Nonylphenol, branched, ethoxylated

Repeated dose toxicity: oral

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-reference

Cross-reference 1

Reason / purpose for cross-reference:

reference to same study

Cross-reference 2

Reason / purpose for cross-reference:

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

Test material information

Constituent 1

Reference substance name:

NPE-4

IUPAC Name:

NPE-4

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 or test system 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 / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0 mg/kg bw/d (control)
Basis:
nominal in diet

Doses / concentrations 2

Remarks:

Doses / Concentrations:
40 mg/kg bw/d
Basis:
nominal in diet

Doses / concentrations 3

Remarks:

Doses / Concentrations:
200 mg/kg bw/d
Basis:
nominal in diet

Doses / concentrations 4

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).