Registration Dossier

Oral repeated dose toxicity
The NOAEL for 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.
In view of the structural and chemical similarities, it is considereed that the results of the study can be used for read-across to Alcohols, C16-18.
Dermal repeated dose toxicity
A 90-day dermal toxicity study in rats with fatty alcohol blend (56.7% decanol, 42.7% octanol) at dose levels of 0, 100, 300, or 1,000 mg/kg resulted in severe irritation at the application site. Severe irritation including fissuring of the skin occurred in 40% of the animals at 100 mg/kg/day and 80% of the animals at the limit dose. Slight changes in hematology, clinical chemistry, and organ weights were noted at the limit dose of 1,000 mg/kg/day.
NOAEL has been based on a local irritation effect rather than a systemic effect. Therefore it is proposed (by the author of the EPSR) that on the basis of a lack of systemic effects reported in the study, the NOAEL following dermal administration of fatty alcohol blend for a minimum of 90 days is greater than 1000 mg/kg/day.
Inhalation repeated dose toxicity
Under the conditions of the test no treatment-related toxic effects were found in male and female Wistar rats which were exposed to 2-ethylhexanol vapor up to 120 ppm ie. 638.4 mg/m³ . (Klimisch HJ; Deckardt K; Gembardt C; Hildebrand B,1998).The substance Alcohols, C16-18, the subject of this dossier) is expected to exhibit very similar toxicity due to its close structural similarity to 2-ethylhexanol.Comparable metabolism would occur. Correcting for molecular weight, a conservative NOAEC of 1188.79 mg/m3 can be derived (638.4 x 242.45) / 130.2 =1188.79 mg/m3

Toxic effect type:

dose-dependent

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Justification for type of information:

Alcohols, C16-18 is a member and is from Long Chain Alcohols (C6-22 primary aliphatic alcohols) category.
The Long Chain Alcohols (C6-22 primary aliphatic alcohols) category is considered suitable as a source of data for Alcohols, C16-18.
Considered valid for read-across for purposes of classification.
No further vertebrate testing can be justified.

Long Chain Alcohols (C6-22 primary aliphatic alcohols) category covers a family of 30 primary aliphatic alcohols within a carbon chain length range of C6-C22. Commercial products generally include several aliphatic alcohol components, with a range of carbon chain lengths present. The family consists of alcohols with varying compositions and structures. Composition depends on the route to manufacture and the related feedstocks. Most of the alcohols have linear carbon chains but certain manufacturing processes create branched structures. Data are also available for eleven other similar substances, which support the category. Non-sponsored alcohols may not be HPV or may not be produced by members of the consortium, but have structures similar to sponsored linear alcohols.

Key points are that the members share:
• The same structural features
• Similar metabolic pathways
• Common mode of ecotoxicological action
• Common levels and mode of human health related effects.

Reason / purpose for cross-reference:

read-across: supporting information

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:

Rats treated via the diet for 90 days with limited evaluation

GLP compliance:

not specified

Remarks:

Pre-dates widespread introduction of GLP Data set considered valid

Limit test:

no

Species:

rat

Strain:

other: albino

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories Inc.
- Age at study initiation: no data but "young"
- Weight at study initiation: males 104.1 g, females 90.5 g
- Fasting period before study: no data
- Housing: individually in suspended wire-mesh cages
- Diet (e.g. ad libitum): Purina Laboratory Chow, ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data but "controlled within narrow limits"
- Humidity (%): no data but "controlled within narrow limits"
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data

IN-LIFE DATES: no data

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

DIET PREPARATION
- Rate of preparation of diet (frequency): weekly
- Mixing appropriate amounts with (Type of food): basal laboratory diet (Purina Laboratory Chow)
- Storage temperature of food: no data

Analytical verification of doses or concentrations:

yes

Remarks:

At least weekly checks to confirm stability and achieved concentrations

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

continuous in diet

Dose / conc.:

4 257 mg/kg bw/day (actual dose received)

Remarks:

5%

Dose / conc.:

1 822 mg/kg bw/day (actual dose received)

Dose / conc.:

723 mg/kg bw/day (actual dose received)

Remarks:

1%

No. of animals per sex per dose:

10 (treated), 20 (controls)

Control animals:

yes, plain diet

Details on study design:

- Dose selection rationale: no data
- Rationale for animal assignment (if not random): no data
- Rationale for selecting satellite groups: no satellite groups

Positive control:

none

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: 5 days/week
- Cage side observations included: general physical appearance, gross signs of systemic toxicity and/or pharmacological effect, behaviour, mortality

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Time schedule for examinations: weekly
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as mg/kg bw/day: Yes

FOOD EFFICIENCY: No

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: days 30 and 90
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: 5/sex per group
- Parameters examined: microhaematocrit, haemoglobin, total and differential leukocyte count

CLINICAL CHEMISTRY: No

URINALYSIS: Yes
- Time schedule for collection of urine: days 30 and 90
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- How many animals: 5/sex per group (samples pooled)
- Parameters examined: albumin, acetone, bilirubin, colour, occult blood, sugar, pH, appearance, microscopic examination of sediment

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes

ORGAN WEIGHTS: brain, thyroid, heart, liver, spleen, kidneys, adrenals, gonads (testes or ovaries)

HISTOPATHOLOGY: Yes
- brain, thyroid, parathyroid, heart, lung, liver, spleen, stomach, small intestine, large intestine, pancreas, kidney, urinary bladder, adrenal, gonad, lymph node, bone, bone marrow
- all listed tissues from 5/sex from high dose and controls examined

Other examinations:

none

Statistics:

Chi-squared test for comparing relative organ weights. Original organ weight analyses using the Chi square test were supplemented by Tukey tests carried out by the Weinberg group (see 'Any other information on materials and methods')

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

not examined

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not examined

Details on results:

CLINICAL SIGNS AND MORTALITY
- all animals survived the 13 week treatment period.
- all surviving animals appeared normal

BODY WEIGHT AND WEIGHT GAIN
- 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)
- 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).

FOOD EFFICIENCY
- no data

WATER CONSUMPTION
- not examined

OPHTHALMOSCOPIC EXAMINATION
- not examined

HAEMATOLOGY
- no effects

CLINICAL CHEMISTRY
- not examined

URINALYSIS
- no effects

NEUROBEHAVIOUR
- not examined

ORGAN WEIGHTS
- the original report indicated 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 (see 'Remarks on results' section)

GROSS PATHOLOGY
- unremarkable

HISTOPATHOLOGY: NON-NEOPLASTIC
- there were no treatment related histopathological changes in the control and top dose animals examined (including testes & ovaries).

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
- not applicable

HISTORICAL CONTROL DATA (if applicable)
- no data

Dose descriptor:

NOAEL

Effect level:

> 4 257 mg/kg bw/day (nominal)

Based on:

other: based on highest dose tested.

Sex:

male

Basis for effect level:

other: see 'Remark'

Dose descriptor:

NOAEL

Effect level:

> 4 567 mg/kg bw/day (nominal)

Based on:

other: based on highest dose tested.

Sex:

female

Basis for effect level:

other: see 'Remark'

Dose descriptor:

NOAEL

Effect level:

723 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: based on the reductions in body weight gain and food consumption

Dose descriptor:

NOAEL

Effect level:

875 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: based on the reductions in body weight gain and food consumption

Dose descriptor:

NOAEL

Effect level:

750 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: 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.

Critical effects observed:

not specified

In a 13-week study in rats1-hexadecanol was administered in the diet at concentrations of 0 (control), 1, 2.5 or 5%; the level in the highest dose group being increased stepwise to 10% during the last 3 weeks of the study. Reductions in body weight gain (82-90% of control values) and food consumption (76 – 90% of control values) in the highest dose group and, occasionally, at the 2.5% level were the main findings of this study. Relative liver weights were increased in males at the top dose level (124% of control values) but in the absence of any microscopic findings the significance of this change is uncertain. A NOAEL was established at a dietary concentration of 1% (equivalent toca.750 mg/kg/day) based on the reductions in body weight gain and food consumption

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.
In view of the structural and chemical similarities, it is considereed that the results of this study can be used for read-across to Alcohols, C16-18.

Executive summary:

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.

In view of the structural and chemical similarities, it is considereed that the results of this study can be used for read-across to Alcohols, C16-18.

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

750 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Reference

Endpoint:: short-term repeated dose toxicity: inhalation
Type of information:: experimental study
Adequacy of study:: key study
Reliability:: 2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:: guideline study with acceptable restrictions
Justification for type of information:: Alcohols, C16-18 is a member and is from Long Chain Alcohols (C6-22 primary aliphatic alcohols) category.
The Long Chain Alcohols (C6-22 primary aliphatic alcohols) category is considered suitable as a source of data for Alcohols, C16-18.
Considered valid for read-across for purposes of classification.
No further vertebrate testing can be justified.

Long Chain Alcohols (C6-22 primary aliphatic alcohols) category covers a family of 30 primary aliphatic alcohols within a carbon chain length range of C6-C22. Commercial products generally include several aliphatic alcohol components, with a range of carbon chain lengths present. The family consists of alcohols with varying compositions and structures. Composition depends on the route to manufacture and the related feedstocks. Most of the alcohols have linear carbon chains but certain manufacturing processes create branched structures. Data are also available for eleven other similar substances, which support the category. Non-sponsored alcohols may not be HPV or may not be produced by members of the consortium, but have structures similar to sponsored linear alcohols.

Key points are that the members share:
• The same structural features
• Similar metabolic pathways
• Common mode of ecotoxicological action
• Common levels and mode of human health related effects.
Reason / purpose for cross-reference:: read-across: supporting information
Qualifier:: according to guideline
Guideline:: OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
GLP compliance:: yes
Limit test:: no
Species:: rat
Strain:: Wistar
Sex:: male/female
Details on test animals or test system and environmental conditions:: TEST ANIMALS
- Source: Dr. K. Thomae GmbH, Biberach, Germany
- Age at delivery: 7 weeks
- Weight at study initiation: males 238 (+/- 2.3) g; females 238 (170 +/- 2.2) g
- Housing: singly in wire cages
- Diet: e.g. ad libitum
- Water: ad libitum
- Acclimation period: at least 5 days acclimation to the inhalation chamber

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24°C
- Humidity (%): 30-70%
- Photoperiod (hrs dark / hrs light): 12 hrs light/dark

IN-LIFE DATES: From: day1 To: day 93
Route of administration:: inhalation
Type of inhalation exposure:: whole body
Vehicle:: other: unchanged (no vehicle)
Details on inhalation exposure:: GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: whole-body inhalation chamber (glas/steel construction, volumes approx. 1.1 m³)
- Method of holding animals in test chamber: rats were kept individually in wire cages
- Test atmosphere generation: the test substance was delivered to heated evaporators by mean of metering pumps. The warmed air was mixed with compressed air and delivered to teh inhalation chamber.
- Source and rate of air: compressed air; variable rate
- Temperature, humidity, pressure in air chamber: 23.1 to 23.8°C; positive pressure 10.1 Pascal (ciontrol groups), negative pressure -10.2 Pascal (treated groups); 41.8 to 46.2% relative humidity
- Air flow rate: not reported in publication
- Air change rate: not reported in publication
- Treatment of exhaust air: not reported in publication
TEST ATMOSPHERE
- Brief description of analytical method used: samples were analyzed at intervals of about 15 min by gas chromatography (GC-FID; column 1mx22 mm with 10% Triton x 305 on Supelcoport, 102/120 mesh; oven temperature 120 °C; c15-paraffin as internal standard)
- Samples taken from breathing zone: yes
Analytical verification of doses or concentrations:: yes
Details on analytical verification of doses or concentrations:: Samples were analyzed at intervals of about 15 min by gas chromatography (GC-FID; column 1mx22 mm with 10% Triton x 305 on Supelcoport, 102/120 mesh; oven temperature 120 °C; c15-paraffin as internal standard)
Duration of treatment / exposure:: 90 days
Frequency of treatment:: 6 hours/day, 5 days/week (total of 65 exposures)
Remarks:: Doses / Concentrations:
0, 15, 40 and 120 ppm
Basis:
nominal conc.
Remarks:: Doses / Concentrations:
15 (SD 0.67), 39.9 (SD 1.33), 120 (SD 4.8) ppm
Basis:
analytical conc.
No. of animals per sex per dose:: 10
Control animals:: yes
Details on study design:: Post-exposure period: none
Positive control:: not required
Observations and examinations performed and frequency:: CAGE SIDE OBSERVATIONS:
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: yes
- Time schedule: pre-treatment and at termination

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION:
- Food consumption: no data contained in the publication; not required

FOOD EFFICIENCY:
- Body weight gain: yes, but no data contained in the publication; not required
WATER CONSUMPTION: no data contained in the publication; not required

OPHTHALMOSCOPIC EXAMINATION: yes
- Time schedule for examinations: pre-treatment and at termination
- Dose groups that were examined: all animals

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at termination, day 94 of the study
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: all animals
- Parameters: white and red blood cells, hemoglobin, hematocrit, mean corpuscular volume. mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelets, differential blood count
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at termination, day 94 of the study
- Animals fasted: No data
- How many animals: No data
- Parameters: sodium, potassium, chloride, glucose, inorganic phosphate, calcium, urea, creatinine, glucose, total bilirubin, total protein, albumin, globulins, triglycerides, cholesterol, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, clotting time

URINALYSIS: No data

OTHER:
- cyanide-insensitive palmitoyl-CoA oxidation in liver homogenates
- gross pathology of all animals at termination; determination of organ weights (lungs, liver, kidneys, adrenal glands, and testes)
- histopathology of organs/tissues required by guidelines, and all gross lesions
Sacrifice and pathology:: GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Statistics:: - Mean values +/- standard deviation: body weight, body weight gain, hematological and clinical biochemistry parameters, absolute and relative organ weights.
Dunnett's test: comparison of exposure groups with the control group.
Analysis of variance subsequent to Dunnett's test: body weight, body weight gain, hematological and clinical biochemistry parameters
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):: no effects observed
Food efficiency:: no effects observed
Water consumption and compound intake (if drinking water study):: no effects observed
Ophthalmological findings:: no effects observed
Haematological findings:: no effects observed
Clinical biochemistry findings:: no effects observed
Urinalysis findings:: not specified
Behaviour (functional findings):: not specified
Organ weight findings including organ / body weight ratios:: no effects observed
Gross pathological findings:: no effects observed
Histopathological findings: non-neoplastic:: no effects observed
Histopathological findings: neoplastic:: no effects observed
Details on results:: 1) Analysis of the daily inhalation chamber concentrations revealed that the values obtained closely fitted with the desired nominal level

2) There were no effects regarding the issues below noted at any dose level:

CLINICAL SIGNS AND MORTALITY

BODY WEIGHT AND WEIGHT GAIN

FOOD CONSUMPTION
FOOD EFFICIENCY

WATER CONSUMPTION

OPHTHALMOSCOPIC EXAMINATION

HAEMATOLOGY

CLINICAL CHEMISTRY

URINALYSIS

NEUROBEHAVIOUR
ORGAN WEIGHTS

GROSS PATHOLOGY

HISTOPATHOLOGY: NON-NEOPLASTIC

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
Dose descriptor:: NOAEC
Effect level:: 120 ppm
Based on:: test mat.
Sex:: male/female
Basis for effect level:: other: overall effects
Dose descriptor:: NOAEC
Effect level:: 638.4 mg/m³ air (analytical)
Based on:: test mat.
Sex:: male/female
Basis for effect level:: other: overall effects
Dose descriptor:: NOAEC
Effect level:: 1 188.79 mg/m³ air (analytical)
Based on:: test mat.
Sex:: male/female
Basis for effect level:: other: Correcting for molecular weight, a conservative NOAEC of 1188.79 mg/m3 can be derived (638.4 x 242.45) / 130.2 =1188.79 mg/m3
Critical effects observed:: not specified
Conclusions:: Under the conditions of the test no treatment-related toxic effects were found in male and female Wistar rats which were exposed to 2-ethylhexanol vapor up to 120 ppm ie. 638.4 mg/m³ .
Correcting for molecular weight, a conservative NOAEC of 1188.79 mg/m3 can be derived
(638.4 x 242.45) / 130.2 =1188.79 mg/m3
Executive summary:: No treatment-related effects were noted in a OECD Guideline 413 study (Subchronic Inhalation Toxicity: 90-Day) using male and female Wistar rats (10 rats per sex and dose). Exposure levels were 0, 15, 40, and 120 ppm (120 ppm is equivalent to saturation at 20°C). As there were no effects compared with the control groups in either sex on body weight or body weight gain, clinical signs of toxicity and mortality, hematological and clinical biochemistry parameters, ophthalmological parameters, absolute or relative organ weights including testes, or cyanide-insensitive palmitoyl-CoA oxidation as a parameter for hepatic peroxisome proliferation, the NOAEC was 120 ppm, ie. 638.4 mg/m³ (Klimisch, 1998).

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

1 188.79 mg/m³

Study duration:

subacute

Species:

rat

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

32.6 mg/m³

Study duration:

subacute

Species:

rat

Quality of whole database:

Inhalation exposure:
There are no reliable Inhalation Repeated studies available for local effects.
The oral dose for the rat is converted to the corresponding air concentration using a standard breathing volume for the rat (1.15 m3/kg for 24 hours exposure. The resulting air concentration needs to be additionally corrected for 24 hlight activity (20 m3), assuming 100 % absorption for both routes.
NOAEL rat
750 mg/kg bw/day
÷1.15 m3/kgbw
÷20m3/rat
NOAECrat 32.6 mg/m3

Reference

Endpoint:

chronic toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Justification for type of information:

Alcohols, C16-18 is a member and is from Long Chain Alcohols (C6-22 primary aliphatic alcohols) category.
The Long Chain Alcohols (C6-22 primary aliphatic alcohols) category is considered suitable as a source of data for Alcohols, C16-18.
Considered valid for read-across for purposes of classification.
No further vertebrate testing can be justified.

Long Chain Alcohols (C6-22 primary aliphatic alcohols) category covers a family of 30 primary aliphatic alcohols within a carbon chain length range of C6-C22. Commercial products generally include several aliphatic alcohol components, with a range of carbon chain lengths present. The family consists of alcohols with varying compositions and structures. Composition depends on the route to manufacture and the related feedstocks. Most of the alcohols have linear carbon chains but certain manufacturing processes create branched structures. Data are also available for eleven other similar substances, which support the category. Non-sponsored alcohols may not be HPV or may not be produced by members of the consortium, but have structures similar to sponsored linear alcohols.

Key points are that the members share:
• The same structural features
• Similar metabolic pathways
• Common mode of ecotoxicological action
• Common levels and mode of human health related effects.

Reason / purpose for cross-reference:

read-across: supporting information

Qualifier:

according to guideline

Guideline:

OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- 10 of each gender per test group and control group

Type of coverage:

semiocclusive

Vehicle:

other: 0.9% Sodium chloride (this was dosed to the control group at a dose volume of 1.2 ml/kg.

Details on exposure:

TEST SITE
- Area of exposure: dorsal skin

- Type of wrap if used: gauze binder, secured with tape

REMOVAL OF TEST SUBSTANCE
- Washing (if done): test article was removed from the application site with a wet paper towel

- Time after start of exposure: six hours

TEST MATERIAL - Control group
- Amount(s) applied (volume or weight with unit): 1.2 ml/kg

- Concentration (if solution): 0.9% saline

- Constant volume or concentration used: yes
TEST MATERIAL - Test groups(1-3)
- Amount(s) applied (volume or weight with unit): 100, 300 and 1000 mg/kg/day respectively

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

The application sites were wrapped for six hours with a gauze binder, secured with tape.

Frequency of treatment:

Application for five days a week over thirteen consecutive weeks to the shaved intact dorsal skin of each rat for a minimum of 65 applications.

Dose / conc.:

1 000 mg/kg bw/day (nominal)

Remarks:

Basis:
other: volume or weight with unit

Dose / conc.:

300 mg/kg bw/day (nominal)

Remarks:

Basis:
other: volume or weight with unit

Dose / conc.:

100 mg/kg bw/day (nominal)

Remarks:

Basis:
other: volume or weight with unit

No. of animals per sex per dose:

Control group: 20 rats (10 male and 10 female) which received 0.9% saline on a comparable regimen at a dose volume of 1.2 ml/kg.

Three test groups: 20 rats (10 males and 10 females) administered dosage levels of 100, 300 and 1000 mg/kg/day respectively.

Control animals:

yes, concurrent no treatment

Observations and examinations performed and frequency:

The animals were observed for signs of overt toxicity, dermal irritation, effects on body weight and consumption, haematology and serum chemistry parameters.

Sacrifice and pathology:

Complete necropsies were performed on all animals.

Other examinations:

Selected organs were weighed and a microscopic examination was conducted on selected tissues from all animals at the scheduled necropsy.

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Marked dermal irritation was noted in all dose groups and consisted of very slight to severe erythema, very slight to moderate edema, persistant desquamation, eschar, exfoliation, clear exudate and fissuring.

Dermal irritation:

effects observed, treatment-related

Description (incidence and severity):

Marked dermal irritation was noted in all dose groups and consisted of very slight to severe erythema, very slight to moderate edema, persistant desquamation, eschar, exfoliation, clear exudate and fissuring.

Mortality:

mortality observed, treatment-related

Description (incidence):

Marked dermal irritation was noted in all dose groups and consisted of very slight to severe erythema, very slight to moderate edema, persistant desquamation, eschar, exfoliation, clear exudate and fissuring.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

The mean body weights were lower in the middle and high dose groups compared to the control group. This was attributed to the test article.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Mean food consumption (evaluated as g/animal/day) was slightly but consistently decreased in the high dose group (males) during the first two thirds of the study period, and this was attributed to the test article.

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not specified

Description (incidence and severity):

No information provided

Ophthalmological findings:

not specified

Description (incidence and severity):

No test related ophthalmic lesions were present at the week 12 opthalmologic examinations.

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

Mean white blood cell counts were increased in a non dose related manner in all the test groups (not the control). This was attributed to the acute dermal inflammation that was observed.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

In the serum chemistry parameters albumin means were decreased and globulin means were increased (resulting in decreased A/G ratios). Again this was attributed to the acute dermal inflammation that was observed.

Urinalysis findings:

not specified

Description (incidence and severity):

No information provided

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

The adrenals, brain, kidneys, liver, ovaries and testes were weighed at necropsy. No remarkable statistically significant changes in organ weight were note for any of the organs, except for the adrenals.

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

No significant changes reported (except for the dermal application sites for all the dose groups)

Histopathological findings: neoplastic:

no effects observed

Description (incidence and severity):

No significant changes reported (except for the dermal application sites for all the dose groups)

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: on the basis of a lack of systemic effects reported in the study, the NOAEL following dermal administration of fatty alcohol blend for a minimum of 90 days is greater than 1000 mg/kg/day.

Critical effects observed:

not specified

Clinical signs

Vocalisation (due to pain) was the predominant sign observed in the high dose group (females) generally on one to three days most often during the second week of test article administration. Excessive struggling was also reported during exposure on single occasions for one male in the low dose group and two female in the high dose group. Hypersensitivity to touch was also reported on two separate occasions for a single high dose male.

Marked dermal irritation was noted in all dose groups and consisted of very slight to severe erythema, very slight to moderate edema, persistant desquamation, eschar, exfoliation, clear exudate and fissuring.

Organ weights

The adrenals, brain, kidneys, liver, ovaries and testes were weighed at necropsy. No remarkable statistically significant changes in organ weight were note for any of the organs, except for the adrenals which was most likely related to stress resulting from severe dermal irritation that was observed in all dose groups.

Macroscopic examination

The only test article related gross lesions observed included scabbing and thickening of the skin at the test site. (Irritant related effects). There were no other test article related gross findings at the scheduled necropsy.

Conclusions:

Based on the data that was reported a NOAEL following dermal administration of fatty alcohol blend for a minimum of 90 days was less than 100 mg/kg/day.
However the NOAEL has been based on a local irritation effect rather than a systemic effect. Therefore it is proposed (by the author of the EPSR) that on the basis of a lack of systemic effects reported in the study, the NOAEL following dermal administration of fatty alcohol blend for a minimum of 90 days is greater than 1000 mg/kg/day.

Executive summary:

A 90-day dermal toxicity study in rats with fatty alcohol blend (56.7% decanol, 42.7% octanol) at dose levels of 0, 100, 300, or 1,000 mg/kg resulted in severe irritation at the application site. Severe irritation including fissuring of the skin occurred in 40% of the animals at 100 mg/kg/day and 80% of the animals at the limit dose. Slight changes in hematology, clinical chemistry, and organ weights were noted at the limit dose of 1,000 mg/kg/day.

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Reference

Endpoint:

chronic toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Justification for type of information:

Alcohols, C16-18 is a member and is from Long Chain Alcohols (C6-22 primary aliphatic alcohols) category.
The Long Chain Alcohols (C6-22 primary aliphatic alcohols) category is considered suitable as a source of data for Alcohols, C16-18.
Considered valid for read-across for purposes of classification.
No further vertebrate testing can be justified.

Long Chain Alcohols (C6-22 primary aliphatic alcohols) category covers a family of 30 primary aliphatic alcohols within a carbon chain length range of C6-C22. Commercial products generally include several aliphatic alcohol components, with a range of carbon chain lengths present. The family consists of alcohols with varying compositions and structures. Composition depends on the route to manufacture and the related feedstocks. Most of the alcohols have linear carbon chains but certain manufacturing processes create branched structures. Data are also available for eleven other similar substances, which support the category. Non-sponsored alcohols may not be HPV or may not be produced by members of the consortium, but have structures similar to sponsored linear alcohols.

Key points are that the members share:
• The same structural features
• Similar metabolic pathways
• Common mode of ecotoxicological action
• Common levels and mode of human health related effects.

Reason / purpose for cross-reference:

read-across: supporting information

Qualifier:

according to guideline

Guideline:

OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- 10 of each gender per test group and control group

Type of coverage:

semiocclusive

Vehicle:

other: 0.9% Sodium chloride (this was dosed to the control group at a dose volume of 1.2 ml/kg.

Details on exposure:

TEST SITE
- Area of exposure: dorsal skin

- Type of wrap if used: gauze binder, secured with tape

REMOVAL OF TEST SUBSTANCE
- Washing (if done): test article was removed from the application site with a wet paper towel

- Time after start of exposure: six hours

TEST MATERIAL - Control group
- Amount(s) applied (volume or weight with unit): 1.2 ml/kg

- Concentration (if solution): 0.9% saline

- Constant volume or concentration used: yes
TEST MATERIAL - Test groups(1-3)
- Amount(s) applied (volume or weight with unit): 100, 300 and 1000 mg/kg/day respectively

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

The application sites were wrapped for six hours with a gauze binder, secured with tape.

Frequency of treatment:

Application for five days a week over thirteen consecutive weeks to the shaved intact dorsal skin of each rat for a minimum of 65 applications.

Dose / conc.:

1 000 mg/kg bw/day (nominal)

Remarks:

Basis:
other: volume or weight with unit

Dose / conc.:

300 mg/kg bw/day (nominal)

Remarks:

Basis:
other: volume or weight with unit

Dose / conc.:

100 mg/kg bw/day (nominal)

Remarks:

Basis:
other: volume or weight with unit

No. of animals per sex per dose:

Control group: 20 rats (10 male and 10 female) which received 0.9% saline on a comparable regimen at a dose volume of 1.2 ml/kg.

Three test groups: 20 rats (10 males and 10 females) administered dosage levels of 100, 300 and 1000 mg/kg/day respectively.

Control animals:

yes, concurrent no treatment

Observations and examinations performed and frequency:

The animals were observed for signs of overt toxicity, dermal irritation, effects on body weight and consumption, haematology and serum chemistry parameters.

Sacrifice and pathology:

Complete necropsies were performed on all animals.

Other examinations:

Selected organs were weighed and a microscopic examination was conducted on selected tissues from all animals at the scheduled necropsy.

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Marked dermal irritation was noted in all dose groups and consisted of very slight to severe erythema, very slight to moderate edema, persistant desquamation, eschar, exfoliation, clear exudate and fissuring.

Dermal irritation:

effects observed, treatment-related

Description (incidence and severity):

Marked dermal irritation was noted in all dose groups and consisted of very slight to severe erythema, very slight to moderate edema, persistant desquamation, eschar, exfoliation, clear exudate and fissuring.

Mortality:

mortality observed, treatment-related

Description (incidence):

Marked dermal irritation was noted in all dose groups and consisted of very slight to severe erythema, very slight to moderate edema, persistant desquamation, eschar, exfoliation, clear exudate and fissuring.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

The mean body weights were lower in the middle and high dose groups compared to the control group. This was attributed to the test article.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Mean food consumption (evaluated as g/animal/day) was slightly but consistently decreased in the high dose group (males) during the first two thirds of the study period, and this was attributed to the test article.

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not specified

Description (incidence and severity):

No information provided

Ophthalmological findings:

not specified

Description (incidence and severity):

No test related ophthalmic lesions were present at the week 12 opthalmologic examinations.

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

Mean white blood cell counts were increased in a non dose related manner in all the test groups (not the control). This was attributed to the acute dermal inflammation that was observed.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

In the serum chemistry parameters albumin means were decreased and globulin means were increased (resulting in decreased A/G ratios). Again this was attributed to the acute dermal inflammation that was observed.

Urinalysis findings:

not specified

Description (incidence and severity):

No information provided

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

The adrenals, brain, kidneys, liver, ovaries and testes were weighed at necropsy. No remarkable statistically significant changes in organ weight were note for any of the organs, except for the adrenals.

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

No significant changes reported (except for the dermal application sites for all the dose groups)

Histopathological findings: neoplastic:

no effects observed

Description (incidence and severity):

No significant changes reported (except for the dermal application sites for all the dose groups)

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: on the basis of a lack of systemic effects reported in the study, the NOAEL following dermal administration of fatty alcohol blend for a minimum of 90 days is greater than 1000 mg/kg/day.

Critical effects observed:

not specified

Clinical signs

Vocalisation (due to pain) was the predominant sign observed in the high dose group (females) generally on one to three days most often during the second week of test article administration. Excessive struggling was also reported during exposure on single occasions for one male in the low dose group and two female in the high dose group. Hypersensitivity to touch was also reported on two separate occasions for a single high dose male.

Marked dermal irritation was noted in all dose groups and consisted of very slight to severe erythema, very slight to moderate edema, persistant desquamation, eschar, exfoliation, clear exudate and fissuring.

Organ weights

The adrenals, brain, kidneys, liver, ovaries and testes were weighed at necropsy. No remarkable statistically significant changes in organ weight were note for any of the organs, except for the adrenals which was most likely related to stress resulting from severe dermal irritation that was observed in all dose groups.

Macroscopic examination

The only test article related gross lesions observed included scabbing and thickening of the skin at the test site. (Irritant related effects). There were no other test article related gross findings at the scheduled necropsy.

Conclusions:

Based on the data that was reported a NOAEL following dermal administration of fatty alcohol blend for a minimum of 90 days was less than 100 mg/kg/day.
However the NOAEL has been based on a local irritation effect rather than a systemic effect. Therefore it is proposed (by the author of the EPSR) that on the basis of a lack of systemic effects reported in the study, the NOAEL following dermal administration of fatty alcohol blend for a minimum of 90 days is greater than 1000 mg/kg/day.

Executive summary:

A 90-day dermal toxicity study in rats with fatty alcohol blend (56.7% decanol, 42.7% octanol) at dose levels of 0, 100, 300, or 1,000 mg/kg resulted in severe irritation at the application site. Severe irritation including fissuring of the skin occurred in 40% of the animals at 100 mg/kg/day and 80% of the animals at the limit dose. Slight changes in hematology, clinical chemistry, and organ weights were noted at the limit dose of 1,000 mg/kg/day.

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

5.62 mg/cm²

Study duration:

chronic

Species:

rat

Oral repeated dose toxicity

1. In a 13-week study in rats 1-hexadecanol (as a read across for Alcohols, C16-18) was administered in the diet at concentrations of 0 (control), 1, 2.5 or 5%; the level in the highest dose group being increased stepwise to 10% during the last 3 weeks of the study. Reductions in body weight gain (82-90% of control values) and food consumption (76 – 90% of control values) in the highest dose group and, occasionally, at the 2.5% level were the main findings of this study. Relative liver weights were increased in males at the top dose level (124% of control values) but in the absence of any microscopic findings the significance of this change is uncertain. A NOAEL was established at a dietary concentration of 1% (equivalent to ca.750 mg/kg/day) based on the reductions in body weight gain and food consumption (Scientific Assoc., 1966).

2. 1-Hexadecanol [CAS 36653-82-4] (as a read across for Alcohols, C16-18).In a 13-week study groups of 2 dogs/sex/dose received dietary concentrations of 0 (control), 0.5, 1.0 or 3% 1-hexadecanol. There no were adverse effects reported except for elevations of AST at week 13 at all incorporation levels, without evidence of a clear dose response relationship. The small groups sizes used in this study preclude a definitive conclusion about the significance of these changed enzyme levels, especially in the absence of any further corroborating evidence of liver toxicity (liver weight and histology). A NOAEL of 1000 mg/kg (highest dose tested) is therefore proposed (Scientific Assoc., 1966).

3. 1-Hexanol [CAS 111-27-3] (as a read across for Alcohols, C16-18). Rats exposed to 1-hexanol via the diet for 13 weeks showed no signs of significant toxicity when administered at nominal concentrations up to 1% (with staged increases at concentrations up to 6% during the last phase of the exposure period). There were no microscopic alterations recorded in the animals receiving concentrations of 1-6% (equivalent to 1127 mg/kg/day). Examination of testes and the ovaries did not show any abnormalities (Scientific Associates, 1966).

4. 1-Hexadecanol [CAS 36653-82-4] (as a read across for Alcohols, C16-18) was without toxic effects in a 28-day study in rats receiving daily oral [gavage] doses of 0 (control), 100, 500 and 1000 mg/kg/day (Henkel, 1985).

5.In a 4-week oral study1-octadecanol (as a read across forAlcohols, C16-18) was administered daily (5 times/week) in olive oil to groups of 10 male and female Sprague-Dawley rats at levels of 0 (control), 100, 500 and 1000 mg/kg/day. There were no adverse effects reported in this study during all stages of the study (Henkel, 1986).

6. C16-18 and C18 unsaturated alcohols [CAS 68002-94-8] (as a read across for Alcohols, C16-18) were without adverse effects in rats upon daily administration of 1 ml/kg/day (ca.850 mg/kg/day) for 4 weeks (Henkel, 1973).

NOAEL -750 mg/kg bw/day for male and female rats.

Dermal repeated dose toxicity

A 90-day dermal toxicity study in rats with fatty alcohol blend (56.7% decanol, 42.7% octanol) at dose levels of 0, 100, 300, or 1,000 mg/kg resulted in severe irritation at the application site. Severe irritation including fissuring of the skin occurred in 40% of the animals at 100 mg/kg/day and 80% of the animals at the limit dose. Slight changes in hematology, clinical chemistry, and organ weights were noted at the limit dose of 1,000 mg/kg/day.

NOAEL has been based on a local irritation effect rather than a systemic effect. Therefore it is proposed (by the author of the EPSR) that on the basis of a lack of systemic effects reported in the study, the NOAEL following dermal administration of fatty alcohol blend for a minimum of 90 days is greater than 1000 mg/kg/day.

Inhalation repeated dose toxicity

Under the conditions of the test no treatment-related toxic effects were found in male and female Wistar rats which were exposed to 2-ethylhexanol vapor up to 120 ppm ie. 638.4 mg/m³ . (Klimisch HJ; Deckardt K; Gembardt C; Hildebrand B,1998).The substanceAlcohols, C16-18, the subject of this dossier) is expected to exhibit very similar toxicity due to its close structural similarity to2-ethylhexanol.Comparable metabolism would occur.

Correcting for molecular weight, a conservative NOAEC of 1188.79 mg/m3 can be derived (638.4 x 242.45) / 130.2 =1188.79 mg/m3

Justification for selection of repeated dose toxicity dermal - local effects endpoint:
The generic modification from the NOAELtest (in mg/kg of body weight) to NOAELmodified (in mg/cm2/day) will be
NOAELin mg/cm2 = ((dose in mg/kg bw)x (average animal weight in kg)) / Treated surface in cm2)
NOAELtest* 0.25/44.5= NOAELmodified

The highest dose not causing irritation/corrosion was 1000 mg/kg bw in dermal toxicity study in rats of U.S.EPA.1996.
the modified dose descriptor would be
NOAELmodified =1000 mg/kg*0.25 kg/44.5cm2=5.62 mg/cm2

Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: liver; other: all gross lesions and masses

Repeated dose toxicity: inhalation - systemic effects (target organ) digestive: stomach; other: all gross lesions and masses

Repeated dose toxicity: dermal - systemic effects (target organ) other: all gross lesions and masses

Based on the hazard assessment of Alcohols, C16-18 in section 2.1 and 2.2. in IUCLID 5.4., available data for the substance and following the “Guidance on Information Requirement and Chemical Safety Assessment R.8. Characterisation of dose [concentration]- response for human health”, according to the EU’s list of dangerous substances (OJEC No L200/130.7.99) and according to the criteria described in Directive 67/548 and in the CLP Regulation:

Directive 67/548

Repeated dose toxicity

R33 Danger of cumulative effects.

T; R48/23 Toxic; Toxic: danger of serious damage to health by prolonged exposure through inhalation.

T; R48/23/24 Toxic; Toxic: danger of serious damage to health by prolonged exposure through inhalation and in contact with skin.

T; R48/23/24/25 Toxic; Toxic: danger of serious damage to health by prolonged exposure through inhalation, in contact with skin and if swallowed.

T; R48/23/25 Toxic; Toxic: danger of serious damage to health by prolonged exposure through inhalation, in contact with skin and if swallowed.

T; R48/24 Toxic; Toxic: danger of serious damage to health by prolonged exposure in contact with skin.

T; R48/24/25 Toxic; Toxic: danger of serious damage to health by prolonged exposure in contact with skin and if swallowed.

T; R48/25 Toxic; Toxic: danger of serious damage to health by prolonged exposure if swallowed.

Xn; R48/20 Harmful; Harmful: danger of serious damage to health by prolonged exposure through inhalation.

Xn; R48/20/21 Harmful; Harmful: danger of serious damage to health by prolonged exposure through inhalation and in contact with skin.

Xn; R48/20/21/22 Harmful; Harmful: danger of serious damage to health by prolonged exposure through inhalation, in contact with skin and if swallowed.

Xn; R48/20/22 Harmful; Harmful: danger of serious damage to health by prolonged exposure through inhalation and if swallowed.

Xn; R48/21 Harmful; Harmful: danger of serious damage to health by prolonged exposure in contact with skin.

Xn; R48/21/22 Harmful; Harmful: danger of serious damage to health by prolonged exposure in contact with skin and if swallowed.

Xn; R48/22 Harmful; Harmful: danger of serious damage to health by prolonged exposure if swallowed.

CLP

Repeated dose toxicity

STOT Rep. Exp. 1

STOT Rep. Exp. 2

H372: Causes damage to organs <or state all organs affected, if known> through prolonged or repeated exposure <state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard>.

H373: May cause damage to organs <or state all organs affected, if known> through prolonged or repeated exposure <state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard>.

It is concluded that the substance Alcohols, C16-18 does not meet the criteria to be classified for human health hazards for Repeated dose toxicity