Disodium phthalate

Toxicity to reproduction

Administrative data

Endpoint:

toxicity to reproduction

Remarks:

other: reproductive organs were examined in a 2 year study

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Well documented and scientifically acceptable

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1979

Materials and methods

Principles of method if other than guideline:

Groups of 50 rats of each sex were administered phthalic anhydride at one of 2 doses, either 7.500 or 15.000 ppm (ca. 500, 1000 mg/kg bw/d) for 105 weeks. Matched controls consisted of 20 untreated rats of each sex. At the end all animals were killed using CO2 inhalation and necropsied; gross and microscopic examination of: all major organs, including reproductive organs; in male rats preputial gland, prostate, seminal vesicle, testis and epididymis, and the mammary gland; in female rats mammary gland, uterus, endothelial gland, and ovary.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Phthalic anhydride

EC Number:

201-607-5

EC Name:

Phthalic anhydride

Cas Number:

85-44-9

IUPAC Name:

2-benzofuran-1,3-dione

Details on test material:

Purity: 98.8 %

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 6 weeks

Administration / exposure

Route of administration:

oral: feed

Vehicle:

other: diet

Details on mating procedure:

Not applicable - reproductive organs were examined in a 2 years study

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Analytical analyses indicated that when phthalic anhydride was mixed with Lab Meal at a concentration of 15,000 ppm and stored at room temperature for 2 weeks, the loss was 2.59% (372 ppm) per day.

Duration of treatment / exposure:

105 weeks

Frequency of treatment:

Daily

Doses / concentrations

Remarks:

Doses / Concentrations:
7500, 15000 ppm = ca. 500, 1000 mg/kg bw/d
Basis:
nominal in diet

No. of animals per sex per dose:

50 male and 50 female animals per dose

Control animals:

yes, plain diet

Examinations

Parental animals: Observations and examinations:

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily observations for sick, tumor bearing and moribund animals, twice daily checked for deaths.

BODY WEIGHT: Yes
- Time schedule for examinations: Each rat was weighed once per month.

Postmortem examinations (parental animals):

GROSS NECROPSY AND HISTOPATHOLOGY
At the end all animals were killed using CO2 inhalation and necropsied; gross and microscopic examination of:
all major organs, including reproductive organs; in male rats preputial gland, prostate, seminal vesicle, testis and epididymis, and the mammary gland; in female rats mammary gland, uterus, endothelial gland, and ovary.

Results and discussion

Results: P0 (first parental generation)

Details on results (P0)

MORTALITY (PARENTAL ANIMALS)
Reduced from week 75 onwards in dosed male and female rats as well as in controls:
high-dose males: 36/50, and females: 41/50
low-dose males: 44/50, and females: 42/50
control males: 14/20, and females: 17/20

CLINICAL SIGNS (PARENTAL ANIMALS)
Dosed groups: low incidences: arched back, rough hair coat, ulceration and corneal opacity (no further details given)

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
High dose males lower than controls
High dose females and low dose males and females comparable with controls

HISTOPATHOLOGY (PARENTAL ANIMALS)
By inspection: no difference between the dosed and control groups

Effect levels (P0)

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (nominal)

Sex:

male/female

Overall reproductive toxicity

Reproductive effects observed:

not specified

Any other information on results incl. tables

Nonneoplastic lesions on reproductive organs:

Organ control (20) low dose (50) high dose (50)

Males:

preputial gland cyst

0/20 1/50 (2%) 0/50

prostate calculus

0/20 0/48 2/45 (4%)

inflammation, suppurative

0/20 2/48 (4%) 1/45 (2%)

abscess

0/20 0/48 1/45 (2%)

Inflammation, chronic

1/20 (5%) 0/48 0/45

inflammation, chronic suppurative

1/20 (5%) 0/48 0/45

fibrosis

0 1/48 (2%) 0/45

hyperblasia, focal

1/20 (5%) 0/48 0/45

seminal vesicle inflammation, suppurative

1/20 (5%) 0/50 0/50

testis hemorrhage

0/20 0/50 1/50 (2%)

infarct

0/20 1/50 (2%) 0/50

atrophy

0/20 3/50 (6%) 2/50 (4%)

epididymis inflammation, chronic

0/20 0/50 1/50 (2%)

mammary gland dilatation/ducts

5/20 (25%) 12/50 (24%) 12/50 (24%)

Females:

mammary gland

20 50 50

dilatation/ducts

13 (65%) 33 (66%) 24 (48%)

galactocele 1 (5%) 4 (8%) 1 (2%)

inflammation, granulomatous

0 1 (2%) 0

fibrosis

0 0 1 (2%)

hyperplasia, Nos

0 0 1 (2%)

hyperplasia, focal

1 (5%) 0 0

hyperplasia, cystic

0 0 1 (2%)

uterus

19 47 50

hematoma

0 0 1 (2%)

dilatation, nos

0 1 (2%) 0

necrosis, nos

1 (5%) 0 0

uterus/endometrium

19 47 50

dilatation, nos

0 1 (2%) 1 (2%)

cysti, nos

0 1 (2%) 0

hyperplasia, epithelial

1 (2%) 0

endothelial gland

19 47 50

dilatation, nos

3 (16%) 0 0

ovary

19 47 50

cyst, nos

1 (5%) 3 (6%) 1 (2%)

inflamation, chronic

1 (5%) 0 0

hypoplasia, nos

0 1 (2%) 0

Applicant's summary and conclusion

Conclusions:

The NOAEL was determined to be 1000 mg/kg bw/day (male and female), the pathological examination revealed no difference between the dosed and control groups.

Executive summary:

Groups of 50 rats of each sex were administered phthalic anhydride at one of 2 doses, either 7.500 or 15.000 ppm (ca. 500, 1000 mg/kg bw/d) for 105 weeks. Matched controls consisted of 20 untreated rats of each sex. At the end all animals were killed using CO2 inhalation and necropsied; gross and microscopic examination of: all major organs, including reproductive organs; in male rats preputial gland, prostate, seminal vesicle, testis and epididymis, and the mammary gland; in female rats mammary gland, uterus, endothelial gland, and ovary.

The NOAEL was determined to be 1000 mg/kg bw/day (male and female), the pathological examination revealed no difference between the dosed and control groups.