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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP guideline study (OECD combined repeat dose and reproductive/developmental toxicity screening test)
Cross-reference
Reason / purpose for cross-reference:
reference to same study
Reference
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
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
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
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
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
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
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).
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.
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

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).

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.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1995

Materials and methods

Test guideline
Qualifier:
equivalent or similar 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
preliminary reproduction toxicity screening test performed as dose range finder with doses of 0, 50, 100, 200, 500, and 1000 mg/kg bw/day

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: sesame oil
Details on mating procedure:
Male and female animals were exposed to the test substance 14 days before mating.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Exposure period: 44 days (male) and from 14 days before mating to day 3 of lactation (females).
Frequency of treatment:
once daily
Details on study schedule:
Males were sacrificed on day 45. Females were sacrificed on day 4 of lactation.
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

Examinations

Parental animals: Observations and examinations:
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)

for further information see chapter 7.8.1 (reference to same study)
Litter observations:
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities

GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities
Postmortem examinations (parental animals):
see IUCLID chapter 7.5.1
plus: histopathology of reproductive organs (e.g. ovary)
Postmortem examinations (offspring):
external anomalies and visceral anomalies
Reproductive indices:
copulation index, fertility index, implantation index, gestation index, delivery index
Offspring viability indices:
live birth index, viability index

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

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
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Decrease in food consumption at >= 100 mg/kg bw (males).
Haematological findings:
no effects observed
Description (incidence and severity):
No effects on urinary, hematological and blood chemical findings in the males (females not given).
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Description (incidence and severity):
No effects on urinary, hematological and blood chemical findings in the males (females not given).
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
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 treated 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

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed

Details on results (P0)

The parental animals exhibited no significant effects on reproductive parameters including copulation index, fertility index, numbers of corpora lutea and implantation sites, gestation index and gestation lenghts - see Table 5 attached

Effect levels (P0)

open allclose all
Key result
Dose descriptor:
NOEL
Effect level:
30 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: maternal toxicity
Key result
Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: fertility
Remarks on result:
other: The parental animals exhibited no significant effects on reproductive parameters including copulation index, fertility index, numbers of corpora lutea and implantation sites, gestation index and gestation lengths.

Target system / organ toxicity (P0)

Key result
Critical effects observed:
no

Results: F1 generation

General toxicity (F1)

Mortality / viability:
mortality observed, treatment-related
Description (incidence and severity):
the number of pups alive on day 4 of lactation was reduced in the 1000 mg/kg bw group compared to control (in male pups not significant; in female pups significant (p<0.05)) - see Table 6 attached
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
body weight on day 0 of male and female pups in 1000 mg/kg bw group lower than control (not significant) - see Table 6 attached
Gross pathological findings:
no effects observed
Description (incidence and severity):
no treatment related external or visceral anomalies - see Table 7 attached

Effect levels (F1)

Key result
Dose descriptor:
NOEL
Generation:
F1
Effect level:
300 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
viability
other: The number of live pups and the viability index on day 4 of lactation decreased with 1000 mg/kg.

Target system / organ toxicity (F1)

Key result
Critical effects observed:
no

Overall reproductive toxicity

Key result
Reproductive effects observed:
yes
Lowest effective dose / conc.:
300 mg/kg bw/day
Treatment related:
yes
Relation to other toxic effects:
not specified
Dose response relationship:
yes

Any other information on results incl. tables

The parental animals exhibited no significant effects at dosages of 30, 100, 300, or 1000 mg/kg bw/day on reproductive parameters including copulation index, fertility index, numbers of corpora lutea and implantation sites, gestation index, gestation lenght, absolute and relative weight of examined reproductive organs and histopathological findings.

Applicant's summary and conclusion

Executive summary:

In an OECD combined repeat 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. Absolute and relative reproductive organ weight and reproductive parameters were determined.


Maternal toxicity became obvious as body weight gain decrease in males and mortality of 3 males and 2 females in the 1000 mg/kg bw groups. 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 for maternal toxicity was thus determined with 30 mg/kg bw for both sexes.


The parental animals exhibited no significant effects at dosages of 30, 100, 300, or 1000 mg/kg bw/day on reproductive parameters including copulation index, fertility index, numbers of corpora lutea and implantation sites, gestation index, gestation length, absolute and relative weight of examined reproductive organs and histopathological findings. The NOEL for reproductive toxicity is therefore 1000 mg/kg bw/day for both sexes.