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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Remarks:
combined repeated dose and reproduction / developmental screening
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)

Data source

Reference
Reference Type:
publication
Title:
Maternal and offspring toxicity but few sexually dimorphic behavioral alterations result from nonylphenol exposure
Author:
Sherry A. Fergusona,*, Katherine M. Flynna, K. Barry Delclosb, Retha R. Newboldc
Year:
2000
Bibliographic source:
Neurotoxicology and Teratology 22 (2000) 583–591

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Principles of method if other than guideline:
Combined repeated dose repro-devp. Screen of para –Nonylphenol in Sprague-Dawley rats
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
not specified
Details on test material:
- Name of test material (as cited in study report): para –Nonylphenol (NP)
- Molecular formula (if other than submission substance): C15-H24-O
- Molecular weight (if other than submission substance): 20.354 g/mole
- Substance type: Organic
- Physical state: No data available
- Impurities (identity and concentrations): < 5 %

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals and environmental conditions:
Details on test animal
TEST ANIMALS
- Source: National Center for Toxicological
Research (NCTR) breeding colony
- Age at study initiation: No data available
- Weight at study initiation: No data available
- Fasting period before study: No data available
- Housing: Animals were housed individually in a standard polycarbonate tub cage lined with wood chip bedding.
- Diet (e.g. ad libitum): Irradiated soy and alfalfa-free powdered diet (5K96, purchased from Purina Mills, St. Louis, MO, USA). This diet is based on the NIH-31 formula, except that casein replaces the protein contributed by soy and alfalfa, soy oil is replaced by corn oil, and the vitamin mix is adjusted for irradiation, ad libitum.
- Water (e.g. ad libitum): Water, ad libitum.
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 ± 3®C
- Humidity (%): 50 ± 10%
- Air changes (per hr): No data available
- Photoperiod (hrs dark / hrs light): 12:12-h light-dark cycle,

IN-LIFE DATES: From: To: No data available

Administration / exposure

Route of administration:
oral: feed
Vehicle:
other: Irradiated soy and alfalfa-free powdered diet (5K96)
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: para –Nonylphenol (NP) was mixed into the standard 5K96 feed by the Diet Preparation Staff, Bionetics at NCTR using Good Laboratory Practices guidelines.

DIET PREPARATION
- Rate of preparation of diet (frequency): No data available
- Mixing appropriate amounts with (Type of food): 5K96 feed
- Storage temperature of food: No data available

VEHICLE
- Justification for use and choice of vehicle (if other than water): 5K96 feed
- Concentration in vehicle: 0, 25, 500 and 2000 ppm (0, 2.5, 50and 200 mg/kg/day)
- Amount of vehicle (if gavage): No data available
- Lot/batch no. (if required): No data available
- Purity: No data available
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
by using HPLC analytical methods by the Division of Chemistry at NCTR. No batch of feed was ± 10% of the target dose.
Duration of treatment / exposure:
15 days
Frequency of treatment:
Daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 2.5, 50 and 200 mg/kg/day (0, 25, 500 and 2000 ppm)
Basis:
nominal in diet
No. of animals per sex per dose:
Total: 40
0 mg/kg/day: 11 female
2.5 mg/kg/day: 10 female
50 mg/kg/day: 10 female
200 mg/kg/day: 9 female
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Doses were chosen with the goal of choosing a high dose that alters the reproductive tract or other estrogen-sensitive organs of the offspring while causing only minimal maternal toxicity or other overt fetal toxicity.
- Rationale for animal assignment (if not random): Animals were assigned to treatment groups based on their GD 0 body weights such that all treatment groups had approximately equal body weights.
- Rationale for selecting satellite groups: No data available
- Post-exposure recovery period in satellite groups: No data available
- Section schedule rationale (if not random): No data available
Positive control:
No data available

Examinations

Observations and examinations performed and frequency:
Observations and examinations performed & frequency
CAGE SIDE OBSERVATIONS: No data available
- Time schedule: No data available
- Cage side observations checked in table [No.?] were included. No data available

DETAILED CLINICAL OBSERVATIONS: No data available
- Time schedule: No data available

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes, 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 time-weighted averages from the consumption and body weight gain data: Yes

FOOD EFFICIENCY: No data available
- 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 data available

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data available
- Time schedule for examinations: No data available

OPHTHALMOSCOPIC EXAMINATION: No data available
- Time schedule for examinations: No data available
- Dose groups that were examined: No data available

HAEMATOLOGY: No data available
- Time schedule for collection of blood: No data available
- Anaesthetic used for blood collection: No data available
- Animals fasted: No data available
- How many animals: No data available
- Parameters checked in table [No.?] were examined. No data available

CLINICAL CHEMISTRY: No data available
- Time schedule for collection of blood:
- Animals fasted: No data available
- How many animals: No data available
- Parameters checked in table [No.?] were examined. No data available

URINALYSIS: No data available
- Time schedule for collection of urine: No data available
- Metabolism cages used for collection of urine: No data available
- Animals fasted: No data available
- Parameters checked in table [No.?] were examined. No data available

NEUROBEHAVIOURAL EXAMINATION: No data available
- Time schedule for examinations: No data available
- Dose groups that were examined: No data available
- Battery of functions tested: sensory activity / grip strength / motor activity / other: No data available

OTHER: No data available
Sacrifice and pathology:
No data available
Other examinations:
Total and live pups per litter, total and live sex ratios and average weight per live pup were examined.
Statistics:
Analyses of variance (ANOVAs) were used to determine treatment effects using NP dose as a between- groups variable. Several analyses involved repeated measures over days or sessions and were done with multivariate techniques that were implemented using a mixed model. Homogeneity of variance was tested using a likelihood ratio test based on the negative log likelihoods from two different models, a mixed auto regressive and a mixed heterogeneous auto regressive model. If a chi square test yielded p < 0.10, the heterogeneous variance model was rejected. Post hoc tests (two-sided Dunnett’s or Student’s– Newman–Keuls) were applied only if the ANOVA attained significance at or below the 0.05 level.

Results and discussion

Results of examinations

Clinical signs:
not specified
Mortality:
not specified
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 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:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Details on results:
Clinical signs and mortality: No data available
Body weight and weight gain: No significant effect on body weight and body weight gain during pregnancy and lactation were observed in treated rats as compared to control.
Food consumption:
When treated with 2.5, 50 and 200 mg/kg/day, significant decrease in food consumption were observed in treated rats as compared to control.

The observed effect associated with a 17% less weight gain during GDs 1 to 21 in dams of the 200 mg/kg/day group, although this effect was not statistically significant.

Food efficiency: No data available

Water consumption and compound intake: No data available

Opthalmoscopic examination: No data available

Haematology: No data available

Clinical chemistry: No data available

Urinanalysis: No data available

Neurobehaviour: No data available

Organ weights No data available

Gross pathology: No data available

Histopathology: No data available

Details on results: No significant effect on Gestation duration, birth weight, sex ratio of live pups, and number of live or dead pups per litter were observed in treated rats as compared to control.

Effect levels

Dose descriptor:
NOAEL
Effect level:
200 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: No effect on body weight, food intake and reproductive performances

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Maternal and litter measures (mean ± SEM)

Treatment

Gestational

duration

(days)

Maternal

weight gain

(GDs 1-21)

(g)

Maternal

weight loss

(GDs 21–PPD 21) (g)

Maternal

food intake

(GD 7–PPD 21) (g/day)

Sex ratio

(male/female)

Live

pups/litter

Dead

pups/little

0 ppm

(n= 11)

22.6 ± 0.2

154.0 ±6.7

99.0 ± 7.6

38.2 ± 2.0

1.07 ± 0.17

13.2 ± 0.4

0.2 ± 0.3

25 ppm

(n =10)

22.4 ± 0.2

131.8 ± 15.9

93.3 ± 18.3

34.4 ± 1.6*

0.84 ± 0.13

13.1 ± 0.6

0.7 ± 0.4

500 ppm (n= 10)

22.6 ± 0.2

133.8 ± 13.5

83.8 ± 16.3

34.8 ± 1.9*

1.38 ± 0.19

13.6 ± 0.9

0.3 ± 0.3

2000 ppm (n= 9)

22.7 ± 0.2

128.3 ± 8.7

97.6 ± 11.5

30.6 ± 1.8*

1.23 ± 0.24

13.0 ± 0.8

0.7 ± 0.5

* Significantly less than 0-ppm group (p < 0.05).

Applicant's summary and conclusion

Conclusions:
NOAEL was considered to be 200 mg/kg/day when Sprague-Dawley rats were treated wtih para –Nonylphenol (NP).
Executive summary:

In a Combined repeated dose repro-devp. Screen study,Sprague-Dawley female rats were treated wtih para –Nonylphenol (NP) in the concentration of 0, 2.5, 50 and 200 mg/kg/day orally in diet from gestational day (GD) 7 to 21.No significant effect on body weight and body weight gain during pregnancy and lactation were observed in treated rats as compared to control.Significant decrease in food consumption was observed in 2.5, 50 and 200 mg/kg/day treated rats as compared to control.The observed effect associated with a 17% less weight gain during GDs 1 to 21 in dams of the 200 mg/kg/day group, although this effect was not statistically significant. In addition, No significant effect on Gestation duration, birth weight, sex ratio of live pups, and number of live or dead pups per litter were observed in treated rats as compared to control. Therefore, NOAEL was considered to be 200 mg/kg/day when Sprague-Dawley rats were treated wtih para –Nonylphenol (NP) orally in feed for 15 days.