Tetrabutylurea

Endpoint summary

Description of key information

The NOAEL of 27 mg/cm2 was calculated from an applied dose of 110 mg/kg bw/d, which has been distributed over a surface area of approximately 4 cm2.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: dermal

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:

other: OECD Guideline 414 (Prenatal Developmental Toxicity Study)

GLP compliance:

no

Limit test:

no

Species:

rat

Strain:

other: Crl:CD(SD)BR

Sex:

female

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

Type of coverage:

not specified

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

Duration of treatment / exposure:

Rats were treated once daily from days 6 to 15 of gestation, i.e. 10 days

Frequency of treatment:

once daily

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

Observations and examinations performed and frequency:

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.

Sacrifice and pathology:

study was terminated on day 21 of gestation

Statistics:

Fisher's exact probability test, analyses of variance and least significant difference tests, Mann-Whitney U test

Clinical signs:

no effects observed

Dermal irritation:

effects observed, treatment-related

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Details on results:

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). The examination of different tissues and organs (not further specified) gave no indication for adverse effects.

Dose descriptor:

NOAEL

Effect level:

110 mg/kg bw/day

Sex:

female

Basis for effect level:

other: Skin irritation and a reduction in maternal bodyweight gains

Critical effects observed:

not specified

Conclusions:

In dosed rats no adverse effects were seen at a dose level of 110 mg/kg bw

Executive summary:

In a study focussed on developmental toxicity and teratogenicity, female rats were dosed dermally with 0, 110, 225 or 475 mg/kg bw once daily over 10 days. At 110 mg/kg bw no adverse effects were observed (NOAEL), while at the higher doses skin irritation and a reduction in bodyweight gains was seen. The examination of different tissues and organs (not further specified) gave no indication for adverse effects.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

110 mg/kg bw/day

Study duration:

subacute

Species:

rat

Repeated dose toxicity: dermal - local effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: dermal

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:

other: OECD Guideline 414 (Prenatal Developmental Toxicity Study)

GLP compliance:

no

Limit test:

no

Species:

rat

Strain:

other: Crl:CD(SD)BR

Sex:

female

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

Type of coverage:

not specified

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

Duration of treatment / exposure:

Rats were treated once daily from days 6 to 15 of gestation, i.e. 10 days

Frequency of treatment:

once daily

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

Observations and examinations performed and frequency:

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.

Sacrifice and pathology:

study was terminated on day 21 of gestation

Statistics:

Fisher's exact probability test, analyses of variance and least significant difference tests, Mann-Whitney U test

Clinical signs:

no effects observed

Dermal irritation:

effects observed, treatment-related

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Details on results:

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). The examination of different tissues and organs (not further specified) gave no indication for adverse effects.

Dose descriptor:

NOAEL

Effect level:

110 mg/kg bw/day

Sex:

female

Basis for effect level:

other: Skin irritation and a reduction in maternal bodyweight gains

Critical effects observed:

not specified

Conclusions:

In dosed rats no adverse effects were seen at a dose level of 110 mg/kg bw

Executive summary:

In a study focussed on developmental toxicity and teratogenicity, female rats were dosed dermally with 0, 110, 225 or 475 mg/kg bw once daily over 10 days. At 110 mg/kg bw no adverse effects were observed (NOAEL), while at the higher doses skin irritation and a reduction in bodyweight gains was seen. The examination of different tissues and organs (not further specified) gave no indication for adverse effects.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

27 mg/cm²

Study duration:

subacute

Species:

rat

Additional information

In a study focussed on developmental toxicity and teratogenicity, female rats were dosed dermally with 0, 110, 225 or 475 mg/kg bw once daily over 10 days. At 110 mg/kg bw no adverse effects were observed (NOAEL), while at the higher doses skin irritation and a reduction in bodyweight gains was seen. The examination of different tissues and organs (not further specified) gave no indication for adverse effects.

In an older study with male rabbits, which cannot finally be evaluated (original reference not available), the dermal application of 1500 mg/kg bw on 6 h per day over 10 days (applied as 40% solution in dimethyl phthalate) caused no mortality. Apart from weight loss and skin irritation no other effects were reported.