Reaction mass of Fatty acids, montan-wax and Montan wax

Carcinogenicity

Administrative data

Endpoint:

carcinogenicity: oral

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable well-documented publication which meets basic scientific principles (similar to OECD guideline 451 with some deviations)

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

2007

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 451 (Carcinogenicity Studies)

Deviations:

yes

Remarks:

: slight food restriction after growth period, restricted range of haematological examinations

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

312700-63-3

Cas Number:

312700-63-3

IUPAC Name:

312700-63-3

Constituent 2

Reference substance name:

-

IUPAC Name:

-

Constituent 3

Reference substance name:

D-003

IUPAC Name:

D-003

Details on test material:

- Name of test material (as cited in study report): D-003
- Substance type: mixture of very long chain aliphatic acids purified from sugarcane wax (Saccharum officinarium)
- Composition of test material, percentage of components: 1-tetracosanoic acid (0.9%), 1-pentacosanoic acid (0.5%), 1-hexacosanoic acid (1.0%), 1-heptacosanoic acid (3.0%), 1-octacosanoic acid (40%), 1-nonanoic acid (3.0%), 1-triacontanoic acid (18%), 1-hentriacontanoic acid (1.0%), 1-dotriacontanoic acid (8.0%), tritriacontanoic acid (2.0%), 1-tetratriacontanoic acid (12%), 1-pentatriacontanoic acid (0.5%), and 1-hexatriacontanoic acid (4.0%)
- Stability under test conditions: test substance: > 5 years, test suspensions: > 1 month

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: National Centre for Laboratory Animals Production (CENPALAB), Havana, Cuba
- Age at study initiation: 5-7 weeks
- Weight at study initiation: 145.3 +/- 0.6 g
- Housing: three per cage
- Diet: standard chow (CENPALAB), ad libitum throughout the growing period, 80% thereafter
- Water: ad libitum
- Acclimation period: 15 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 25 +/- 2
- Humidity (%): 60 +/- 5
- Air changes (per hr): 16
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: acacia gum/water (10mg/ml)

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
suspensions in vehicle prepared weekly

VEHICLE
- Amount of vehicle (if gavage): 10 ml/kg

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

24 months

Frequency of treatment:

daily for 5 days/week

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0 mg/kg bw/day
Basis:
other: vehicle control

Doses / concentrations 2

Remarks:

Doses / Concentrations:
50 mg/kg bw/day
Basis:
actual ingested

Doses / concentrations 3

Remarks:

Doses / Concentrations:
500 mg/kg bw/day
Basis:
actual ingested

Doses / concentrations 4

Remarks:

Doses / Concentrations:
1500 mg/kg bw/day
Basis:
actual ingested

No. of animals per sex per dose:

60

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: highest dose based on a no-effect level of 1250 mg/kg/day in 90 days and 6 months studies, > 5000-times the proposed maximal therapeutic dose in humans, lowest dose about 700-times the minmal therapeutic dose

Examinations

Observations and examinations performed and frequency:

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly during the first 13 weeks, monthly thereafter

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at the end of the exposure period
- Anaesthetic used for blood collection: Yes (ether)
- Animals fasted: Yes, 12 h
- How many animals: all survivors
- Parameters checked: haemoglobin, red and white blood cell counts

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at the end of the exposure period
- Animals fasted: Yes
- How many animals: all survivors
- Parameters checked: alanine transaminase (ALT), aspartate transaminase (AST), creatinine phophokinase, lactate dehydrogenase, alkaline and acid phosphatase, albumin, cholesterol, triglycerides, and glucose


URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

OTHER:

Sacrifice and pathology:

GROSS PATHOLOGY: Yes, all organs and cavities
HISTOPATHOLOGY: Yes, all organs, according to the criteria of the National Toxicology Program

Other examinations:

organ/body weights ratios detemined for: liver, kidneys, heart, spleen, lungs, thymus, adrenals, gonads, and brain

Statistics:

Mortality data: Cox, Cox-Mantel, Log-rank, Gehans Wilcoxon, and Peto&Peto's Wilcoxon tests
Categorical data: Fisher's exact probability test
Coontinous variables: ANOVA

Results and discussion

Results of examinations

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:

not examined

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

no effects observed

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

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:

No treatment related effects were observed with respect to body weight gain, food consumption, clinical symptoms, blood biochemistry (except a reduction in serum cholesterol in the mid and high dose group, which was not reported in detail), organ weights, as well as non-neoplastic and neoplastic effects

Relevance of carcinogenic effects / potential:

Based on the results of this study there is no carcinogenic potential of the test substance D-003.

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

1 500 mg/kg bw/day (actual dose received)

Sex:

male/female

Basis for effect level:

other: no carcinogenic effects observed

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

2

Dose descriptor:

NOAEL

Effect level:

1 500 mg/kg bw/day (actual dose received)

Sex:

male/female

Basis for effect level:

other: no non-neoplastic adverse effects observed

Remarks on result:

other: Effect type: toxicity (migrated information)

Any other information on results incl. tables

Sprague-Dawley rats (60 per sex and dose) were exposed to D-003 on 5 d/w for 24 months via gavage in doses of 0, 50, 500 and 1500 mg/kg bw/d . No treatment related effect was observable

with respect to body weight gain, food consumption, clinical symptoms, blood biochemistry (except a reduction in serum cholesterol in the mid and high dose group, which was not reported in detail), organ weights, as well as non-neoplastic and neoplastic effects.

Malignant and benign tumours occured less frequently in treated groups compared to controls, as shown in the following table. The reduction of incidence in treated females for malignant tumours was significant with respect to control values. The most prominent non-neoplastic lesion was glomerulonephritis, which occured in 9, 1, 5 and 7 males of the control, 50, 500 and 1500 mg/kg/day groups, respectively, and in 6 control females and 1 female treated with 500 mg/kg/day. Several inflammations were observed at low frequencies, and no differences were evident between control and treated animals.

Doses (mg/kg/day	Male animals with malignant tumours	Male animals with benign tumours	Female animals with malignant tumours	Female animals with benign tumours
Controls (n=60 per sex)	6	26	19	39
50 (n=60 per sex)	2	19	11	34
500 (n=60 per sex)	3	16	6	37
1500 (n=60 per sex)	2	18	9	34

Applicant's summary and conclusion

Conclusions:

With the exception of the reduction of serum cholesterol (an effect specific for D-003), the chronic oral treatment in doses up to 1500 mg/kg bw/day did not produce non-neoplastic or carcinogenic effects in rats.

Executive summary:

The test substance (D-003) was administered to Sprague-Dawley rats (60 per sex and dose) by oral gavage in daily doses of 0, 50, 500 and 1500 mg/kg bw/day, 5 days per week, for 24 months. No treatment related effects were observed with respect to survival, body weight gain, food consumption, clinical symptoms, blood biochemistry (except serum cholesterol reduction, an effect specific for D-003), organ weights, and non-neoplastic or carcinogenic histopathological effects.