Potassium carbamoylcarbamate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

no study available

Effects on developmental toxicity

Description of key information

As summarised in the read-across documentation provided as an attachment to this CSR, potassium allophonate quickly hydrolyses to urea under physiological conditions; therefore, read-across to developmental toxicity information for urea is used to assess developmental toxicity. Teramoto et al. (1981) conducted a study of limited design in which urea failed to produce any teratogenic or systemic effects when pregnant mice and rats were administered a single gavage dose of 2000 mg/kg bw. Furthermore, Seipelt et al. (1969) found no effects on the kidney weights of pups when dams were administered oral doses of urea during pregnancy. Additionally, urea is produced in large quantities by the human body as an endogenous product of normal metabolism. Furthermore, the level of primary and secondary occupational exposures to urea are likely to be insignificant compared to the quantities (20-50 g/day) produced by normal metabolism and present at high concentrations in the blood. Therefore, the weight-of-evidence (WoE) indicates that urea is not a developmental toxicant.

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

other: No guideline followed. The study performed with relatively small numbers of animals and a single dose

Qualifier:

no guideline followed

Deviations:

not specified

Principles of method if other than guideline:

Dams were dosed via oral gavage to pregnant rats on day 12 of pregnancy and sacrificed on day 20 of pregnancy.

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

Wistar

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: purchased from CLEA, Japan
- Age at study initiation: (P) 15 wks
- Diet: laboratory chow (Oriental Yeast MF), ad libitum
- Water: tap water ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 ±1
- Humidity (%): 55 ± 5

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

Aqueous solutions of the compounds (10 mL/kg) were prepared and orally administered to dams.

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

Females were paired overnight with a male. The following morning they were examined for the presence of vaginal plug and were designated as being in day 0 of pregnancy when the plug was observed.

Duration of treatment / exposure:

Dams were dosed at day 12 of pregnancy

Frequency of treatment:

Single dosing

Duration of test:

Dosed on day 12 of pregnancy, and sacrificed at day 20 of pregnancy

Remarks:

Doses / Concentrations:

Basis:
nominal conc.
2000 mg/kg

No. of animals per sex per dose:

4

Control animals:

yes, concurrent vehicle

Fetal examinations:

- External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: [ half per litter]
- Skeletal examinations: Yes: [ half per litter]
- Head examinations: No data

Details on maternal toxic effects:

Maternal toxic effects:no effects

Details on maternal toxic effects:
Mortality was not observed.

Dose descriptor:

NOAEL

Effect level:

2 000 mg/kg bw (total dose)

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No significant changes were observed in number of implants, number of live fetuses, % of fetal resorptions, fetal weight or % fetal malformation.

Abnormalities:

not specified

Developmental effects observed:

not specified

	No. Dams	Mean No of implants	Mean No. of live fetuses	% Fetal resorptions	Mean fetal weight (mg)	& Fetuses malformed
Urea (2000mg/kg)	4	13.8±2.2	13.8±2.2	0	3626±104	1.8
control	6	13.7±1.0	13.3±0.8	2.4	3671±197	0

 

Conclusions:

Based on the study, no adverse developmental/teratogenicity effects were observed due to a single, high-dose urea treatment.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

2 000 mg/kg bw/day

Species:

other: rat and mice

Quality of whole database:

No guideline followed. The study performed with relatively small numbers of animals. Single dose on one dose level.

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

No developmental toxicity data are available for potassium allophonate; however, as summarised in the read-across documentation provided as an attachment to this CSR, potassium allophonate quickly hydrolyses to urea under physiological conditions. Therefore, read-across to reproductive/developmental toxicity information on urea is appropriate.

In Teramoto et al. (1981), four pregnant rats and ten pregnant mice were administered a single gavage dose of urea at 2000 mg /kg bw on day 12 and day 10 of pregnancy, respectively. Animals were sacrificed eight days later (day 20 for rats and day 18 for mice). For rats and mice, no significant changes were observed regarding the number of implants, number of live fetuses, percent of fetal resorptions, fetal weight or percent fetal malformation. Based on the rat study, no adverse developmental/teratogenicity effects were observed due to a single, high dose urea treatment. In a study summarised in the United States Environmental Protection Agency’s (U.S. EPA) Integrated Risk Information System’s (IRIS) toxicological review of urea, six pregnant rats were administered two doses of urea, totaling 50 g/kg bw/day, during pregnancy (Seipelt et al., 1969). Within 48 hours of birth, pups were sacrificed by decapitation and kidneys were removed and weighed; the right kidney was then dried at 105 deg C and weighed. No evidence of maternal toxicity or effects on the pups' kidney weights were observed in this study.

References:

Seipelt, H., Zoellner, K., Hilgenfeld, E. and Grossmann, H. 1969. Studies on kidneys of newborn rats after chronic urea administration to the mother [Article in German]. Zeitschrift Urol. Nephrol., 62(8): 623-7. As cited in: United States Environmental Protection Agency’s (U.S. EPA). 2011. Toxicological Review of Urea: Studies on kidneys of newborn rats after chronic urea administration to the mother. Integrated Risk Information System (IRIS).

Teramoto, S., Kaneda, M., Aoyama, H. and Shirasu, Y. 1981. Correlation between the molecular structure of N-alkylureas and N-alkylthioureas and their teratogenic properties. Teratology, 23(3): 335-42.

Justification for selection of Effect on developmental toxicity: via oral route:
Read-across from urea.

Justification for classification or non-classification

The reproductive/developmental toxicity of potassium allophonate was evaluated based on read-across from appropriate studies on urea, since it has been documented that potassium allophonate readily hydrolyses to urea under physiological conditions. Prenatal developmental toxicity studies of limited design are available for rats and mice, none of which found any evidence of developmental toxicity for urea. Therefore, the weight-of-evidence (WoE) from these studies indicates that urea is unlikely to be a developmental toxicant. Additionally, urea is produced in large quantities by the human body as an endogenous product of normal metabolism. Furthermore, the level of primary and secondary occupational exposures to urea are likely to be insignificant compared to the quantities (20-50 g/day) produced by normal metabolism and present at high concentrations in the blood. Therefore, the weight-of-evidence (WoE) indicates that urea is not a developmental toxicant and, based on read-across, potassium allophonate does not warrant classification for the repeat-dose toxicity endpoint.