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Key value for chemical safety assessment

Effects on fertility

Description of key information

No additional information is available.

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the study does not need to be conducted because (i) the substance is of low toxicological activity (no evidence of toxicity seen in any of the tests available), (ii) it can be proven from toxicokinetic data that no systemic absorption occurs via relevant routes of exposure (e.g. plasma/blood concentrations below detection limit using a sensitive method and absence of the substance and of metabolites of the substance in urine, bile or exhaled air) and (iii) there is no or no significant human exposure
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
Additional information

Large quantities of urea are formed naturally in the human body as a consequence of normal protein catabolism. Urea is shown to be essentially without toxicity in the available studies and no effects (organ weight, gross pathology, histopathology) were observed on the reproductive organs of rats and mice exposed to urea at very high dietary levels for 12 months (Fleischman et al, 1980). The level of any primary, occupational or secondary exposure to urea is likely to be insignificant compared to the quantities (20-50 g/day) produced by normal metabolism and present at high concentrations in the blood. It is therefore considered that urea is very unlikely to be a reproductive toxin and testing cannot be justified scientifically.

Short description of key information:

No standard studies are available.  It is considered extremely unlikely that occupational, primary or secondary exposure to urea will result in any effects on fertility as the levels of exposure will be insignificant compared to those present in the body as a result of protein catabolism.

Effects on developmental toxicity

Description of key information

No standard studies are available.  It is considered extremely unlikely that occupational, primary or secondary exposure to urea will result in developmental toxicity as the levels of exposure will be insignificant compared to those present in the maternal and foetal circulation as a result of protein catabolism.

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: Published public domain study, non-standard method
Qualifier:
no guideline followed
Principles of method if other than guideline:
Screening assay: test substance injected into the air sac of chicken eggs during incubation
GLP compliance:
not specified
Remarks:
: published study
Limit test:
no
Species:
other: chick embryo
Strain:
not specified
Details on test animals or test system and environmental conditions:
Chick embryo, at days 16, 17 and 18 of incubation
Route of administration:
other: injection into egg air sac
Vehicle:
water
Details on exposure:
Urea dissolved in distilled water was injected into the air sac of the chick eggs on day 16, 17, and 18 of incubation.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No information available
Details on mating procedure:
Not relevant
Duration of treatment / exposure:
Exposure to substance occurred at day 16, 17, and 18 of incubation
Frequency of treatment:
Exposure to substance occurred at day 16, 17, and 18 of incubation
Remarks:
Doses / Concentrations:
200, 400, 800, and 1200 mg/kg egg
Basis:
nominal in water
No. of animals per sex per dose:
No information available
Control animals:
yes
Details on study design:
Blood samples were taken on Day 19; AST and LDH activities were assessed. T3 and T4 were measured by RIA
Maternal examinations:
Not relevant
Ovaries and uterine content:
Not relevant
Fetal examinations:
Electron microscopy and plasma biochemistry
Details on maternal toxic effects:
Maternal toxic effects:not examined

Details on maternal toxic effects:
Not relevant
Dose descriptor:
other: mortality varied between 8.8 and 38.9%, dose dependently
Effect level:
>= 200 - <= 1 200 mg/kg bw/day (nominal)
Based on:
test mat. (dissolved fraction)
Basis for effect level:
mortality
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
Mortality of the embryos varied between 8.8 and 38.9%, dose-dependently. Plasma T3 level increased and plasma T4 level decreased. Electron microscopy revealed cytoplasmic oedema, mitochondrial swelling and membrane damage in thyroid cells.
Dose descriptor:
NOAEL
Effect level:
500 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: teratogenicity
Abnormalities:
not specified
Developmental effects observed:
not specified

The mortality in the control group was 6.1%.

Conclusions:
Mortality of the embryos varied between 8.8 and 38.9%, dose-dependently. The mortality in the control group was 6.1%. Plasma T3 level increased and plasma T4 level decreased. Electron microscopy revealed cytoplasmic oedema, mitochondrial swelling and membrane damage in thyroid cells.
Executive summary:

Urea in 0.05 ml water was injected into incubated fertilised chick eggs on Days 16, 17 and 18 at dose levels of 200, 400, 800 or 1200 mg/kg egg weight. AST and LDH activities were assessed in Day 19 blood samples. T3 and T4 levels were measured by RIA. The thyroid was investigated by electron microscopy. Mortality of the embryos varied between 8.8 and 38.9%, dose-dependently. The mortality in the control group was 6.1%.

Plasma T3 level increased and plasma T4 level decreased. Electron microscopy revealed cytoplasmic oedema, mitochondrial swelling and membrane damage in thyroid cells. The authors indicate that urea causes thyroid damage, however this conclusion is not considered to be reliable given the absence of other investigations and the level of general toxicity seen in this study.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
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

A study of limited design did not indicate any teratogenicity or effects on renal development in the rat (Seipelt et al, 1969), however slightly lower pup weights were seen at the dose level of 500 mg/kg bw/d in this study. A screening assay in chick eggs is considered to be of limited value (Mora et al, 1991).

Large quantities of urea are formed naturally in the human body as a consequence of normal protein catabolism. Urea is shown to be essentially without toxicity in the available studies. The level of any primary, occupational or secondary exposure to urea is likely to be insignificant compared to the quantities (20-50 g/day) produced by normal metabolism and present at high concentrations in the maternal and foetal circulation. It is therefore considered that urea is very unlikely to be a reproductive toxin and testing cannot be justified scientifically.

Toxicity to reproduction: other studies

Description of key information

No additional information is available.

Justification for classification or non-classification

There are no studies in animals showing clear evidence of reproductive effects. The results of the available studies do not trigger classification according to Regulation EC 1272/2008.

Additional information