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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.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

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available

Effects on developmental toxicity

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1979-1980
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study well documented, acceptable for assessment
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
other: Crl:CD(SD)BR
Details on test animals or test system and environmental conditions:
TEST ANIMALS
Source: Charles River Breeding Laboratories, Inc., North Wilmington, MA
Housing: individually
Diet: ad libitum
Water: ad libitum
Acclimation period: ca. 2 days

ENVIRONMENTAL CONDITIONS
Temperature (°C): 24 +/- 4
Humidity (%): 50 +/- 20
Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
dermal
Vehicle:
other: Dimethyl phthalate
Details on exposure:
Rats were grouped on gestation days 3 and 4 so that group mean body weights were similar. Three groups, each of 27 rats, were treated dermally with ca. 0, 110, 225 or 475 mg/kg bw/d. Rats were treated once daily from day 6 to day 15 of gestation. Doses were delivered as the appropriate concentration of 1,1,3,3-tetrabutylurea in 0.5 ml dimethyl phthalate. For the low-, intermediate- and high-dose groups, the concentrations of 1,1,3,3-tetrabutylurea in dimethyl phthalate were 5, 10 and 20% (v/v), respectively. Daily applications were made to the clipped intact skin of the back, and hair was removed by clipping whenever necessary during the 10-day dosing period. Each dose of 1,1,3,3-tetrabutylurea or dimethyl phthalate was delivered by a separate pipette; the last drop was touched off and the liquid was gently distributed over a surface area of approximately 4 cm2.
Analytical verification of doses or concentrations:
no
Details on mating procedure:
The rats arrived in the laboratory on day 3 of gestation
Duration of treatment / exposure:
Rats were treated once daily from days 6 to 15 of gestation
Frequency of treatment:
once daily
Duration of test:
study was terminated on day 21 of gestation
Remarks:
Doses / Concentrations:
ca. 0, 110, 225 or 475 mg/kg bw/d
Basis:

No. of animals per sex per dose:
Number of pregnant rats per group: 24, 24, 22 and 18
Control animals:
yes, concurrent vehicle
Details on study design:
Dose levels were selected following pilot studies
Maternal examinations:
Rats were weighed five times during gestation and observations for clinical signs were made daily. On day 21 of gestation, each rat was killed by chloroform inhalation. The uterus was removed, weighed and opened and the foetuses were separated from the uterine wall and examined. The number of corpora lutea in each ovary, the number of implantation sites in each uterine horn and the numbers and locations of all live and dead foetuses and resorptions were recorded. The uterus and ovaries of each rat were examined for gross changes and preserved, while other tissues and organs were examined grossly and discarded if found to be normal.
Ovaries and uterine content:
see above
Fetal examinations:
Each foetus was weighed and was given a thorough inspection under a long focal length lens of x 2.5 magnification to determine structural characteristics. Approximately one half of the foetuses from each litter were examined for skeletal integrity, while the remaining foetuses were examined for visceral and neural anomalies.
Statistics:
The Fisher's exact probability test was used to evaluate the incidence of litters with resorptions. Foetal body weights and lengths and maternal body weights were assessed by analyses of variance and least significant difference tests. The numbers of corpora lutea, implantations and live foetuses per litter were analysed by the Mann-Whitney U test. In all cases, two-tailed significance tests were performed and significance was judged at the 0.05 significance level.
Historical control data:
no data
Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
All rats survived the entire test period. No abnormal clinical signs were observed among rats receiving either solvent control or 110 mg/kg bw. In rats receiving 225 mg/kg bw, mild to moderate skin irritation was observed at the application site, generally after two to five doses. Moderate skin irritation after two to five doses and fissuring after five to eight doses was seen in most rats treated with 475 mg/kg bw. No other unusual clinical signs were seen in the rats treated at the two highest dose levels.
Body-weight gain over days 6-16 was markedly reduced in rats receiving 475 mg/kg bw. It was moderately reduced during the treatment period in the 225 mg/kg bw group, but had recovered somewhat by day 21. Body-weight gain was only slightly depressed during the treatment period at 110 mg/kg bw (81, 71, 60 or 25 g, respectively).
No gross pathological changes were detected in the ovaries or uteri of 1,1,3,3-tetrabutylurea-treated rats. Examined parameters included no. of females pregnant, no. of corpora lutea/pregnant female, no. of implantations/litter, no. of live foetuses/litter, no. of litters with resorptions, no. of resorptions/litter, foetal weights. At 475 mg/kg bw, the number of pregnant females (those with foetuses or implantation sites) was significantly lower than in the control group. In three pregnant females of this group, all fertilized ova were resorbed shortly after implantation; the few remnants of deciduomas were barely visible and involution of the corpora lutea was apparent. The numbers of resorptions in this group were not elevated overall, but the number per litter calculated only on the litters showing some resorptions was somewhat increased (3.3 vs. 1.6 in controls). The outcome of pregnancy in rats receiving <= 225 mg/kg bw was comparable with the controls.
Dose descriptor:
NOAEL
Effect level:
110 mg/kg bw/day
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
Subcutaneous haematomas and petechial haemorrhages on various parts of the body were found in foetuses in all groups. Two foetuses from two females in the control group were small and were classified as runts. An umbilical hernia was detected in one foetus in each of the test groups treated with <= 225 mg/kg bw. One foetus in a litter of nine exposed to 110 mg/kg bw had multiple malformations (protruding dark left eye, exencephalocoele, micrognathia, anophthalmia of the right eye, and misshapen and large kidneys). Most of the visceral alterations in foetuses from other litters involved the urinary system, and included dilatation of the renal pelvis and ureter, reduction of the renal papilla and hydronephrosis. Other less frequent variants were liver peliosis, distension of the nasal cavity, a space between the brain and the skull, a large umbilical vein and displaced testes. The incidence of these (except peliosis in the liver) was not significantly different in the test and control groups. Peliosis was increased in foetuses derived from dams treated with 225 but not with 475 mg/kg bw.
The incidence of skeletal alterations among foetuses from females exposed to >= 225 mg/kg bw was higher than that in the control group, was dose related, and involved ribs, sternebrae, thoracic and lumbar centra and skull bones. None of the alterations were classified as malformations. However, in the two high-level test groups, the incidences of an extra 14th rudimentary and full-sized rib(s), partially ossified and unossified sternebrae, and dumb-bell-shaped centra were significantly higher compared with controls. Even though the weights of the foetuses in these two groups were not statistically different compared with controls, the foetuses were somewhat smaller. Both the smaller size of the foetuses and the increased incidence of skeletal alterations were attributed to the observed maternal toxicity at >= 225 mg/kg bw.
Dose descriptor:
NOAEL
Effect level:
475 mg/kg bw/day
Basis for effect level:
other: teratogenicity
Abnormalities:
not specified
Developmental effects observed:
not specified
Conclusions:
Under the conditions of this study, 1,1,3,3-tetrabutylurea was not teratogenic when applied dermally to rats at doses up to 475 mg/kg bw/d
Executive summary:

The teratogenic potential of 1,1,3,3-tetrabutylurea was evaluated in Crl:CD(SD)BR rats. Doses of ca. 0, 110, 225 or 475 mg/kg bw were applied to the shaven dorsal skin on days 6–15 of gestation, the day on which a sperm-positive vaginal smear was present being designated day 1. The rats were killed 1 day before natural delivery and the foetuses were examined for external development, structure and integrity of internal tissues and organs, and skeletal development. No maternal effects were seen in rats exposed to 110 mg/kg bw, but skin irritation and a reduction in maternal body-weight gains were seen in rats treated with >= 225 mg/kg bw, the effects being more pronounced in the 475 mg/kg bw group. In the latter group, the number of pregnancies maintained was reduced and the number of resorptions per litter, calculated only on the litters with resorptions, was increased. Foetuses derived from the females treated with 475 mg/kg bw were slightly smaller than the controls but were structurally normal. The outcome of pregnancy was unaltered in rats given <= 225 mg/kg bw. No increase in malformed foetuses was observed in any of the test groups.

Under the conditions of this study, 1,1,3,3-tetrabutylurea was not teratogenic when applied dermally to rats at doses up to 475 mg/kg bw.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
475 mg/kg bw/day
Study duration:
subacute
Species:
rat

Toxicity to reproduction: other studies

Additional information

Rats were treated dermally once daily with ca. 0, 110, 225 or 475 mg/kg bw/d from day 6 to day 15 of gestation. All rats survived the entire test period and in dams no adverse effects were seen at a dose level of 110 mg/kg bw. Under the conditions of this study, 1,1,3,3-tetrabutylurea was not teratogenic when applied dermally to rats at doses up to 475 mg/kg bw.

Justification for classification or non-classification

As effects on the offspring were only seen at maternally toxic dose levels, there is no need for classification and labelling.

Additional information