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Toxicological information

Repeated dose toxicity: dermal

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Administrative data

Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)

Data source

Reference
Reference Type:
publication
Title:
Comparative estrogenic effects of p-nonylphenol by 3-day uterotrophic assay and female pubertal onset assay
Author:
Hyung Sik Kima, Jae-Ho Shin a, Hyun Ju Moona, Il Hyun Kanga, Tae Sung Kima, In Young Kima, Ji-Hyun Seok a, Myoung-Yun Pyob, Soon Young Hana,∗
Year:
2002
Bibliographic source:
Reproductive Toxicology 16 (2002) 259–268

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
other: OECD 440
Principles of method if other than guideline:
Subcutaneous repeated dose toxicity study of Nonylphenol in Sprague–Dawley Crl:CD female rats
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): p-Nonylphenol (NP)
- Molecular formula (if other than submission substance): C15-H24-O
- Molecular weight (if other than submission substance): 220.354 g/mole
- Substance type: Organic
- Physical state: No data available
- Impurities (identity and concentrations): 1 %

Test animals

Species:
rat
Strain:
other: Sprague–Dawley Crl:CD
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: KFDA Laboratory Animal Resources (Seoul, South Korea)
- Age at study initiation: 20 days old
- Weight at study initiation: No data available
- Fasting period before study: No data available
- Housing: Animals wre housed in clear polycarbonate cages.
- Diet (e.g. ad libitum): Certified Rodent Lab Diet (Purina, USA), ad libitum.
- Water (e.g. ad libitum): Filtered and chlorinated tap water was supplied using glass bottles, ad libitum.
- Acclimation period: 2 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 ± 2 ◦C
- Humidity (%):50 ± 10%.
- Air changes (per hr): No data available
- Photoperiod (hrs dark / hrs light): 12-h light–dark cycle

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

Administration / exposure

Type of coverage:
not specified
Vehicle:
not specified
Details on exposure:
Details on dermal exposure
PREPARATION OF DOSING SOLUTIONS: The amount administered was calculated based on body weight of the animal on the treatment day. All doses were prepared daily prior to injection.

TEST SITE
- Area of exposure: No data available
- % coverage: No data available
- Type of wrap if used: No data available
- Time intervals for shavings or clipplings: No data available

REMOVAL OF TEST SUBSTANCE
- Washing (if done): No data available
- Time after start of exposure: No data available

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): No data available
- Concentration (if solution): 0, 10, 25, 50, 100, and 200 mg/kg
- Constant volume or concentration used: yes
- For solids, paste formed: no

VEHICLE
- Justification for use and choice of vehicle (if other than water): No data available
- Amount(s) applied (volume or weight with unit): No data available
- Concentration (if solution): 4.0 ml/kg.
- Lot/batch no. (if required): No data available
- Purity: No data available

USE OF RESTRAINERS FOR PREVENTING INGESTION: No data available
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
3 days
Frequency of treatment:
Daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 10, 25, 50, 100, and 200 mg/kg
Basis:
nominal per unit body weight
No. of animals per sex per dose:
Total: 60
0 mg/kg body weight: 10 female
10 mg/kg body weight: 10 female
25 mg/kg body weight: 10 female
50 mg/kg body weight: 10 female
100 mg/kg body weight: 10 female
200 mg/kg body weight: 10 female
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: No data available
- Rationale for animal assignment (if not random): the animals were allocated to the various treatment groups in accordance with their body weight (b.w.). The body weight variation per group was ±5 g.
- 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:
Diethylstilbestrol DES (0.2 and 1.0g/kg) used as a positive control.

Examinations

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

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

DERMAL IRRITATION (if dermal study): No data available
- Time schedule for examinations: No data available

BODY WEIGHT: Yes
- Time schedule for examinations:
No data available

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

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: 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: No data available
- 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: Organ weight was examined.
Sacrifice and pathology:
GROSS PATHOLOGY: No data available

HISTOPATHOLOGY: No data available
Other examinations:
No data available
Statistics:
All values are expressed as mean ± S.D. (n = 10 animals). Organ weights were analyzed statistically for homogeneity of variance using Bartlett’s test. When samples were proven to be homogeneous, nonparametric analysis of variance was applied. Organ weights were analyzed using analysis of covariance (ANCOVA) with the body weight at necropsy as a covariate. When a significant treatment effect was present, Dunnett’s test (control versus treatment group) was used to compare treatment groups. The level of statistical significance was set a priori at α = 0.05.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Dermal irritation:
not specified
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
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:
effects observed, treatment-related
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Details on results:
Mortality:
No effect on survival were observed in treated rats as compared to control.

Clinical signs:
No effect on overt toxicity and clinical sign of toxicity were observed in treated rats as compared to control.

Dermal Irritation: No data available

Body weight and weight gain When treated with 200 mg/kg/day, significant decrease in body weight were observed in treated female rats as compared to control.

Food consumption and compound intake: No data available

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 When treated with 200 mg/kg/day, Significant increase in absolute and relative uterine weights and relative vaginal weights were observed as compared to control.

When treated with 100 mg/kg/day, Significant increase in absolute uterine weights was observed as compared to control.

Gross pathology: No data available

Histopathology: No data available

Details on results: p-NP significantly increased uterine weight at doses of 100 mg/kg and above in the 3-day uterotrophic assay using immature rats given the test article subcutaneously.

Effect levels

Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: Effect on survival, clinical sign, body weight and organ weight.

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Absolute organ weights in immature Sprague–Dawley rats treated with diethylstilbestrol (DES) and nonylphenol in uterotrophic assaya

Treatment

Dosage

Body weight (g)

Uterus (mg)

Vagina (mg)

Combined

ovaries (mg)

Liver (g)

 

 

Initialb

Finalc

 

 

 

 

Control

0

49.0 ± 1.8

62.3 ± 2.3

23.9 ± 4.0

34.4 ± 8.3

24.5 ± 3.1

2.51 ± 0.14

DES

0.2 μg/kg

49.5 ± 2.2

61.8 ± 3.2

42.7 ± 7.4

39.3±6.7

19.5±6.4

2.51±0.15

 

1.0 μg/kg

49.1 ± 1.6

62.6 ± 2.6

171.9 ± 7.5

71.6±8.8

15.7±4.2

2.52±0.16

Nonylphenol

10 mg/kg

49.7 ± 2.6

62.2 ± 3.1

28.2 ± 6.3

31.5 ± 8.2

20.3 ± 7.4

2.60 ± 0.22

 

25 mg/kg

49.6 ± 2.4

61.4 ± 2.6

29.3 ± 4.3

34.1 ± 6.1

20.2 ± 6.7

2.66 ± 0.14

 

50 mg/kg

48.9 ± 2.5

61.1 ± 4.6

31.7 ± 5.8

34.6 ± 7.4

17.6 ± 6.4

2.59 ± 0.22

 

100mg/kg

50.2 ± 2.6

61.7 ± 3.8

57.3 ± 9.9

50.2±6.3

17.1±3.9

2.56±0.27

 

200mg/kg

49.1 ± 2.7

54.8 ± 2.9

76.2±9.1

61.0±9.2

16.4±6.5

2.49±0.18

aMean ± S.D. (n = 10 animals per treatment group).

bBody weight on the first day of treatment (20 days of age).

cBody weight on the day of necropsy (23 days of age).

Significantly different from control by Dunnett’s test (P <0.05).

Applicant's summary and conclusion

Conclusions:
NOAEL was considered to be 50 mg/kg body when Sprague–Dawley Crl:CD female rats were treated with p-Nonylphenol (NP)
Executive summary:

In a Subcutaneous repeated dose toxicity study, Sprague–Dawley Crl:CD female rats were treated with p-Nonylphenol (NP) subcutaneously in the concentration of 0, 10, 25, 50, 100, and 200 mg/kg dor 3 days. No effect on survival and clinical sign were observed in treated rats as compared to control. Significant decrease in body weight was observed in 200 mg/kg treated female rats as compared to control. In addition, Significant increase in absolute and relative uterine weights and relative vaginal weights at 200 mg/kg and Significant increase in absolute uterine weights was observed at 100 mg/kg as compared to control. Therefore, NOAEL was considered to be 50 mg/kg body when Sprague–Dawley Crl:CD female rats were treated withp-Nonylphenol (NP) for 3 days.