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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1990
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1991
Report date:
1991

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
EPA OTS 798.4900 (Prenatal Developmental Toxicity Study)
Principles of method if other than guideline:
Tributyl phosphate was administrated by gastric intubation to mated New Zealand White rabbits (18 mated females/group) at dose levels of 50, 150 and 400 mg/kg/day during the day 6-18 gestation period. Included in this study was a vehicle-treated control group. During gestation, body weights and food consumption were recorded.
GLP compliance:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
Tributyl phosphate
EC Number:
204-800-2
EC Name:
Tributyl phosphate
Cas Number:
126-73-8
Molecular formula:
C12H27O4P
IUPAC Name:
tributyl phosphate
Constituent 2
Reference substance name:
200-800-2
IUPAC Name:
200-800-2
Constituent 3
Reference substance name:
tributyl phospate
IUPAC Name:
tributyl phospate
Details on test material:
purity 99.7 %

Test animals

Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Hazelton Research Products Inc. Denver Pennlylvania
- Weight at study initiation: 4019 g mean
- Fasting period before study: no
- Housing: individually
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 75 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 58-74°F
- Humidity (%): 30-67%
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: 1990

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Homogeneity analyses for the batch sizes used in this study were
performed at the low- and high-concentration levels (50 and 400 mg/ml,
respectively). The mean percents of nominal± standard deviation (S.O.) for
this set of six samples at the low- and high-concentration 1eve1s were 103 ±
1.03% and 102 ± 1.22%, respective1y. On the basis of these data, dosing
solutions at these concentration levels as prepared were considered homogeneous.
Analyses of dosing solutions used for the study demonstrated a mean
percent of nominal ± S.O. of 106 ± 3.21% for Group II, 103 ± Q.84% for Group III
and 105 ± 2.74% for Group IV.
Details on mating procedure:
each female selected for mating was paired with 2 males.
Duration of treatment / exposure:
day 6 to 18 of gestation
Frequency of treatment:
once daily
Duration of test:
sacrifice on day 30 of gestation
Doses / concentrationsopen allclose all
Dose / conc.:
50 mg/kg bw/day
Dose / conc.:
150 mg/kg bw/day
Dose / conc.:
400 mg/kg bw/day
No. of animals per sex per dose:
18 pregnant females per dose
Control animals:
yes
Details on study design:
Sex: female
Duration of test: up to day 30 of gestation

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: days 0, 6, 9, 12, 15, 19, 24, and 30 of gestation

FOOD CONSUMPTION: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 30
- Organs examined:
Complete gross postmortem examinations
were perfonned on all mated rabbits
including those dying spontaneously
during the study. Only abnormal tissues
were saved (10% neutral buffered
fonnalin). Females showing signs of
abortion (passing of placental/fetal
tissue prior to Day 26 of gestation) or
premature delivery (presence of
fetuses/pups at Day 26 of gestation or
later) were killed via intravenous
injection of sodium pentobarbital in the
marginal ear vein on the day such
evidente was observed. Reproductive
systems were examined. Fetuses/
delivered pups recovered during the Day
26-30 gestation interval were evaluated
for external malfonnations, eviscerated
and processed for staining of the
skeletal structures with Alizarin Red S.
These stained specimens were evaluated
for ske1etal malfonnations only. Intact
fetuses recovered from females aborting
their pregnancies were eva1uated for
external malfonnations and discarded.
Liver weights were also recorded for
females surviving to Day 30 gestation
sacrifice.
Ovaries and uterine content:
The intact uterus (ovaries attached) was
removed from the abdominal cavity,
weighed and the number and location of
the following were recorded for each
uterine horn:
live fetuses
dead fetuses (no evidence of tissue degeneration)
late resorptions {recognizable dead fetus undergoing degeneration
regardless of size) early resorptions (evidence of
implantation but no recognizable
fetus) implantation sites
The ovaries were dissected free from the
uterus and evaluated for the presence
and number of corpora lutea.
When no uterine implants were grossly
apparent, the uterus was stained with
ammonium sulfide (method of Salewski). Foci visualized
following this staining procedure were
counted and females with such foci were
included as pregnant in the calculation
of pregnancy rate. The numbers of foci
were not included in the calculation of
uterine implantation data. When no foci
were visualized post-staining, the
female was considered not pregnant.
Fetal examinations:
All fetuses were given a gross examination for external malformations/variations to include observation for palatal defects. Subsequently, each fetus was weighed and tagged
individually for identification.
All fetuses were examined for visceral and skeletal malformations.
Statistics:
Data were analyzed between control (Group I) and treatment groups (Groups
II-IV}. Statistically significant differences between the control and treatment group data are presented in summary and mean tables of the appendices.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Description (incidence and severity):
Findings noted during the physical examinations of the females in
the treatment groups occurred at low incidence or with comparable frequency as
in the control group and no adverse effects of treatment at doses up to and
including 400 mg/kg/day were evident.
Mortality:
mortality observed, treatment-related
Description (incidence):
No mortality occurred in the control (Group I) or treatment Groups
II and III.
In Group IV, two femates died (mortality rate= 10.5%, Appendix G).
The death of one of these females (No. 4503) was not considered tobe related to
treatment. This female which died on Day 8 of gestation, was difficult to
handle at the time of dosing and was set aside tobe dosed later. However, she
was found dead prior to the second attempt to administer the dose. The death of
this female was attributed to injuries/complications incurred while handling to
administer the dose. The other death in Group IV was female No. 4505. This
female, which was found dead on Day 28 of gestation, had lost 441 grams during
the Oay 6-19 gestation interval and 188 grams during the Day 19-24 posttreatment
gestation interval. This female had also experienced a reduction in
food consumption from Day 10 of gestation to Day 24 (the last recording
interval). At gross postmortem examination, tesions of the tungs (edema) and
bronchi (presence of dark red fluid) were noted and 10 fetuses were recovered in
utero; however, the cause of death could not be determined from these findings.
Thus, only at the 400 mg/kg/day dose level was a low incidence of
maternat mortality encountered. (see Table G in Attachment)
Description (incidence and severity):
Mean body weights for each recording interval during gestation
(Days 0, 6, 9, 12, 15, 19, 24 and 30) were comparable between the control and
each treatment group (Table C in Attachment).
No adverse effect of treatment at doses up to and including
150 mg/kg/day was evident from maternal weight data or weight change data during
gestation. At the 400 mg/kg/day dose level, maternal toxicity was suggested
from the weight losses experienced during the several weighing intervals of the
treatment period, albeit, only for the Oay 6-9 gestation interval was this
difference from control data statistically significant.
Description (incidence and severity):
no adverse effect of treatment at doses up to and including
150 mg/kg/day was evident from gestation food consumption data. At the 400
mg/kg/day dose level, a slight reduction in food consumption seen over the Oay
7-14 gestation interval was considered suggestive of a treatment-related
response.
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
no adverse effect of treatment at doses up to and including
400 mg/kg/day was evident from liver weight data. (see Table J-2 in Attachment)
Gross pathological findings:
no effects observed
Description (incidence and severity):
Tan/red foci in the lungs were observed in some animals from all
groups with a slightly greater incidence of red foci seen in the treatment
animals. The toxicological significance of this finding on the basis of gross
examination only is unclear.
Other postmortem findings observed grossly occurred sporadically
and were not considered tobe related to the test article.
Description (incidence and severity):
Pregnancy rates were 88.9% for the control and treatment Groups II
and III and 100.0% for Group IV.
No adverse effect of treatment at doses up to and including 400
mg/kg/day was evident from pregnancy rates. (see Table G-1 in Attachment)

Maternal developmental toxicity

Number of abortions:
no effects observed
Description (incidence and severity):
The incidences of females that aborted or delivered prematurely for
the control group and treatment Groups II, III and IV were 6.3% (1/16), 12.5%
(2/16), 0% (16 pregnancies) and 5.9% {1/17) respectively. These incidences
were considered comparable between the control and each treatment group.
Thus, no adverse effect of treatment at doses up to and including
400 mg/kg/day was evident from abortion or premature delivery data. (see Table G-1 in Attachment)
Pre- and post-implantation loss:
effects observed, treatment-related
Description (incidence and severity):
no adverse effect of treatment at doses up to and including
150 mg/kg/day was evident from uterine implantation data. At the 400 mg/kg/day
dose level, the mean number of resorptions and the mean resorption/implant ratio
were increased sufficiently to be suggestive of a treatment-related response. (see Table G-1 in Attachment)

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
> 150 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
no adverse effect of treatment at doses up to and including
400 mg/kg/day was evident from fetal weight data. (see Table G-1 in Attachment)
Changes in sex ratio:
no effects observed
Description (incidence and severity):
up to and including the 400 mg/kg/day dose level, no adverse
effect of treatment was evident from fetal sex distribution data. (see Table G-1 in Attachment)
External malformations:
no effects observed
Description (incidence and severity):
No external malformations were seen in the 124 control fetuses
(15 litters), 117 Group II fetuses {14 litters} or 134 Group III fetuses (16
litters) recovered and evaluated at Day 30 gestation maternal sacrifice. In
Group IV, the incidence of fetuses with external malformations was 2.6% (3/117
fetuses). The incidence of litters containing fetuses with external
malformations for Group IV was 12.5% (2/16 litters). These incidences of
external malformations for treatment Group IV on both a per fetus and per litter
basis, did not differ statistically from the concurrent control data.
no clear adverse effect of treatment at doses up to and
including 400 mg/kg/day was evident from fetal external malformation data. (see Table L-1 in Attachment)
Description (incidence and severity):
The incidences of fetuses with skeletal malfonnations for the
control and treatment Groups II, III and IV were 3.2% (4/124 fetuses), 6.0%
(7/117 fetuses), 0.8% (1/125 fetuses) and 4.3% (5/117 fetuses), respectively.
The incidences of litters containing fetuses with skeletal malfonnations for
these same groups were 26.7% (4/15 litters), 50.0% (7/14 litters), 6.7% (1/15
litters) and 25.0% (4/16 litters), respectively. These incidences on aper
fetus and per litter basis did not differ statistically between the control and
treatment groups and were considered comparable between these same groups.
no adverse effect of treatment at doses up to and
including 400 mg/kg/day was evident from fetal skeletal malformation data. (see Table N-1 in Attachment)
Visceral malformations:
no effects observed
Description (incidence and severity):
No visceral malformations were seen in the 124 control fetuses
(15 litters), 116 Group II fetuses (14 litters) or 134 Group III fetuses (16
litters) evaluated. In Group IV, the incidence of fetuses with visceral
11alfonoations was 1.7% {2/117) and the incidence of litters containing affected
fetuses was 6.3% (1/16 litters}. These incidences on both aper fetus and per
litter basis, did not differ statistically from control data.
The only visceral malformation seen was distention of the
lateral ventricle of the brain. This malfonnation was seen in the two fetuses
from a single Group IV litter noted externally with domed cranium. In the
absence of other visceral malfonnations among the Group IV fetuses, the
relatively low incidence of this one finding was not considered indicative of a
treatment-related response. (see Table M-1 in Attachment)

Effect levels (fetuses)

open allclose all
Dose descriptor:
NOAEL
Effect level:
> 150 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: embryotoxicity
Dose descriptor:
NOAEL
Effect level:
> 150 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: fetotoxicity
Dose descriptor:
NOAEL
Effect level:
> 150 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: teratogenicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
no

Any other information on results incl. tables

at the 400 mg/kg/day dose level maternal toxic effect
(mean weight loss) and not statistically significant
increase of resorptions, no fetotoxic or teratogenic
effects, at the 50 and 150 mg/kg/day dose level no maternal
toxicity, no embryotoxic, fetotoxic or teratogenic
effects.

Applicant's summary and conclusion

Executive summary:

Under the conditions of this study, tributyl phosphate mixed in corn oil and administered by gastric intubation to pregnant New Zealand White rabbits over the Day 6-18 gestation interval was not maternally toxic, embryotoxic, fetotoxic or teratogenic at dose levels of 50 and 150 mg/kg/day.
At the 400 mg/kg/day dose level, one female died late in gestation (Day 28) but the cause of death could not be determined on the basis of gross postmortem observations. The death of a second female in this group was attributed to injuries incurred while handling to administer the dose. Maternal toxicity at the 400 mg/kg/day dose level was indicated from mean weight loss experienced during the Day 6-9 gestation interval; this difference in comparison to the mean weight gain experienced by the concurrent control group during this interval was statistically significant. Other changes seen at the 400 mg/kg/day dose level which did not differ statistically from control data but which were considered suggestive of a maternal toxic response were as follows: mean weight losses during several intervals of the treatment period (Days 9-12 and 12-15) in comparison to mean weight gains for the control; mean weight loss over the entire Day 6-19 gestation interval in comparison to a mean weight gain for the control group; and reduced levels of food consumption over the Day 7-14 gestation interval. At Day 30 of gestation, the mean number of resorptions per pregnant female and the mean resorption/implant ratio for the 400 mg/kg/day dose level were increased in cornparison to concurrent control and recent historical control data for this laboratory, and while these differences were not statistically significant, an embryotoxic response rnay be suggested. The 400 mg/kg/day dose level was not considered tobe fetotoxic or teratogenic.


Thus, the no-observable-adverse-effect level (NOAEL) for developmental toxicity of tributy phosphate in the rabbit for this study was 150 mg/kg/day.