Nonanoic acid

Carcinogenicity

Description of key information

No clearly treatment-related systemic effects were observed in a dermal carcinogenicity study (Celanese/Kettering, 1985, RL3). No information is available for other routes of exposure.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via dermal route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: dermal

Type of information:

experimental study

Adequacy of study:

other information

Study period:

Start of exposure: 18 May 1981, treatment 80 weeks

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

significant methodological deficiencies

Reason / purpose for cross-reference:

reference to same study

Principles of method if other than guideline:

dermal carcinogenicity study

GLP compliance:

not specified

Species:

mouse

Strain:

C3H

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Jackson Laboratory, Bar Harbour, Maine, USA
- Age at study initiation: 6-8 weeks
- Housing: 5 percage
- Diet (ad libitum): Rodent Laboratory Chow 5001 (Ralston Purina)
- Water (ad libitum): hyperchlorinated-acidified water
- Acclimation period: 3 weeks


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23.3 +/- 1.1
- Humidity (%): 45 +/- 10
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

dermal

Vehicle:

unchanged (no vehicle)

Details on exposure:

TEST SITE
- Area of exposure: interscapular region


REMOVAL OF TEST SUBSTANCE: no


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 50 mg/animal per treatment
- Constant volume or concentration used: yes

USE OF RESTRAINERS FOR PREVENTING INGESTION: no

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

80 wks

Frequency of treatment:

2x/wk

Post exposure period:

Post-exposure recovery period: none

Remarks:

Doses / Concentrations:
50 mg/animal/treatment (undiluted)
Basis:
other: nominal, maximum tolerated dose

Remarks:

Doses / Concentrations:
400 mg/kg bw/day
Basis:
other: dermal dose

No. of animals per sex per dose:

50 males

Control animals:

yes, concurrent no treatment

Details on study design:

Post-exposure period: none

Positive control:

benzo(a)pyrene (50 mg/animal/treatment)

Observations and examinations performed and frequency:

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily with approx. 8 h interval

DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly during the first month of the study and every teo weeks thereafter

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No

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

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Additionally to the skin of the interscapular area (test site), a complete macroscopic and microscopic examination of all internal organs was performed in all animals).

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):

not specified

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

no effects observed

Details on results:

HISTOPATHOLOGY: NON-NEOPLASTIC

Result (carcinogenicity): negative

HISTOPATHOLOGY: NEOPLASTIC: negative
The positve control substance, benzo(a)pyrene, produced a high incidence of skin neoplasms.

Dose descriptor:

NOAEL

Effect level:

400 mg/kg bw/day (nominal)

Sex:

male

Basis for effect level:

other: dose calculated (50 mg/treatment, twice weekly)

Remarks on result:

not determinable because of methodological limitations

The test substance did not increase the incidence of skin tumors (0/48, compared to 1/50 in untreated animals and 0/48 in mineral oil-treated animals. The incidences of non-neoplastic or carcinogenic effects in internal organs are shown in the table below. No clearly treatment-related effects are obvious.

Non-neoplastic skin effects are presented in chapter 7.5.2.

Summary table of neoplastic and non-neoplastic organ changes

	untreated (n = 49)	mineral oil (n = 47)	C-182 (nonanoic acid) (n = 48)
Lung
pneumonia	10	11	15
abscess	4	1	1
fibrosis	3	5	2
atelectasis	6	3	3
edema/hemorrhage	2	3	1
adenoma	2	0	0
carcinoma	0	0	1
metastasis	3 (liver)	1 (liver)	0
Kidneys
chron. interstit. nephritis	9	6	4
Spleen/lymph nodes
hemosiderin	5	7	5
leukemia/lymphoma	0	0	3
Liver
degeneration	0	7	8
hepatocarcinoma	18	11	23
Intestinal tract
gastritis/entero-colitis	3	8	6
abscess	4	4	0
Testes
atrophy	2	3	1

Conclusions:

Under the conditions of this study the test item did not produce clearly treatment-related non-neoplastic or carcinogenic effects, apart from skin irritation. A slight increase in hepatocellular liver carcinomas in the group treated with the test substance might be produced by the exposure, but could also be a random error.

Executive summary:

50 male C3H mice were dermally exposed to the test item (purity not stated) for 80 weeks (twice weekly, 50 mg per treatment, maximum tolerated dose based on a pre-test). Control groups of equal size received no treatment or were treated with the vehicle (mineral oil, used for other compounds in this study), respectively. The treatment did not reduce survival. Non-neoplastic skin effects were at least partially evoked by the repeated clipping during the exposure period. No skin tumours were observed. The positive control substance, benzo(a)pyrene, caused a high incidence of skin neoplasms. Compared to the control groups the test item produced no clearly treatment-related systemic non-carcinogenic or carcinogenic effects. The NOAEL of this study for carcinogenicity was approx. 400 mg/kg bw/day (Celanese/Kettering, 1985).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

400 mg/kg bw/day

Study duration:

chronic

Species:

mouse

Quality of whole database:

sufficiently good. No adverse effect or target organ was identified in a dermal cancer study. Though the study is not considered to be reliable due to methodological deficiencies, the available information is considered to be sufficient because there is no structural alert, and no genetic toxicity was seen in appropriate studies.

Mode of Action Analysis / Human Relevance Framework

In the absence of information on a species specific effect the data are regarded as relvant for humans.

Justification for classification or non-classification

Based on the available data a classification according to Regulation (EC) No 1272/2008 is not required.

Additional information

50 male C3H mice were dermally exposed to the test item for 80 weeks (twice weekly, 50 mg per treatment, maximum tolerated dose based on a pre-test). Control groups of equal size received no treatment or were treated with the vehicle (mineral oil, used for other compounds in this study), respectively. The treatment did not reduce survival. Non-neoplastic skin effects were at least partially evoked by the repeated clipping during the exposure period. No skin tumours were observed. The positive control substance, benzo(a)pyrene, caused a high incidence of skin neoplasms. Compared to the control groups the test item produced no clearly treatment-related systemic non-carcinogenic or carcinogenic effects. The NOAEL of this study for carcinogenicity was approx. 400 mg/kg bw/day (Celanese/Kettering, 1985).

This study was not judged to be reliable with respect to carcinogenic effects (RL3) due to significant methodological deficiencies.