisch 1 study according to Directive 79/831/EEC, Annex V, Part B, in rats.

Groups op 10 male and 10 female Sprague-Dawley rats were dosed at 0, 30, 100, or 300 / 600 mg/kg bw/day (ca. 0, 27, 90 or 270 / 540 mg active substance/kg bw per day).Satellite groups for recovery (0 or 300 / 600 mg/kg bw) consisted of 5 males and females and were observed over 29 days p.a.. Mortality and clinical signs were observed twice daily; body weight and food consumption were observed weekly. Ophthalmologic examination was performed. Haematology and clinical chemistry were examined at termination. Gross pathology and histopathology was performed and organ weights were recorded. No adverse effects were noted ≤ 100 mg/kg bw test substance (ca. 90 mg/kg bw active substance). At 300 / 600 mg TS/kg bw mortality was increased (1 male and 1 female). Feed intake and weight gain were decreased in high dose males. At 300 / 600 mg following effects were noted: decrease in haematocrit and MCV levels, and in relative thymus weights; increase in water intake, in number of leucocytes and neutrophile leucocytes, in ALT levels, and in relative weights of adrenals, kidney, brain, gonads and liver; ulcerations and bleedings in the stomach; alterations of the tongue and myocard (fully reversible within 29 days p.a.) and fore stomach (partially reversible within 29 days p.a.). NOAEL was<= 100 mg /kg bw test substance or ca. 90 mg/kg bw active substance. LOAEL was ca. 270 – 540 mg/kg bw based on active substance.

 

Reference: Henkel KGaA (1987) Texapon K 12. 28-Tage-Test mit wiederholter oraler Verabreichung an Ratten (Unpublished Report No. 870121).Henkel KGaA, Duesseldorf, 67 pp.

.

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1985
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Remarks:
Comparable to guideline study with acceptable restrictions. Report in German language, English summary page.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
GLP compliance:
yes
Limit test:
no
Specific details on test material used for the study:
OTHER SPECIFICS: Tradename Lanette 16
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Weight at study initiation: M 84-98 g; F 81-93g
Route of administration:
oral: gavage
Vehicle:
olive oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
- Total volume applied: 5 mL/kg
- Doses: 0, 100, 500 and 1000 mg/kg/day

VEHICLE (olive oil)
- Concentration in vehicle: 0, 2, 10 or 20%
Duration of treatment / exposure:
27-28 days exposure (5 days/week)
Frequency of treatment:
daily, 5 days/week
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Dose / conc.:
500 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
10M+10F per dose level plus 5M+5F per dose level for reversibility.
Control animals:
yes, concurrent vehicle
Observations and examinations performed and frequency:
CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily. Mortality: Daily

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Daily

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Weekly

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: At end of study

HAEMATOLOGY: Yes
- Time schedule for collection of blood: After 21/22 daily doses
- Parameters examined: Haematocrit, MCV, Hb, RBC, WBC, Thrombocytes, differential white count.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: After 21/22 daily doses
- Parameters examined: Serum Urea, creatinine, Na, K, calcium, alkaline phosphatase, ALAT, ASAT, GT, bilirubin, chloride, albumin, total protein, cholesterol.

URINALYSIS: No

Sacrifice and pathology:
GROSS PATHOLOGY: Yes

HISTOPATHOLOGY: Yes. All organs from the control and top dose animals were examined plus the animals from the reversibility study.

Other examinations:
ORGAN WEIGHTS: thyroid, adrenals, thymus, kidney, spleen, heart, brain, testes, liver
Statistics:
T-test. U-test for organ weights.
Clinical signs:
no effects observed
Description (incidence and severity):
Unremarkable other than top dose females appearing rather defensive when handled.
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Comparable with controls.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Similar to control group
Description (incidence and severity):
Similar to control group
Ophthalmological findings:
no effects observed
Description (incidence and severity):
Comparable in treated and control animals.
Description (incidence and severity):
No differences between treated and control animals other than an increase in neutrophils containing rodlike bodies observed in top dose females (confidence level 95%*). Values obtained (% rod like cells) were controls 2.5, low dose 3.3, mid dose 2.9, high dose 5.3*.
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
Statistically significant changes (*95%, ** 99% confidence) in some clinical chemical parameters were noted as follows:
500 mg/kg/day males increased potassium*, 500 mg/kg/day females increased GGT*, cholesterol** and chloride*. Glucose was elevated in top dose males (1000 mg/kg/day)**. These changes were not dose and/or sex related and not correlated with any histopathological findings and are therefore not considered of toxicological significance.
Description (incidence and severity):
Both absolute and relative organ weights were essentially comparable in treated and control animals.
Sporadic changes were observed as follows (*95% ** 99% confidence): increases in absolute organ weight male kidney 500 mg/kg/day*, male testes 1000 mg/kg/day*. The only change in relative organ weight was an increase in male adrenal weight at 1000 mg/kg/day*.
Description (incidence and severity):
Gross pathology: No treatment related histopathological changes in test, control or reversibility groups.
Description (incidence and severity):
No treatment related histopathological changes in test, control or reversibility groups.
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: based on lack of toxicologically significant treatment related effects at this dose level (top dose level).
Critical effects observed:
no
Conclusions:
NOAEL is considered to be >1000 mg/kg/day based on lack of toxicologically significant treatment related effects at this dose level (top dose level). Sporadic statistically significant changes in some organ weights and clinical chemical parameters were observed but these were not associated with histopathological changes and were not considered of toxicological significance.
Executive summary:

Lanette 16 in olive oil was administered to 10 male and female Sprague-Dawley rats ( and 5 male and female per dose level for reversibility) by oral gavage 5 days/week for 27-28 days at doses levels of 1000, 500 and 1000 mg/kg in a subacute repeated dose toxicity study similar to OECD TG 407.

No mortality was observed at any dose level. Clinical signs were unremarkable other than top dose females appearing rather defensive when handled. Body weight gain, food and water consumption and ophthalmoscopic examination were comparable with controls. Clinical chemistry results statistically significant changes in some clinical chemical parameters as 500 mg/kg/day males increased potassium, 500 mg/kg/day females increased GGT, cholesterol and chloride. Glucose was elevated in top dose males (1000 mg/kg/day). These changes were not dose and/or sex related and not correlated with any histopathological findings and are therefore not considered of toxicological significance. No haematological differences between treated and control animals other than an increase in neutrophils containing rodlike bodies were observed in top dose females. Both absolute and relative organ weights were essentially comparable in treated and control animals. No treatment related histopathological changes were observed in test, control or reversibility groups.

NOAEL is considered to be >1000 mg/kg/day based on lack of toxicologically significant treatment related effects at this dose level (top dose level). Sporadic statistically significant changes in some organ weights and clinical chemical parameters were observed but these were not associated with histopathological changes and were not considered of toxicological significance.

References:

-Henkel KGaA 1985a. Lanette 16: 28-Tage-Test mit wiederholter oraler Verabreichung an Ratten.November 1985. Report No. TBD 850499. With pathology report No. 840394

-Henkel KGaA. 1999. Hexadecanol: Evaluation of repeated dose oral toxicity. Unpublished data, English summary and evaluation of Henkel 1985a report No. TBD 850499.

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1966
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Remarks:
Reliability 2 however there were methodological deficiencies, animal group size too small (2M + 2F in test groups), no statistical analysis in original study, subsequent analysis by The Weinberg Group Inc of limited relevance because of small group sizes.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 409 (Repeated Dose 90-Day Oral Toxicity Study in Non-Rodents)
Principles of method if other than guideline:
The results were reported to USEPA in accordance with TSCA 8(e).
GLP compliance:
no
Limit test:
no
Specific details on test material used for the study:
This substance corresponds to CAS# 36653-82-4. Tradename is Alfol 16. Described as a white, wax-like solid. No other analytical details.
Species:
dog
Strain:
Beagle
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age : 5 months
- Weight at study initiation: M4.77-8.63 kg; F5.45-7.49 kg


Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Remarks:
in diet
Dose / conc.:
0.5 other: % in diet
Remarks:
Actual dose received: M 208 mg/kg/day; F 186 mg/kd/day
Dose / conc.:
1 other: % in diet
Remarks:
Actual dose received: M 502 mg/kg/day; F 374 mg/kg/day
Dose / conc.:
3 other: % in diet
Remarks:
Actual dose received: M 1175 mg/kg/day; F 1054 mg/kg/day
No. of animals per sex per dose:
2M+2F treated; 4M+5F controls

Control animals:
yes
Observations and examinations performed and frequency:
CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily 5 days/week.
Complete physical examination, body temperature, pulse rate, reflexes, mucous membranes, auscultation pretreatment at 3, 6 & 13 weeks. ECG pretreatment, 3 and 13 weeks.Mortality: Daily

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly

FOOD CONSUMPTION: Weekly

WATER CONSUMPTION AND COMPOUND INTAKE (no drinking water study): Not recorded.

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes / No / Not specified
- Time schedule for collection of blood: pretreatmentand at 3, 6 and 13 weeks.
- Anaesthetic used for blood collection: Not specified
- Animals fasted: Not specified
- Parameters examined: Total & differential leucocyte counts, Hb, haematocrit, erythrocyte sedimentation rate, prothrombin time measured pretreatmentand at 3, 6 and 13 weeks.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: pretreatment, 3, 6 and 13 weeks
- Animals fasted: Not specified
- Parameters examined: Plasma levels of glucose, total protein & albumin, albumin/globulin ratios, urea nitrogen, liver function assessed by BSP retention, alkaline phosphatase & SGOT

URINALYSIS: Yes
- Time schedule for collection of urine: pretreatment, 3, 6 and 13 weeks
- Parameters examined: albumin, glucose, bilirubin, pH, vol. , specific gravity, microscopic examination of sediment, total nitrogen.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes: complete, organ weights determined for brain, thyroid, heart, liver, kidneys, adrenals, spleen, gonads.

HISTOPATHOLOGY: Yes. Brain, pituitary, sub-maxillary salivary gland, thyroid, parathyroid, heart, lung, liver, spleen, stomach (fundic & pyloric), small intestine (3 levels), large intestine, pancreas, gall bladder, kidney, urinary bladder, adrenal, gonads, lymph node (cervical & mesenteric), bone, bone marrow, muscle (striated). All fixed tissues from controls & high dose animals examined microscopically. Stomach & intestinal tissues from mid dose animals also examined plus any abnormal tissues identified at necropsy.
Statistics:
There was no statistical analysis of the study data in the original report. Subsequent analysis of organ weights using Tukeys test did not reveal any statistical differences between treated and control animals. This analysis was carried out by The Weinberg Group Inc.
Clinical signs:
no effects observed
Description (incidence and severity):
No specific clinical signs, all animals appeared normal and healthy throughout the study. This was supported by the clinical examinations at weeks 3, 6 and 13 which were within normal limits. ECG's showed no difference between the initial pattern recorded pretreatment and those seen at 3 and 13 weeks.
Mortality:
no mortality observed
Description (incidence):
No animals died.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Comparable in test and control groups.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Comparable in test and control groups.
Description (incidence and severity):
Comparable in test and control groups.
Ophthalmological findings:
not examined
Description (incidence and severity):
No adverse effects.
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
No treatment related adverse effects for most parameters. Plasma ALAT levels were increased at all dose levels at 13 weeks only.

Description (incidence and severity):
No adverse effects.
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
Organ weights were within normal limits and comparable to controls. Tukeys test did not indicate any statistical differences (however sample size was small).
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
Lymph node hyperplasia in both control and treated animals was considered due to roundworm infestation (despite routine deworming throughout the study). There were no treatment related findings.
Description (incidence and severity):
No treatment related changes.
Dose descriptor:
NOAEL
Effect level:
> 1 175 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: highest dose level tested (3% in diet)
Dose descriptor:
NOAEL
Effect level:
> 1 054 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: highest dose level tested (3% in diet)
Critical effects observed:
no
Conclusions:
The NOAEL for Alfol 16 following dietary administration is considered to be >1175 mg/kg/day for male dogs and >1054 mg/kg/day for females. This was the highest dose level tested (3% in diet). The elevated ALAT values seen at 13 weeks in most test animals at all dose levels were apparently not dose related or accompanied by histopathological liver change. Other markers of liver function appeared normal.
Executive summary:

Groups of male and female Beagle dogs (2 per sex per dose) were administered Alfol 16 at dietary concentrations of 0.5, 1% and 3% in diet of for 13 weeks. 4 Male and 5 female dogs served as controls.

No animal died during the study. No specific clinical signs, all animals appeared normal and healthy throughout the study. This was supported by the clinical examinations at weeks 3, 6 and 13 which were within normal limits. Body weight gain and food and water consumption were comparable in test and control groups. Clinical chemistry: revealed no treatment related adverse effects for most parameters. Plasma ALAT levels were increased at all dose levels at 13 weeks only. There were no adverse effects for haematology and urinalysis. Organ weights were within normal limits and comparable to controls. Tukeys test did not indicate any statistical differences (however sample size was small). Lymph node hyperplasia in both control and treated animals was considered due to roundworm infestation (despite routine deworming throughout the study). There were no treatment related findings. There were no treatment related histopathological changes. ECG's showed no difference between the initial pattern recorded pretreatment and those seen at 3 and 13 weeks.

The NOAEL for Alfol 16 following dietary administration is considered to be >1175 mg/kg/day for male dogs and >1054 mg/kg/day for females. This was the highest dose level tested (3% in diet). The elevated ALAT values seen at 13 weeks in most test animals at all dose levels were apparently not dose related or accompanied by histopathological liver change. Other markers of liver function appeared normal.

References

-Iuclid 2000 European Commission - European Chemicals Bureau Hexadecan-1-ol Cas# 36653-82-4

-Scientific Associates, Inc. 1966b. Exhibit III. Final report on thirteen-week subacute feeding in Beagle dogs of Alfol 6 and Alfol 16.

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1966
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Remarks:
Valid with restrictions including lack of biochemical investigations and limited reporting of statistical findings. Study reasonably well documented, meets generally accepted scientific principles, acceptable for assessment.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Principles of method if other than guideline:
The results were reported to USEPA in accordance with TSCA 8(e).
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
other: Albino rats ex-Charles River
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: : Actual age not reported, described as young.
- Weight at study initiation: M 103.8 g; F 90.4 g
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Remarks:
in diet
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
daily in diet
Dose / conc.:
1 other: %
Remarks:
for 13 weeks. Actual dose received: M 723 mg/kg/day; F875 mg/kg/day
Dose / conc.:
2.5 other: %
Remarks:
for 13 weeks. Actual dose received: M1822 mg/kg, day; F 2064 mg/kg/day
Dose / conc.:
5 other: %
Remarks:
for 10 weeks , then 7.5% (week 11) and 10.0 % (weeks 12 & 13). Actual dose received: M 4257 mg/kg/day; F4567 mg/kg/day
No. of animals per sex per dose:
10M + 10F per test group, 20M + 20 F controls.
Observations and examinations performed and frequency:
CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily (5 days/week). Mortality: Daily (5 days/week)

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly

FOOD CONSUMPTION (if feeding study): Weekly

WATER CONSUMPTION AND COMPOUND INTAKE (no drinking water study): Not recorded

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes / No / Not specified
- Time schedule for collection of blood: At 30 days and 90 days
- Anaesthetic used for blood collection: Not specified
- Animals fasted: Not specified
- How many animals: on 5M+5F
- Parameters examined: Micro haematocrit, Hb, total & differential leucocytes

CLINICAL CHEMISTRY: No

URINALYSIS: Yes
- Time schedule for collection of urine: At 30 days and 90 days on pooled samples from 5 rats of each sex.
- Metabolism cages used for collection of urine: Not specified
- Animals fasted: Not specified
Sacrifice and pathology:
GROSS PATHOLOGY: Yes. Complete necropsy performed, organ weights measured were brain, thyroid, heart, liver, spleen, kidneys, adrenals, ovaries & testes.

HISTOPATHOLOGY: Yes. Tissues fixed: brain, thyroid, parathyroid, heart, lung, liver, spleen, stomach, small & large intestine, pancreas, kidney, urinary bladder, adrenals, ovaries, testes, lymph node, bone, bone marrow, muscle. All tissues from 5M+5F high dose and control animals were examined.
Statistics:
The original report indicates that a Chi square test was carried out on the organ:bodyweight ratio. It is not clear what statistical methods were used (if they were) for body weights, food consumption & haematological parameters. Subsequently The Weinberg Group Inc. used Tukeys test to re-analyse the organ weight data.
Clinical signs:
no effects observed
Description (incidence and severity):
All surviving animals appeared normal.
Mortality:
no mortality observed
Description (incidence):
All animals survived the 13 week treatment period.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Significantly reduced (84.7 - 89.8% of controls) in top dose males for most study weeks, in mid dose females at weeks 4-13 and high dose females (81.7-89.7%) throughout the study. Changes were attributed at least in part to reduced food consumption and the high content of test material in the diet.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Significantly reduced (76.4 - 89.2% of controls) in top dose males at weeks 1 and 12, in mid dose males at week 13, in mid dose females at week 1 and high dose females weeks 1 and 12 (79.1 - 89.9% of controls).

Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Description (incidence and severity):
No treatment-related changes
Clinical biochemistry findings:
not examined
Description (incidence and severity):
No treatment related changes
Description (incidence and severity):
The original report indicates that there were significant differences in some relative organ weights from treated groups compared to controls. These were reanalysed by the Weinberg Group using the Tukey test. The significant changes found in the original report together with the results of the Weinberg analysis are:
Organ: Sex, Orig. sig. at, Weinberg report
Brain: M, low-dose, Not significant; M, high-dose, Significant; F, mid dose, Significant; F, high-dose, Significant
Heart: M, high-dose, Significant; F, high-dose, Not significant
Liver: M, mid dose, Not significant; M, high-dose, Significant; F, low-dose, Not significant; F, mid dos, Not significant; F, high-dose , Significant
Spleen: F, mid dose, Not significant; F, high-dose, Significant
Gonad: M, low-dose, Not significant; M, high-dose, Significant
Additionally Weinberg reanalysed the organ weight data for the kidney and adrenal and thyroid which showed no significant changes from the original statistical analysis. The thyroid weight showed a significant increase in mid dose males only according to the Weinberg analysis.
Gross pathological findings:
no effects observed
Description (incidence and severity):
Unremarkable
Description (incidence and severity):
There were no treatment related histopathological changes in the control and top dose animals examined (including testes & ovaries).
Dose descriptor:
NOAEL
Effect level:
723 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
body weight and weight gain
food consumption and compound intake
Dose descriptor:
NOAEL
Effect level:
875 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
body weight and weight gain
food consumption and compound intake
Critical effects observed:
no
Conclusions:
The NOAEL for this 13 week dietary feeding study in rats is ca 750 mg/kg/day (males 723, females 875) based on reduced weight gain and food consumption. The toxicological significance of observed changes in organ weights, all in the absence of histopathological change, is questionable. Increased liver weights at higher dose levels may be indicative of a mild adaptive effect on the liver.
Executive summary:

In a 13 week dietary feeding study in rats 10 male and 10 female albino rats per dose group (20 M and 20 F as controls) were dosed with Alfol 16 at dose levels of 1.0, 2.5 and 5% in the diet. The 5% dose was increased to 7.5% in week 11 and 10% in weeks 12 and 13.

All animals survived the 13 week treatment period. All surviving animals appeared normal. Body weight was significantly reduced (84.7 - 89.8% of controls) in top dose males for most study weeks, in mid dose females at weeks 4-13 and high dose females (81.7-89.7%) throughout the study. Changes were attributed at least in part to reduced food consumption and the high content of test material in the diet. Food consumption was significantly reduced (76.4 - 89.2% of controls) in top dose males at weeks 1 and 12, in mid dose males at week 13, in mid dose females at week 1 and high dose females weeks 1 and 12 (79.1 - 89.9% of controls). Haematological examinations and urinalysis did not reveal any treatment related changes. The original report indicates that there were significant differences in some relative organ weights from treated groups compared to controls. These were re-analysed by the Weinberg Group using the Tukey test. Additionally Weinberg re-analysed the organ weight data for the kidney and adrenal and thyroid which showed no significant changes from the original statistical analysis. The thyroid weight showed a significant increase in mid dose males only according to the Weinberg analysis. Gross pathology was unremarkable. There were no treatment related histopathological changes in the control and top dose animals examined (including testes & ovaries).

The NOAEL for this 13 week dietary feeding study in rats is ca 750 mg/kg/day (males 723, females 875) based on reduced weight gain and food consumption. The toxicological significance of observed changes in organ weights, all in the absence of histopathological change, is questionable. Increased liver weights at higher dose levels may be indicative of a mild adaptive effect on the liver.

References:

-Iuclid 2000 European Commission - European Chemicals Bureau Hexadecan-1-ol Cas# 36653-82-4

-Scientific Associates, Inc. 1966a. Exhibit II. Final report on thirteen-week subacute feeding of Alfol 6 and Alfol 16 to rats.

Endpoint:
repeated dose toxicity: oral, other
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1991
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Qualifier:
equivalent or similar to guideline
Guideline:
other: Draft OECD 422 combined repeated dose and reproductive/developmental toxicity screening test
GLP compliance:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: 7 weeks
- Water (e.g. ad libitum): Ad libitum
Route of administration:
oral: feed
Vehicle:
other: Diet
Remarks:
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
Details on oral exposure:
- DIET PREPARATION
- Mixing appropriate amounts with (Type of food): 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.




Duration of treatment / exposure:
males: 45 days; females approx. 54 days
Frequency of treatment:
continuous in diet
Dose / conc.:
0 ppm
Remarks:
ca. 0 mg/kg bw/day
Dose / conc.:
1 500 ppm
Remarks:
ca. 100 mg/kg bw/day. Males: 99.25 mg/kg/day (mean of values reported for 2 weeks prior to mating and 3 weeks after mating). Females: 120 mg/kg/day (mean of values reported 2 weeks prior to mating)
Dose / conc.:
7 500 ppm
Remarks:
ca. 500 mg/kg bw/day. Males: 500.25 mg/kg/day (mean of values reported for 2 weeks prior to mating and 3 weeks after mating). Females: 625 mg/kg/day (mean of values reported 2 weeks prior to mating)
Dose / conc.:
30 000 ppm
Remarks:
ca. 2000 mg/kg bw/day. Males: 2146.5 mg/kg/day (mean of values reported for 2 weeks prior to mating and 3 weeks after mating) Females: 2435.5 mg/kg/day (mean of values reported 2 weeks prior to mating)
No. of animals per sex per dose:
12
Control animals:
yes, concurrent vehicle
Observations and examinations performed and frequency:
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily. Mortality: Daily

B ODY WEIGHT: Yes
- Time schedule for examinations: Weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Weekly (except during mating)

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Males only at day 37
- Parameters checked in table: haematocrit, Hb, total RBC & WBC and differential WBC

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Males only at day 37
- Parameters checked in table : Plasma protein, alkaline phosphatase, AAT, glucose, urea, creatinine,total & free cholesterol and triglyceride.

URINALYSIS: No.

OTHER EXAMINATIONS: The results of foetal examinations and reproductive parameters are reported in the appropriate sections.


Sacrifice and pathology:
GROSS PATHOLOGY: Yes. Full necrospy on all animals.

HISTOPATHOLOGY: Yes. Carried out on all control and top dose animals plus any obvious lesions observed at necrospy. Organs examined were liver, kidneys, adrenals, brain, heart, spleen, ovaries or testes and epididymes.
Other examinations:
Organs weights: liver, kidneys, thymus (females) liver, kidney, thymus, testes, epididymes (males)
Statistics:
Using the SAS-stat program analysis of variance plus Dunnett's test if changes were significant.
Clinical signs:
no effects observed
Description (incidence and severity):
None reported.
Mortality:
no mortality observed
Description (incidence):
There were no mortalities.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
There were no significant changes in body weight or body weight gain in the 3 weeks prior to mating for both sexes. Or in males after mating.
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 or food conversion efficiency.
Ophthalmological findings:
not examined
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, treatment-related
Description (incidence and severity):
There were significant (but non-dose related) differences in free cholesterol (increased) and triglycerides (decreased) at all dose levels. Total cholesterol levels were not significantly increased. Plasma glucose was elevated with statistical significance in the low and mid-dose groups. Only males were examined.

Parameter Control 100 500 2000
(mM)
Free chol 0.29 0.38** 0.37** 0.36*
Total chol 1.30 1.56 1.56 1.40
Triglycerides 0.78 0.42** 0.49* 0.46**
Glucose 6.8 7.8* 7.9* 7.6

* p<0.05 ** P<0.01
Urinalysis findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
There were no significant differences in absolute or relative organ weights in males or females.
Gross pathological findings:
no effects observed
Description (incidence and severity):
Unremarkable no changes attributable to treatment.
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
Unremarkable no changes attributable to treatment.
Histopathological findings: neoplastic:
not examined
Details on results:
The method of diet preparation resulted in different dietary content between the different treatment groups and controls.
Dose descriptor:
NOAEL
Effect level:
2 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: highest dose tested
Dose descriptor:
LOEL
Effect level:
100 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical biochemistry
Critical effects observed:
no
Conclusions:
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 triglycerides levels may be indicative of mild effects in the liver, the differences in the composition of the test diets may have confounded these results. The NOAEL can be considered to be 2000 mg/kg/day with a NOEL of 100 mg/kg/day.
Executive summary:

1-Octadenol (CAS 112-92-5) was administered to groups of 12 male and 12 female Wistar rats in the diet for 45 days (males) and ca. 54 days (females) according to the Draft OECD 422 combined repeated dose and reproductive/developmental toxicity screening test. The animals were dosed at 0, 1500, 7500 and 30000 ppm (ca. 0, 100, 500 and 2000 mg/kg bw/day). There was no post exposure period.

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.

Mortality and clinical signs were observed daily; body weight was observed weekly; food consumption was observed weekly (except during mating). Haematology and clinical chemistry were examined at day 37 in males only. Full necropsy was performed on all animals. Histopathological examination was carried out on all control and top dose animals plus any obvious lesions observed at necrospy. Organs examined were liver, kidneys, adrenals, brain, heart, spleen, ovaries or testes and epididymes.

Organ weights were recorded for liver, kidneys, thymus (females) liver, kidney, thymus, testes, epididymes (males).

There were no mortalities and no clinical signs reported.

There were no significant changes in body weight or body weight gain in the 3 weeks prior to mating for both sexes or in males after mating.

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 or food conversion efficiency.

There were significant (but non-dose related) differences in free cholesterol (increased) and triglycerides (decreased) at all dose levels. Total cholesterol levels were not significantly increased. Plasma glucose was elevated with statistical significance in the low and mid-dose groups; only males were examined.

There were no statistically significant differences in haematology between treated and control groups (males only examined).

Gross pathology and histopathology were unremarkable.

NOAEL was considered to be 2000 mg/kg/day with a LOEL of 100 mg/kg/day. 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 triglycerides levels may be indicative of mild effects in the liver, the differences in the composition of the test diets may have confounded these results.

 

(Reference: Hansen, E. 1992b. Combined repeat dose and reproductive/developmental toxicity screening test on 1-octadecanol in rats. Denmark: Institute of Toxicology, National Food Agency, IT 911130).

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1986
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Remarks:
Guideline study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
GLP compliance:
yes
Specific details on test material used for the study:
OTHER SPECIFICS: Tradename Lanette 18
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Wiga GmbH, Sulzburg
- Weight at study initiation: M: 64-97 g; F: 62-99 g
- Water (e.g. ad libitum): Ad libitum
Route of administration:
oral: gavage
Vehicle:
olive oil
Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
- Total volume applied: 5 mL/kg

- VEHICLE
- Concentration in vehicle: 0, 2, 10 or 20%
Duration of treatment / exposure:
27-28 days exposure (5 days/week)
Frequency of treatment:
daily, 5 days/week
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Dose / conc.:
500 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
10M+10F per dose level plus 5M+5F per dose level for reversibility
Control animals:
yes, concurrent vehicle
Observations and examinations performed and frequency:
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily. Mortality: Daily.

B ODY WEIGHT: Yes
- Time schedule for examinations: Weekly

FOOD CONSUMPTION AND COMPOUND INTAKE: Weekly

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: At end of study

HAEMATOLOGY: Yes
- Time schedule for collection of blood: After 21/22 daily doses
- Parameters checked: Haematocrit, MCV, Hb, RBC, WBC, Thrombocytes, differential white count

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: After 21/22 daily doses.
- Parameters checked in table : Serum Urea, creatinine, Na, K, calcium, alkaline phosphatase, ALAT, ASAT, GT, bilirubin, chloride, Albumin, total protein, cholesterol..

URINALYSIS: No.




Sacrifice and pathology:
GROSS PATHOLOGY: Yes

HISTOPATHOLOGY: Yes. All organs from the control and top dose animals were examined plus the animals from the reversibility study
Other examinations:
Organs weights: thyroid, adrenals, thymus, kidney, spleen, heart, brain, testes, liver.
Statistics:
T-test, organ weights U-test.
Clinical signs:
no effects observed
Description (incidence and severity):
Unremarkable
Mortality:
no mortality observed
Description (incidence):
No mortalities.
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
Body weight gains were 95%, 91% and 82% of control values for low, mid and high dose levels respectively at the end of the study. This was attributed to a high mean control bodyweight in males and marked inhibition of bodyweight gain in one male in each of the high and mid dose levels.
Description (incidence and severity):
Food consumption was slightly reduced in males (95% confidence)
Water consumption and compound intake (if drinking water study):
no effects observed
Description (incidence and severity):
Water consumption was comparable in control and treated groups
Description (incidence and severity):
No treatment related ocular lesions.
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
Treated and control groups were comparable. A slight increase (95% confidence *) in neutrophils with rod-like bodies (mid dose males), a marginal decrease in thrombocytes (top dose males) and eosinophils (top dose females) were not considered of biological significance.
Thrombocytes:
Control low mid high
male 633.9 619.9 583.9 511.9*

Eosinophils:
female 1.3 0.8 0.9 0.3**
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
There were some statistically significant changes (p=0.05) in clinical chemical parameters in the top dose group. In males ASAT was increased (control mean 33 U/L; top dose 45.1); Na was also increased (control mean 143.1 mmo/L; top dose 144.4). Serum chloride was reduced (control mean 99.7 mmol/L; top dose 97.9). In females there was an increase in Na (control mean 142 mmol/L; top dose 143) and in phosphorous (control mean 1.99 mmol/L; top dose 21.9. These changes are not clearly dose related and apart from the slight increase in serum sodium do not appear in both sexes. There are no histopathological changes related to these changes which were considered chance observations and not indicative of a trend.
Urinalysis findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
Sporadic changes in absolute or relative organ weights relative weights were not dose and/or sex related. There was no corresponding histopathological change. Relative heart weights were increased* in top dose males, Relative and absolute kidney weights were decreased* in mid-dose females, while other absolute organ weights were changed as follows:

Absolute mean spleen weight:
Control low mid high
male 0.706 0.651 0.585* 0,593*

Absolute mean thyroid weight:
Control low mid high
male 0.024 0.018** 0.02 0.018**

Absolute mean spleen weight:
Control low mid high
male 0.706 0.651 0.585* 0.593*

Relative mean heart weight:
Control low mid high
male 0.281 0.288 0.302 0.314*
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
Pathological changes observed were related to misdosing, respiratory infection or viral infection.
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
Statistically significant changes in some clinical chemical and haematological parameters and organ weights changes were not accompanied by histopathological changes and were either not dose related or appeared in only one sex. These effects are not considered of toxicological significance.
Histopathological findings: neoplastic:
not examined
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: based on a lack of toxicologically significant effects.
Critical effects observed:
no
Conclusions:
NOAEL for this study is considered to be >1000 mg/kg/day based on a lack of toxicologically significant effects. Statistically significant changes in some clinical chemical and haematological parameters and organ weights changes were not accompanied by histopathological changes and were either not dose related or appeared in only one sex. These effects are not considered of toxicological significance.
Executive summary:

Lanette 18 in olive oil was administered to 10 male and female Sprague-Dawley rats (and 5 males and females per dose level for reversibility) by oral gavage 5 days/week for 27-28 days in a subacute repeated dose toxicity study similar to OECD TG 407. The rats were dosed at 100, 500 and 1000 mg/kg bw/day; control animals were dosed with vehicle. The reversibility group was observed 28 days after dosing.

Mortality and clinical signs were observed daily; body weight and food consumption were observed weekly. Ophthalmologic examination was performed at the end of the study. Haematology and clinical chemistry were examined after 21/22 daily doses. Organs weights were recorded for thyroid, adrenals, thymus, kidney, spleen, heart, brain, testes, liver.

No mortality was observed at any dose level.

Clinical signs were unremarkable.

Male body weight gain was reduced compared to controls, body weight gains were 95%, 91% and 82% of control values for low, mid and high dose levels respectively at the end of the study. This was attributed to a high mean control bodyweight in males and marked inhibition of bodyweight gain in one male in each of the high and mid dose levels.

Water consumption was comparable in control and treated groups.

Food consumption was slightly reduced in males (95% confidence).

There were no treatment related ocular lesions.

There were some statistically significant changes( p=0.05) in clinical chemical parameters in the top dose group. In males ASAT was increased (control mean 33 U/L; top dose 45.1); Na was also increased (control mean 143.1 mmol/L; top dose 144.4). Serum chloride was reduced (control mean 99.7 mmol/L; top dose 97.9). In females there was an increase in Na (control mean 142 mmol/L; top dose 143) and in phosphorous (control mean 1.99 mmol/L top dose 21.9). These changes are not clearly dose related and apart from the slight increase in serum sodium do not appear in both sexes. There were no histopathological changes related to these changes which were considered chance observations and not indicative of a trend.

Haematology in treated and control groups was comparable. A slight increase (95% confidence *) in neutrophils with rod-like bodies (mid dose males), a marginal decrease in thrombocytes (top dose males) and eosinophils (top dose females) were not considered of biological significance.

Sporadic changes in absolute or relative organ weights relative weights were not dose and/or sex related. There was no corresponding histopathological change. Relative heart weights were increased in top dose males, relative and absolute kidney weights were decreased in mid-dose females.

NOAEL was considered to be >1000 mg/kg/day based on a lack of toxicologically significant effects. Statistically significant changes in some clinical chemical and haematological parameters and organ weights changes were not accompanied by histopathological changes and were either not dose related or appeared in only one sex. These effects are not considered of toxicological significance.

(Reference:

-Henkel KGaA. 1986a. Lannette 18: 28-Tage-Test mit wiederholter oraler Verabreichung an Ratten.Report No.TBD 860071. Institut fur Toxikologie. With pathology report No. 84023.

-Henkel KGaA. 1999. Octadecanol: Evaluation of repeated dose oral toxicity. Unpublished data, English summary and evaluation of Report No. TBD 860071).

 

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1960
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Qualifier:
according to guideline
Guideline:
other: not specified
GLP compliance:
no
Specific details on test material used for the study:
Sodium Sulfate was obtained as anhydrous powder from Merck, A.C.S.
Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: weanling, young
- Diet (e.g. ad libitum): ad libitum
Route of administration:
oral: feed
Vehicle:
other: Basal diet, cornstarch diet, 67% cornstarch, 24% 'vitamin free' casein, 5% crisco (cristalized cottonseed oil) and 4% salt mixture (3.8% magnesium sulfate, anhydrous and 0.02% maganous sulfate. No sodium sulfate.) and vitamins.
Details on oral exposure:
Total volume applied: the feed intake in week 4 of the rats receiving sodium sulfate is presented: 408 (371-453) g.
Duration of treatment / exposure:
4 weeks
Frequency of treatment:
diets were provided ad libitum for 4 weeks
Dose / conc.:
0.88 other: mmol/kg feed
Remarks:
Experiment A
Dose / conc.:
8.64 other: mmol/kg feed
Remarks:
Day 1-8 (experiment B)
Dose / conc.:
17.28 other: mmol/kg feed
Remarks:
day 9-16 (experiment B)
Dose / conc.:
34.56 other: mmol/kg feed
Remarks:
day 17-24 (experiment B)
Dose / conc.:
65.12 other: mmol/kg feed
Remarks:
day 24 for 4-6 days (experiment B)
Dose / conc.:
138 other: mmol/kg feed
Remarks:
experiment C
No. of animals per sex per dose:
6
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale:
Experiment a 0.88 mmol/kg feed
Experiment b 8.64 mmol/kg feed day 1-8
17.28 mmol/kg feed day 9-16
34.56 mmol/kg feed day 17-24
65.12 mmol/kg feed day 25 for 4-6 days
Experiment c 138 mmol/kg feed
Observations and examinations performed and frequency:
DETAILED CLINICAL OBSERVATIONS: Yes.
Records of any diarrhea that occurred were kept. In experiment c teeth were examined.

BODY WEIGHT: Yes
- Time schedule for examinations: at the beginning of the study, at the end of each week and just before study termination.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Feed intakes and feed:gain ratios were obtained for each week.

FOOD EFFICIENCY: Food conversion efficiency: yes

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study):
-In experiment c the amount of water drunk during the first 48 h of the third week was recorded.

OPHTHALMOSCOPIC EXAMINATION: -

HAEMATOLOGY: Yes
- Time schedule for collection of blood: In experiment c blood was collected from the tail after 3.5 weeks for red and white bloodcell counts and
hemoglobin was determined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At termination of the study blood was collected from the neck vain and analyzed for alkaline phosphate, inorganic phosphate and protein.

URINALYSIS: Yes
-In experiment c the volume of urine was determined.


Sacrifice and pathology:
GROSS PATHOLOGY: Yes , gastrointestinal organs were examined. The small intestine and colon plus rectum were hung full length were measured. Organs were cleaned, dried and weighed.

HISTOPATHOLOGY: Yes, In experiment c a small snip of the stomach was removed for histological examination.
Statistics:
In experments b and c the numerical results were analyzed statistically by analysis of variance, the hypothesis in every case being that the groups were equal. A multiple range test was performed when it was indicated that there was a difference among the groups at the 5% level or less, results were significantly different if P<0.05.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Data for experiment a are not presented in the article because at this low dose level no effects were seen.
Experiment c teeth: no changes compared with control group.
Two slight cases of diarrhea that lasted for a day were observed in experiment b in the sodium sulfate group.
One rat in experiment c showed diarrhea on 4 different days (3 consecutive days) in the middle of the feeding period.
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Data for experiment a are not presented in the article because at this low dose level no effects were seen.
Experiment b and c: no changes compared with control group.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Experiment c: no changes compared with control group.
Haematological findings:
no effects observed
Description (incidence and severity):
Experiment c: no changes compared with control groups or other dose groups in red or white blood cell counts, hemoglobin
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
Experiment c: no changes compared with control groups or other dose groups in protein, alkaline phosphatase or inorganic phosphate.
Urinalysis findings:
no effects observed
Description (incidence and severity):
Experiment c urine volume: no changes compared with control groups or other dose groups.
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
Experiment b and c: no changes compared with control group.
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Dose descriptor:
NOAEL
Effect level:
ca. 2 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: Limit dose
Remarks on result:
other: At the top dose, the food contained around 2% of the respective sulfates, calculated to be around 2000 mg/kg/d.
Critical effects observed:
no
Conclusions:
NOAEL (NOEL), LOAEL (LOEL): At the top dose, the food contained around 2% of the respective sulfates, calculated to be around 2000 mg/kg/d.
Executive summary:

The IUCLID data set of Na2SO4 (CAS 7757 -82 -6) in the OECD SIDS INITIAL ASSESSMENT PROFILE of Sodium sulfate describes the following Klimisch 2 study.

Groups op 6 male Sprague-Dawley rats were dosed by diet for 4 weeks. In experiment A the rats received the dose of 0.88 mmol/kg feed, in experiment B the rats received 8.64 mmol/kg feed during the days 1-8; 17.28 mmol/kg feed during the days 9-19; 34.56 mmol/kg feed during the days17-24 and 65.12 mmol/kg feed on day 25 for 4-6 days and in experiment C the rats received 138 mmol/kg feed. Clinical signs were observed, records of any diarrhea that occurred were kept. In experiment C teeth were examined. Body weights were observed at the beginning of the study, at the end of each week and just before study termination. Feed intakes and feed:gain ratios were obtained for each week. In experiment C the amount of water drunk during the first 48 h of the third week was recorded. In experiment C blood was collected from the tail after 3.5 weeks for red and white blood cell counts and hemoglobin was determined. At termination of the study blood was collected from the neck vain and analyzed for alkaline phosphatase, inorganic phosphate and protein. In experiment C the volume of urine was determined. Gastrointestinal organs were examined. The small intestine and colon plus rectum were hung full length were measured. Organs were cleaned dried and weighed. In experiment C a small snip of the stomach was removed for histological examination.

No mortality was observed. The clinical signs, the body weight, the food and water consumption were unremarkable, except slight diarrhoea in one animal for a few days. There were no changes in hematology and urine production.

At the top dose, the food contained around 2% of the respective sulfates, calculated to be around 2000 mg/kg/ bw/day. NOAEL was ca. 2000 mg/kg bw/day.

 

Reference: Moinuddin, J.F., Wing-Tsit Lee, H., (1960) Alimentary, blood and the other changes due to feeding MnSO4, MgSO4 and Na2SO4. American Journal of Physiology. 199(1): 77-83.

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Dose descriptor:
NOAEL
Effect level:
602 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
organ weights and organ / body weight ratios
Conclusions:
When the NOAEL of the target substance was calculated by concentration addition based on the general equation as presented in the CLP regulation on mixtures (2008), based on NOAEL values of the components (C16 and C18 LCOH, C12 AS as worst case, sodium sulfate), this resulted in an oral systemic NOAEL of 602 mg/kg bw in rats. It can therefore be concluded that the oral systemic NOAEL of the registered substance is 602 mg/kg bw. Target organ based on the subacute and subchronic rat toxicity study in rats of the major LCOH C16 fraction is the liver (reversible weight increase).
Executive summary:

When the NOAEL of the target substance was calculated by concentration addition based on the general equation as presented in the CLP regulation on mixtures (2008), based on NOAEL values of the components (C16 and C18 LCOH, C12 AS as worst case, sodium sulfate), this resulted in an oral systemic NOAEL of 602 mg/kg bw in rats. It can therefore be concluded that the oral systemic NOAEL of the registered substance is 602 mg/kg bw. Target organ based on the subacute and subchronic rat toxicity study in rats of the major LCOH C16 fraction is the liver (reversible weight increase).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
602 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Reliable, based on various studies
System:
hepatobiliary
Organ:
liver

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available
Organ:
liver

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

No extra testing was performed as literature data were available as weight-of-evidence for the various components of the registered substances. A selection of most reliable sources (Klimisch 1-2) was made.

Oral:

Various literature data were available in rats and dogs for the long chain alcohols (LCHO) with chain length between C16 and C18, as summarised below.

-      For LCOH 16 (1-Hexadecanol; CAS 36653-82-4) a 28-day subacute toxicity study in rats treated by oral gavage for 27-28 days at doses levels of 1000, 500 and 1000 mg/kg resulted in a NOAEL >1000 mg/kg bw (SIDS, 2006; Henkel, 1985a; Henkel 1999). A 13 week dietary subchronic toxicity study in rats dosed at 1.0, 2.5 and 5% (increased to 7.5% in week 11 and 10% in weeks 12-13) resulted in a NOAEL of ca. 750 (males 723, females 875) mg/kg bw; observed changes in organ weights in the absence of histopathological changes, was questionable; increased liver weights at higher dose levels may be indicative of a mild adaptive effect (SIDS, 2006; IUCLID 2000; Scientific Associates, Inc., 1996a). A 13 week dietary subchronic toxicity study in dogs dosed at 0.5, 1.0 and 3.0% resulted in a NOAEL of >1175 mg/kg bw for males and >1054 mg/kg/day for females, corresponding with highest dose level tested (3% in diet). Elevated ALAT (liver enzyme) values seen at 13 weeks in most test animals at all dose levels were apparently not dose related or accompanied by histopathological liver change: other markers of liver function appeared normal. (SIDS, 2006; IUCLID 2000; Scientific Associates, Inc., 1996b).

-      For LCOH 18 (1-Octadecanol; CAS 112-925) a 90-day subchronic study in rats treated by oral gavage for 27-28 days at doses levels of 1000, 500 and 1000 mg/kg resulted in a NOAEL >1000 mg/kg bw (SIDS 2006; Henkel, 1985a; Henkel 1999). In a combined repeated dose and reproductive screening study, rats treated in the diet for 45 days (males) and ca. 54 days (females) the only systemic effects seen were significant changes in plasma free cholesterol, triglycerides and glucose, however they were not dose related. Although the reduction in plasma triglycerides levels may be indicative of mild effects in the liver, the differences in the composition of the test diets may have confounded these results. The NOAEL was 2000 mg/kg/day with a NOEL of 100 mg/kg/day (SIDS 2006; Hansen, 1992b).

For the alkyl sulfates (AS), there were no data for the C14-C20 chain lengths, however literature data were available for the C12 chain length. The C12 AS can be considered as a worst case substance.

-      For C12-Alkylsulfate (CAS 151-21-3) a 28-day subacute toxicity study in rats treated 0, 30, 100, or 300/600 mg/kg bw/day (ca. 0, 27, 90 or 270/540 mg active substance/kg bw) with reversibility group for 28 days resulted in a NOAEL<100 mg/kg bw based on following findings at the higher dose levels:mortality , reduced feed intake and weight gain, haematological and serum chemistry changes, changed relative weights of adrenals, kidney, brain, gonads and liver, and ulcerations and bleedings in the stomach, alterations of the tongue and myocard (fully reversible within 29 days) and fore stomach (partially reversible within 29 days) (SIDS, 2007; Henkel, 1987).

For the sodium sulfate, literature data were available:

-      For sodium sulfate (CAS 151-21-3) a 28-day subacute toxicity test was done in rats dosed at 30, 100, 300/600 mg/kg bw per day), followed by a 29-day recovery period. No adverse effects were noted at 100 mg/kg bw. At 300/600 mg/kg bw mortality increased (1 male and 1 female), food consumption and weight gain decreased and water intake increased, haematocrit and MCV levels decreased whereas (neutrophil) leucocytes and serum ALT increased, relative thymus weights decreased whereas relative weights of adrenals, kidney, brain, gonads and liver increased. Ulcerations and bleedings in the stomach, alterations of the tongue and myocard (fully reversible within 29 days) and for stomach (partially reversible within 29 days) were seen. NOAEL was 100 mg /kg bw (SIDS 2005; Henkel, 1987).

Inhalation & dermal routes for repeated dose toxicity (short term) are waived because inhalation is not likely and the oral route is most appropriate.

Conclusion:

When the NOAEL of the target substance was calculated by concentration addition based on the general equation as presented in the CLP regulation on mixtures (2008), based on NOAEL values of the components (C16 and C18 LCOH, C12 AS as worst case, sodium sulfate), this resulted in an oral systemic NOAEL of 602 mg/kg bw in rats. It can therefore be concluded that the oral systemic NOAEL of the registered substance is 602 mg/kg bw. Target organ based on the subacute and subchronic rat toxicity study in rats of the major LCOH C16 fraction is the liver (reversible weight increase).

Justification for classification or non-classification

Based on these results and according to CLP (No. 1272/2008 of 16 December 2008), the registered substance does not have to be classified and has no obligatory labelling requirement for repeated dose toxicity.