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Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Remarks:
combined repeated dose and reproduction / developmental screening
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP guideline study

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1995

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Dibutyl hydrogen phosphate
EC Number:
203-509-8
EC Name:
Dibutyl hydrogen phosphate
Cas Number:
107-66-4
Molecular formula:
C8H19O4P
IUPAC Name:
dibutyl hydrogen phosphate

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on species / strain selection:
Crj:CD (SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Weight at study initiation: males: 331-262 g; females: 192-215 g

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +- 3
- Humidity (%): 55 +- 10

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: sesame oil
Duration of treatment / exposure:
44 days (male) and from 14 days before mating to day 3 of lactation (females)
Frequency of treatment:
once daily
Doses / concentrationsopen allclose all
Dose / conc.:
30 mg/kg bw/day (nominal)
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
300 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
10 male and 10 female animals per dose
Control animals:
yes, concurrent vehicle
Details on study design:
preliminary reproduction toxicity screening test performed as dose range finder with doses of 0, 50, 100, 200, 500, and 1000 mg/kg bw/day

sacrifice:
males on day 45
females on day 4 of lactation
Positive control:
not adequate

Examinations

Observations and examinations performed and frequency:
MORTALITY: Yes

CLINICAL SIGNS: Yes

BODY WEIGHT: Yes
- Time schedule for examinations:
males: days 1, 8, 15, 22, 29, 36, and 43/44
females: days 1, 8, 15 (days of premating); days 0, 7, 14, 20 (days of pregnancy); days 0 and 4 (days of lactation)

HAEMATOLOGY: Yes
- How many animals: 10 males (high dose: 7 males)
- Parameters checked in table [No. 1 - see attachment] were examined.

CLINICAL CHEMISTRY: Yes
- How many animals: 10 males (high dose: 7 males)
- Parameters checked in table [No. 1 - see attachment] were examined.

PLASMA/SERUM HORMONES/LIPIDS: Yes
- How many animals: 10 males (high dose: 7 males)
- Parameters checked in table [No. 1 - see attachment] were examined.
Sacrifice and pathology:
ORGAN WEIGHTS: Yes (table 2 - see attachment)
- males (10 animals): liver, kidneys, thymus, testes, epididymides (absolute and relative weight)
- females (5 to 10 animals): liver, kideys, thymus (absolute and relative weight)

HISTOPATHOLOGY: Yes (table 3 - see attachment)
- males (10 animals): lung, heart, liver, stomach, cecum, kidney, urinary bladder, adrenals, thymus, spleen data shown
Statistics:
yes

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
red urine in 4 males at 100 mg/kg, 7 males at 300 mg/kg, and 5 male survivors at 1000 mg/kg bw
Mortality:
mortality observed, treatment-related
Description (incidence):
3 males and 2 females died in the 1000 mg/kg bw group.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Body weight gain significantly decreased in males at 1000 mg/kg bw/day (about -14% at termination) - see figures 1 and 2 attached
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Description (incidence and severity):
No effects on urinary, hematological and blood chemical findings in the males (females not given), see Table 1 attached.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
No effects on urinary, hematological and blood chemical findings in the males (females not given), see Table 1 attached
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
No effects on urinary findings in the males (females not given), see Table 1 attached.
Behaviour (functional findings):
not specified
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Increase of absolute and relative liver weight and hepatocellular swelling in females with 1000 mg/kg bw - see Table 2 attached
Gross pathological findings:
not specified
Description (incidence and severity):
Epithelial hyperplasia and hyperkeratosis of the forestomach (some with erosion and ulceration in the gastric mucosa) were noted in both sexes >= 300 mg/kg bw.
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Histopathology showed epithelial hyperplasia accompanied by degeneration and ulceration of the urinary bladder mucosa in males and females with >= 100 mg/kg bw. Epithelial hyperplasia and hyperkeratosis of the forestomach (some with erosion and ulceration in the gastric mucosa) were noted in both sexes >= 300 mg/kg bw. - see Tables 3 and 4 attached
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Details on results:
Transient red urine and a decrease in food consumption with >= 100 mg/kg bw (males). 3 males and 2 females died in the 1000 mg/kg bw group. No effects on urinary, hematological and blood chemical findings in the males (females not given). Histopathology showed epithelial hyperplasia accompanied by degeneration and ulceration of the urinary bladder mucosa in males and females with >= 100 mg/kg bw. Epithelial hyperplasia and hyperkeratosis of the forestomach (some with erosion and ulceration in the gastric mucosa) were noted in both sexes >= 300 mg/kg bw. Increase of absolute and relative liver weight and hepatocellular swelling in females with 1000 mg/kg bw. NOEL 30 mg/kg bw for both sexes.  For reproductive effects see chapter 7.8 (Toxicity to reproduction).

Effect levels

Key result
Dose descriptor:
NOAEL
Effect level:
30 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
histopathology: non-neoplastic
Remarks on result:
other:
Remarks:
Histopathology showed epithelial hyperplasia accompanied by degeneration and ulceration of the urinary bladder mucosa in males and females with >= 100 mg/kg bw. Epithelial hyperplasia and hyperkeratosis of the forestomach (some with erosion and ulceration in the gastric mucosa) were noted in both sexes >= 300 mg/kg bw. Increase of absolute and relative liver weight and hepatocellular swelling in females with 1000 mg/kg bw.

Target system / organ toxicity

Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
100 mg/kg bw/day (nominal)
System:
urinary
Organ:
bladder
Treatment related:
yes
Dose response relationship:
yes

Any other information on results incl. tables

Transient red urine and a decrease in food consumption with >= 100 mg/kg bw (males). 3 males and 2 females died in the 1000 mg/kg bw group. No effects on urinary, hematological and blood chemical findings in the males (females not given).
Histopathology showed epithelial hyperplasia accompanied by degeneration and ulceration of the urinary bladder mucosa in males and females with >= 100 mg/kg bw. Epithelial hyperplasia and hyperkeratosis of the forestomach (some with erosion and ulceration in the gastric mucosa) were noted in both sexes >= 300 mg/kg bw. Increase of absolute and relative liver weight and hepatocellular swelling in females with 1000 mg/kg bw.
NOEL 30 mg/kg bw for both sexes.  For reproductive effects see chapter 7.8 (Toxicity to reproduction).

Applicant's summary and conclusion

Conclusions:
The NOEL is considered to be 30 mg/kg bw for both sexes. 

Transient red urine and a decrease in food consumption with >= 100 mg/kg bw (males). 3 males and 2 females died in the 1000 mg/kg bw group. No effects on urinary, hematological and blood chemical findings in the males (females not given). Histopathology showed epithelial hyperplasia accompanied by degeneration and ulceration of the urinary bladder mucosa in males and females with >= 100 mg/kg bw. Epithelial hyperplasia and hyperkeratosis of the forestomach (some with erosion and ulceration in the gastric mucosa) were noted in both sexes >= 300 mg/kg bw. Increase of absolute and relative liver weight and hepatocellular swelling in females with 1000 mg/kg bw. NOEL 30 mg/kg bw for both sexes.
Executive summary:

In an OECD combined repeated dose and reproductive/developmental toxicity screening test 10 male and 10 female rats per group were administered doses of 0, 30, 100, 300 or 1000 mg/kg bw of the test substance per gavage. Administration period for males were 44 days , and for females, from 14 days before mating to day 3 of lactation. Mortality, clinical signs, body weight, urinary, hematological and blood chemistry were examined and a histophatological examination conducted. Males were sacrificed on day 45. Females were sacrificed on day 4 of lactation.


3 males and 2 females died in the 1000 mg/kg bw group. No effects on urinary, hematological and blood chemical findings in the males (females not given). Histopathology showed epithelial hyperplasia accompanied by degeneration and ulceration of the urinary bladder mucosa in males and females with >= 100 mg/kg bw. Epithelial hyperplasia and hyperkeratosis of the forestomach (some with erosion and ulceration in the gastric mucosa) were noted in both sexes >= 300 mg/kg bw. Increase of absolute and relative liver weight and hepatocellular swelling in females with 1000 mg/kg bw. NOEL 30 mg/kg bw for both sexes.