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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
chronic toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, few details but meets basic scientific principles.
Cross-referenceopen allclose all
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
review article or handbook
Title:
Toxicologic studies of alkylphenol polyoxyethylene surfactants
Author:
Smyth HF and Calandra JC
Year:
1969
Bibliographic source:
Toxicol. Appl. Pharmacol. 14:315-334

Materials and methods

Principles of method if other than guideline:
A chronic oral repeated dose study was conducted in rats at 0, 40, 200 and 1,000 mg/kg bw/d to evaluate the systemic effects of NPE-4 in rat. Parameters including bodyweight, food consumption, food utilization, mortality, abnormal behavior, clinical chemistry, haematology, gross and histopathological changes were observed at regular intervals.
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Nonyl 4, also known as NPE-4
- Molecular formula (if other than submission substance): C23H40O5
- Molecular weight (if other than submission substance): 396.5607 g/mol
- Smiles notation (if other than submission substance): O(c1ccc(cc1)CCCCCCCCC)CCOCCOCCOCCO
- InChl (if other than submission substance): InChI=1/C23H40O5/c1-2-3-4-5-6-7-8-9-22-10-12-23(13-11-22)28-21-20-27-19-18-26-17-16-25-15-14-24/h10-13,24H,2-9,14-21H2,1H3
- Structural formula attached as image file (if other than submission substance): see Fig.
- Substance type: Nonionic surfactant

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Housing: Housed individually in wire-bottom cages
- Diet (e.g. ad libitum): Rockland rat diet
- Water (e.g. ad libitum): Ad libitum

Administration / exposure

Route of administration:
oral: feed
Vehicle:
not specified
Details on oral exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): The concentration was adjusted from time to time to maintain the dosage constant
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data
Duration of treatment / exposure:
2 years
Frequency of treatment:
Daily
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0 mg/kg bw/d (control)
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
40 mg/kg bw/d
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
200 mg/kg bw/d
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
1000 mg/kg bw/d
Basis:
nominal in diet
No. of animals per sex per dose:
35 (plus 5 animals per sex in the highest and control dosage group)
Control animals:
yes, plain diet
Details on study design:
No data
Positive control:
No

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes

DETAILED CLINICAL OBSERVATIONS/MORTILITY: Yes
- Time schedule: No data

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly for 13 wk and biweekly to 1 year, then monthly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes (for 12 wk and then irregularly thereafter)
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data

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

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Before the first dose, and after 3, 6, 12, 18, and 24 months
- Anaesthetic used for blood collection: Yes (identity) / No / No data
- Animals fasted: No data
- How many animals: 5 of each sex on the highest dosage and the control diet
- Parameters checked in table [No.?] were examined: Haemoglobin, total red and white blood cell count and differential white cell count

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Before the first dose, and after 3, 6, 12, 18, and 24 months
- Animals fasted: No data
- How many animals: 5 of each sex on the highest dosage and the control diet
- Parameters examined: Urinary reducing substances, protein, and formed elements.

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

OTHER: Animals were observed daily for abnormal behavior
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (including tumors)

After 12 months , 5 of each sex from the highest dosage and from the control groups and 3 of each sex from each of the two lower-dosage groups and after 24 months all were sacrificed

HISTOPATHOLOGY: Yes

- Histopathologic examination of 28 tissues was done on 5 rats of each sex on the highest dosage and in the control diet groups at each sacrifice.
Other examinations:
Organ weights of kidney, liver and testes were measured
Statistics:
Yes, but no details reported

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 specified
Water consumption and compound intake (if drinking water study):
not examined
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:
BODY WEIGHT AND WEIGHT GAIN: At 1000 mg/kg/d both sexes, and at 200 mg/kg/d the females had gained less weight than the controls after 12 months, but did not differ from the controls after 24 months.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): The groups who gained less weight ate less than did the controls, and the growth effect was attributed to poor palatability of the diets.

ORGAN WEIGHTS: A slight elevation of liver weight in relation to body weight in both sexes on an intake of 1000 mg/kg/d was observed

GROSS PATHOLOGY

HISTOPATHOLOGY: Microscopically the livers were normal, hence the slight elevation of liver weight in relation to body weight observed, was not considered to be adverse

Effect levels

Dose descriptor:
NOAEL
Effect level:
40 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: overall effects

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

None

Applicant's summary and conclusion

Conclusions:
The NOAEL of NPE-4 can be considered to be 40 mg/kg bw/d based on no systemic effects observed at any of the tested the dosages in neither sexes.
Executive summary:

A chronic feeding study was conducted to evaluate the systemic toxicity of NPE-4 in rats. The test material was administered at 0, 40, 200 and 1,000 mg/kg bw/d to rats in the diet over a 2-year period. Each dosage group consisted of 35 male and 35 female rats, with 5 male and 5 female rats in addition in the highest and control dosage groups reserved for periodic clinical test. Food consumption was calculated weekly for 12 weeks, irregularly thereafter. The rats were weighed weekly for 13 weeks, biweekly to 1 year, then monthly. Food utilization was calculated for the first 12 weeks. Animals were observed daily for abnormal behavior. Before the first dose, and after 3, 6, 12, 18 and 24 months clinical tests were performed on the 5 of each sex at the highest dosage and the control diet. All rats dying or sacrificed were carefully examined for gross pathologic changes, including tumors. After 12 months 5 of each sex from the highest dosage and from the control group were sacrificed, 3 of each sex from each of the two lower-dosage groups. After 24 months, all rats were sacrificed and organs were weighed. Histopathologic examination of tissues was conducted on 5 rats of each sex at the highest dosage and in the control group at each sacrifice. All numerical results were evaluated by appropriate statistical tests. At 1,000 (both sexes) and 200 (females) mg/kg/ bw/day, animals gained less weight than the controls after 12 months, but did not differ from the controls after 24 months. The groups that gained less weight ate less than controls and the growth effect was attributed to poor palatability of the diets. A slight elevation of liver weight in relation to body weight in both sexes at 1,000 mg/kg bw/d was observed. Microscopically, the livers were normal, hence the slight elevation of liver weight in relation to body weight was not considered to be adverse. Based on the above results, the NOAEL of NPE-4 can be considered to be 40 mg/kg bw/d based on no systemic effects observed at the lowest dosage in either sex (Smyth HF et al.,1969).