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Diss Factsheets

Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
reproductive toxicity, other
Remarks:
reproductive organs in a 2 years study were examined
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

Referenceopen allclose all

Reference Type:
publication
Title:
Phthalate esters carcinogenicity in F344/N rats and B6C3F1 mice
Author:
Huff JE, Kluwe WM
Year:
1984
Bibliographic source:
Ind. Hazards Plastics Synthetic Elastomers, 137-154.
Reference Type:
publication
Title:
Carcinogenic potential of phtahlic acid esters and related compounds: structure-activity relationships
Author:
Kluwe WM (1986). Carcionogenic potential of phtahlic acid esters and related compounds: structure-activity relationships. Environ. Health Perspect 65, 271-278.
Year:
1986
Bibliographic source:
Environ. Health Perspect 65, 271-278.
Reference Type:
publication
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:
not specified

Test material

Constituent 1
Chemical structure
Reference substance name:
Phthalic anhydride
EC Number:
201-607-5
EC Name:
Phthalic anhydride
Cas Number:
85-44-9
Molecular formula:
C8H4O3
IUPAC Name:
2-benzofuran-1,3-dione

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female

Administration / exposure

Route of administration:
oral: feed
Vehicle:
other: diet
Details on mating procedure:
not applicable - reproductive organs of a 2 years study were examined
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
Exposure period: 105 w
Frequency of treatment:
daily
Details on study schedule:
not applicable - reproductive organs of a 2 years study were examined
Doses / concentrations
Remarks:
Doses / Concentrations:
7500, 15000 ppm = ca. 500, 1000 mg/kg bw/d
Basis:

No. of animals per sex per dose:
50 male and 50 female animals
Control animals:
yes, concurrent no treatment

Results and discussion

Results: P0 (first parental generation)

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

SURVIVAL: 
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
MEAN BODYWEIGHTS (no data given):
high dose males lower than controls
high dose females and low dose males and females comparable with controls
CLINICAL SIGNS:
dosed groups: low incidences: arched back, rough hair coat, ulceration and corneal opacity (no further details given)
PATHOLOGICAL EXAMINATION:
by inspection: no difference between the dosed and control groups

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, focal1/20 (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%)
galactccele 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


NOAEL: 15000 ppm.

Applicant's summary and conclusion

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 = 1000 mg/kg bw/day (rats, m+f), the pathological examination revealed no difference between the dosed and control groups

reference: Huff, 1984; Kluwe, 1986; NCI, 1979