Dibutyl hydrogen phosphate

Repeated dose toxicity: oral

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

Test material information

Constituent 1

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 / concentrations

Doses / concentrations 1

Dose / conc.:

30 mg/kg bw/day (nominal)

Doses / concentrations 2

Dose / conc.:

100 mg/kg bw/day (nominal)

Doses / concentrations 3

Dose / conc.:

300 mg/kg bw/day (nominal)

Doses / concentrations 4

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.