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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the study does not need to be conducted because (i) the substance is of low toxicological activity (no evidence of toxicity seen in any of the tests available), (ii) it can be proven from toxicokinetic data that no systemic absorption occurs via relevant routes of exposure (e.g. plasma/blood concentrations below detection limit using a sensitive method and absence of the substance and of metabolites of the substance in urine, bile or exhaled air) and (iii) there is no or no significant human exposure
Justification for type of information:
No effects were seen in a teratogenicity study
In 90 sub-chronic tests in mice and rats, extensive examiniations on sperm morphology and vaginal cytotoxicity were performed, together with full pathology examinations of the sexual organs. There were no adverse effects
Further animal testing is not considered to be justified.
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
data waiving: supporting information
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
10 days dosing between gestation days 6 and 15
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
Data review as part of the US National Toxicity Program (NTP) and considered reliable.
Although testing performed on the acid form (the anhydride quickly hydrates to the acid on ingestion), the data is considered reliable with respect to simple salts such as potassium salt.
It is concluded that further animal testing cannot be justified
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Principles of method if other than guideline:
Treatment during day 6 - 15 by oral gavage at doses from 30 - 10 000 mg/kg
GLP compliance:
not specified
Remarks:
Study performed 1978
Limit test:
no
Specific details on test material used for the study:
Although testing performed on the acid form (the anhydride quickly hydrates to the acid on ingestion), the data is considered reliable with respect to simple salts such as potassium salt.
Species:
rat
Strain:
CD-1
Route of administration:
oral: gavage
Vehicle:
water
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
Not described as study comenced on Day 6 of gestation
Duration of treatment / exposure:
From Day 6 - 15 (10 treatment days)
Frequency of treatment:
Daily
Dose / conc.:
30 mg/kg bw/day (nominal)
Dose / conc.:
300 mg/kg bw/day (nominal)
Dose / conc.:
3 000 mg/kg bw/day
Dose / conc.:
10 000 mg/kg bw/day
No. of animals per sex per dose:
Five females per treatment level
Control animals:
not specified
Maternal examinations:
Yes
Ovaries and uterine content:
Yes
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Death in four animals at 10000 mg/kg and greatly reduced bodyweight gain with anogenital staining
Parental NOAEL considered to be 3000 mg/kg/day
Mortality:
mortality observed, treatment-related
Description (incidence):
Death in four animals at 10000 mg/kg
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Reduced body weight in surviving animals at 10 000 mg/kg
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):
effects observed, treatment-related
Description (incidence and severity):
Subdued
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
not specified
Dead fetuses:
no effects observed
Changes in pregnancy duration:
not specified
Changes in number of pregnant:
not specified
Other effects:
not specified
Details on maternal toxic effects:
NOEAL 3000 mg/kg/day
Dose descriptor:
NOAEL
Effect level:
ca. 3 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
clinical signs
mortality
Abnormalities:
no effects observed
Fetal body weight changes:
no effects observed
Description (incidence and severity):
Noting that maternal mortality was not taken into account
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
Noting that maternal mortality was not taken into account
Changes in sex ratio:
not specified
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Other effects:
no effects observed
Details on embryotoxic / teratogenic effects:
No changes observed to the number of viable or non-viable foeti were observed. There were no compound related effects to resorptions, implantations or corpus lutea
Dose descriptor:
NOAEL
Effect level:
> 3 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Highest treatment level without significant maternal toxicity
Abnormalities:
no effects observed
Developmental effects observed:
no
Conclusions:
In common with this class of substance, thre was no reported teratogenic effects up to the maximum tolerated maternal treatment level.
Executive summary:

Although testing performed on the acid form (the anhydride quickly hydrates to the acid on ingestion), the data is considered reliable with respect to simple salts such as potassium salt.

It is noted that treatment levels were far in excess of those permitted in modern studies in Europe and that in view of the parental toxicity reported, these high treatment levels were inappropriate.

Reason / purpose for cross-reference:
data waiving: supporting information
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
90 days
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Justification for type of information:
Although testing was performed on the chloro derivative and not bromo, the use of this for read-across has been justified in other REACH dossiers on the basis that the chloro derivative will be more biologically active. The justification is driven by the need to avoid unecessary animal testing.
The anhydride will quickly hydrolyse to the acid form once ingested and will behave in the same way as salts that will dissociate under biological conditions.
The source data is from peer-reviewed US National Toxicity Program research.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
GLP compliance:
yes
Limit test:
no
Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Route of administration:
oral: gavage
Vehicle:
corn oil
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
90 days
Frequency of treatment:
Dosed for 5 days a week
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
94 mg/kg bw/day (nominal)
Dose / conc.:
187 mg/kg bw/day (nominal)
Dose / conc.:
375 mg/kg bw/day (nominal)
Dose / conc.:
750 mg/kg bw/day (nominal)
Dose / conc.:
1 500 mg/kg bw/day (nominal)
No. of animals per sex per dose:
10 males and 10 females
Control animals:
yes, concurrent vehicle
Observations and examinations performed and frequency:
Daily clinical observations
Weighed weekly
Sacrifice and pathology:
Necropsies on all animals
Other examinations:
Clinical pathology performed in the 94, 375 and 1500 mg/kg groups on days 6, 20, and at the end of the study.
Hematology performed in all animals at end of study.
Clinical signs:
no effects observed
Mortality:
mortality observed, non-treatment-related
Description (incidence):
One female died, as a result of a dosing accident.
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed
Description (incidence and severity):
Sperm morphology evaluations were performed from the 0, 94, 375, and 750 mg/kg dose groups.
Vaginal cytology evaluations were performed from the 0, 94, 375, and 1500 mg/kg dose groups
For the 7 days prior to sacrifice, the vaginal vaults of the females of each species and dose group were lavaged, and the aspirated lavage fluid and cells were stained with Toluidine Blue. Relative numbers of leukocytes, nucleated epithelial cells, and large squamous epithelial cells were determined and were used to ascertain estrous cycle stage (i.e., diestrus, proestrus, estrus, or metestrus).
Sperm morphology was evaluated at necropsy in the following manner. The right epididymis was isolated and weighed. The tail of the epididymis (cauda epididymis) was then removed from the epididymal body (corpus epididymis) and weighed. Test yolk (rats) or Tyrode's buffer (mice) was applied to slides, and a small incision was made at the distal border of the epididymal tail. The sperm effluxing from the incision were dispersed in the buffer on the slides and the numbers of motile and nonmotile spermatozoa were counted for 5 fields per slide.
Following completion of sperm motility estimates, each right cauda epididymis was placed in buffered 0.9% saline solution. Cauda were gently minced, and the tissue was incubated in the saline solution and then heat fixed at 65°C. Sperm density was then determined microscopically with the aid of a hemacytometer.
Dose descriptor:
NOAEL
Effect level:
ca. 1 500 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects
Critical effects observed:
yes
Lowest effective dose / conc.:
375 mg/kg bw/day (nominal)
System:
urinary
Organ:
kidney
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
not specified
Conclusions:
The toxicity to mice appears to be significantly lower than to the rat
Although the work was performed on the tetrachloro derivative instead of tetrabromo, the effects observed would not have been due to the presence of chlorine ions and can be attributed to the phthalic acid. The anhydride use in the test would quickly form as the acid on ingestion.
The substance is considered a valid read-across surrogate as the potassium salt will dissociate and behave in the same was as the acid form when exposed to biological media.

Reason / purpose for cross-reference:
data waiving: supporting information
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
90 days
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Justification for type of information:
Although testing was performed on the chloro derivative and not bromo, the use of this for read-across has been justified in other REACH dossiers on the basis that the chloro derivative will be more biologically active. The justification is driven by the need to avoid unecessary animal testing.
The anhydride will quickly hydrolyse to the acid form once ingested and will behave in the same way as salts that will dissociate under biological conditions.
The source data is from peer-reviewed US National Toxicity Program research.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Fischer 344/DuCrj
Sex:
male/female
Details on test animals or test system and environmental conditions:
Six weeks old at start of study
Route of administration:
oral: gavage
Vehicle:
corn oil
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
90 days
Frequency of treatment:
Dosed for 5 days a week
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
94 mg/kg bw/day (nominal)
Dose / conc.:
187 mg/kg bw/day (nominal)
Dose / conc.:
375 mg/kg bw/day (nominal)
Dose / conc.:
750 mg/kg bw/day (nominal)
Dose / conc.:
1 500 mg/kg bw/day (nominal)
No. of animals per sex per dose:
10 males and 10 females
Control animals:
yes, concurrent vehicle
Observations and examinations performed and frequency:
Daily clinical observations
Weighed weekly
Sacrifice and pathology:
Necropsies on all animals
Other examinations:
Clinical pathology performed in rats in the 94, 375 and 1500 mg/kg groups on days 6, 20, and at the end of the study.
Hematology performed in all animals at end of study.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
There were no compound-related clinical findings of toxicity in male rats, other than death.
Urine staining in most females in the 750 and 1500 mg/kg groups and diarrhea in all females in the 1500 mg/kg group were attributed to treatment
Mortality:
mortality observed, treatment-related
Description (incidence):
Five male rats dosed at 1500 mg/kg died during wks 5-8. A further two males died; one as a result of a dosing accident and one from unknown causes. These were not considerd treatment related
Two female rats died, one each dosed at 750 and 1500 mg/kg during wks 6 - 10 considered treatment related, One further female died as a result of a dosing accident.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Mean final body weights and weight gains of male rats in the 375, 750 and 1500 mg/kg groups and female rats in all dose groups were less than those of controls
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
All groups showed reduced food intake
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Absolute and relative kidney weights increase. Dose-dependent in female rats.
In males increased relative kidney weights from 187 mg/kg and above.
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
In male rats, renal tubule degnerative changes at the higher dose levels and tubule dilation at lower dose levels. Necrosis of the tubule epithelium was seen in the nmajority of male and female rats in the 1500 mg/kg/day group
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed
Description (incidence and severity):
Sperm morphology evaluations were performed from the 0, 94, 375, and 750 mg/kg dose groups.
Vaginal cytology evaluations were performed from the 0, 94, 375, and 1500 mg/kg dose groups
For the 7 days prior to sacrifice, the vaginal vaults of the females of each species and dose group were lavaged, and the aspirated lavage fluid and cells were stained with Toluidine Blue. Relative numbers of leukocytes, nucleated epithelial cells, and large squamous epithelial cells were determined and were used to ascertain estrous cycle stage (i.e., diestrus, proestrus, estrus, or metestrus).
Sperm morphology was evaluated at necropsy in the following manner. The right epididymis was isolated and weighed. The tail of the epididymis (cauda epididymis) was then removed from the epididymal body (corpus epididymis) and weighed. Test yolk (rats) or Tyrode's buffer (mice) was applied to slides, and a small incision was made at the distal border of the epididymal tail. The sperm effluxing from the incision were dispersed in the buffer on the slides and the numbers of motile and nonmotile spermatozoa were counted for 5 fields per slide.
Following completion of sperm motility estimates, each right cauda epididymis was placed in buffered 0.9% saline solution. Cauda were gently minced, and the tissue was incubated in the saline solution and then heat fixed at 65°C. Sperm density was then determined microscopically with the aid of a hemacytometer.
Dose descriptor:
LOAEL
Effect level:
ca. 187 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
histopathology: non-neoplastic
Critical effects observed:
yes
Lowest effective dose / conc.:
375 mg/kg bw/day (nominal)
System:
urinary
Organ:
kidney
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
not specified
Conclusions:
Although the work was performed on the tetrachloro derivative instead of tetrabromo, the effects observed would not have been due to the presence of chlorine ions and can be attributed to the phthalic acid. The anhydride use in the test would quickly form as the acid on ingestion.
The substance is considered a valid read-across surrogate as the potassium salt will dissociate and behave in the same was as the acid form when exposed to biological media.

Data source

Materials and methods

Results and discussion

Applicant's summary and conclusion