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Toxicological information

Repeated dose toxicity: other routes

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Administrative data

Endpoint:
short-term repeated dose toxicity: other route
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference
Reference Type:
publication
Title:
Effects of repeated intra­venous infusions of the plasticizer di-(2-ethylhexyl) phthalate in young male rats.
Author:
Sjöberg P, Lindquist NG, Montin G
Year:
1985
Bibliographic source:
Arch. Toxicol. 58, 78-83

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Repeated intraveinous treatment in rats with specific investigations in the liver and the testes.
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Source: Fluka AG (Buchs, Switzerland)
- Purity>99%

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: ALAB, Sollentuna, Sweden)
- Age at study initiation: 40 days old and 25 days old (1 group)
- Weight at study initiation: no data
- Fasting period before study: no
- Housing: individually
- Diet (e.g. ad libitum): ad libitum AB-Ewos-Anticimex, Södertälje, Sweden
- Water (e.g. ad libitum): ad libitum tap water
- Acclimation period: at least 4 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22
- Humidity (%): 40-65
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
intravenous
Vehicle:
other: in emulsion (20% DEHP, fractioned egg yolk phosphatides (1.2%), glycerol (2.2%) and distilled water
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
6 d
Frequency of treatment:
1 infusion daily via the implanted canula (3 hours/1ml/h)
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 5, 50, 500 mg/kg
No. of animals per sex per dose:
5-6 rats per group
Control animals:
yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: No data
DETAILED CLINICAL OBSERVATIONS: No data
BODY WEIGHT: No
FOOD CONSUMPTION: No
WATER CONSUMPTION: No
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: No

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: 2-3 hours after the last infusion
- Animals fasted: No
- How many animals: all
- Parameters : ASAT, ALAT, alcaline phosphatase

URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No

OTHER:
Bromosulfophtalein clearance was evaluated in all groups except the 5 mg/kg treated group.
Sacrifice and pathology:
GROSS PATHOLOGY/ORGAN WEIGHTS: Yes: testes, ventral prostate, seminal vesicles, kidneys, liver
HISTOPATHOLOGY: Yes: testes, proximal epididymides, liver, kidneys
Statistics:
ANOVA

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):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not examined
Details on results:
BODY WEIGHT AND WEIGHT GAIN
The mean gain in body weight of the DEHP-treated animals was slightly smaller (not statistically significant) than that of the control-treated animals.

CLINICAL CHEMISTRY
No difference in enzymes or BSP clearance was observed.

ORGAN WEIGHTS
A dose increase in liver weight was observed.

GROSS PATHOLOGY
No alteration in liver or kidneys was observed.

HISTOPATHOLOGY: NON-NEOPLASTIC
A treatment-related increase in the liver peroxisome was found.
Swollen mitochondria occurred in both control and treated animals but were more common after DEHP treatment.

No abnormalities were detected in paraffin-embedded testicular material, nor was there any treatment-related effect on the mean diameter or the percentage of seminiferous tubules in stages VII and VIII.
The number of immature germ cells in the epididymis was similar in treated and control groups. In the Epon-embedded material from three of five animals that had received the highest dose, some altered Sertoli cells in association with seminiferous tubules in stages XIV and I were observed. In these stages some degenerated primary spermatocytes (zygotene) were also seen. The Sertoli cell alterations varied from vacuolisation (dilatation of the endoplasmic reticulum), to degeneration. In Epon sections from the testes of 25-day-old animals given DEHP dose of 500 mg/kg, similar though less pronounced changes were found.

Effect levels

Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw/day
Sex:
male
Basis for effect level:
other: Some altered Sertoli cells at 500 mg/kg bw/d

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Executive summary:
Six intravenous infusions of DEHP (0, 5, 50 or 500 mg/kg bw) were given to 25-day- or 40-day-old rats. In Epon-embedded testicular materials from animals given the highest dose, some altered Sertoli cells (dilated cisternae of endoplasmic reticulum) were observed. No age-related testicular effects were observed.