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Administrative data

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

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

Description of key information

A study performed in rats according to OECD TG 414 using cetyl betaine resulted in an LOAEL of 50 mg/kg bw/d for meaternal toxicity and and NOAEL of 150 mg/kg bw/d for developmental toxicity.

Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
not specified
GLP compliance:
yes
Limit test:
no
Specific details on test material used for the study:
30.4% active cetyl betaine in 10% ethanol (correction factor of 3.2895 was utilized to achieve proper amount of active ingredient)
Species:
rat
Strain:
Sprague-Dawley
Route of administration:
oral: gavage
Vehicle:
ethanol
Details on exposure:
Dosage calculations were based on a 100% active component. Since the test substance was received with a 30.4% active moiety in 10% ethanol, a correction factor of 3.2895 was utilized to achieve the proper amount of active ingredient. The control group received ethanol in deionized water at a volume of 5 ml/kg. The amount of ethanol the control group received was equal to the amount given to the 250 mg/kg/day group. The stock solution was prepared daily. Dose volume was 5 ml/kg body weight, adjusted for body weight on days of gestation 6, 9 and 12.
Duration of treatment / exposure:
The rats received the test material daily for 10 days starting on gestation day 6.
Frequency of treatment:
daily
Duration of test:
Total duration was 20 days.
Dose / conc.:
0 mg/kg bw/day
Dose / conc.:
50 mg/kg bw/day
Dose / conc.:
150 mg/kg bw/day
Dose / conc.:
250 mg/kg bw/day
Control animals:
yes
Maternal examinations:
Animals were observed twice daily for signs of toxicity. Body weights were recorded on day 0, 6, 9, 12, 16 and 20 of gestation. Food consumption intervals were identical to the body weight intervals.
Ovaries and uterine content:
On gestation day 20, all surviving females were sacrificed by carbon dioxide inhalation. The uterus was exposed and the number and location of viable and nonviable fetuses, early and late resorptions and the number of total implantations and corpora lutea were recorded. The uterus was then excised and the fetuses were removed.
Fetal examinations:
Live fetuses were individually weighed, sexed, tagged and examined for external malformations or developmental variations. Approximately one half of the fetuses for each litter were fixed in Bouin's solution to examine the viscera and brain by Wilson's sectioning technique. The remaining one-half of the fetuses were processed (alizarin red staining) and examined for skeletal abnormalities.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Clinical observations noted in animals dosed at 250 mg/kg/day included stained and matted fur (noted primarily on the limbs, neck, ventral thorax and facial area), excessive salivation, respiratory rales, diarrhea, decreased activity, hypothermia, lacrimation, labored breathing and wheezing. Similar observations were evident at 150 mg/kg/day group, stained and mattered fur and respiratory rales were the predominant observations
Mortality:
no mortality observed
Description (incidence):
No deaths occurred in any dams in the control or treated groups.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
A dose-related trend of maternal body weight inhibition was noted during both the overall gestation (days 0 - 20) and treatment (days 6 - 15) periods at all dose levels. Weight loss was observed during the first treatment interval (days 6 - 9) at 150 and 250 mg/kg/day.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Reduced food intake was also noted among all treated groups during the treatment period in an apparent dose-related trend. In addition, consumption was inhibited at 250 mg/kg/day during the overall gestation interval but mean values of the 50 and 150 mg/kg/day groups were comparable to controls.
Gross pathological findings:
no effects observed
Description (incidence and severity):
Necropsy revealed no treatment-related differences among the groups.
Number of abortions:
no effects observed
Total litter losses by resorption:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Dose descriptor:
LOAEL
Effect level:
50 mg/kg bw/day
Based on:
act. ingr.
Basis for effect level:
body weight and weight gain
Abnormalities:
no effects observed
Dose descriptor:
LOAEL
Effect level:
250 mg/kg bw/day
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: developmental effects
Dose descriptor:
NOAEL
Effect level:
150 mg/kg bw/day
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: developmental effects
Abnormalities:
no effects observed
Developmental effects observed:
yes
Lowest effective dose / conc.:
250 mg/kg bw/day
Treatment related:
not specified
Relation to maternal toxicity:
developmental effects as a secondary non-specific consequence of maternal toxicity effects
Dose response relationship:
yes
Relevant for humans:
not specified

In the fetuses, no significant differences between the control and treated groups were evident with respect to number of corpora lutea, total implantations, post implantation loss, viable fetuses, and fetal body weights. Fetal malformation in the treated groups was not significantly different from that of the controls. Reduced or absent ossification of the skull, sternebrae #5 and/or #6, and other sternebrae occurred more frequently in the 250 mg/kg dose group. These effects were considered to be biologically significant as they were observed in conjunction with reduced maternal body weight gains.

No other developmental variations were noted.

Conclusions:
In oral reproductive and developmental toxicity studies of cetyl betaine in rats, the LOAEL for the dams was 50 mg/kg due to decreased body weight gain and a maternal NOAEL could not be calculated. The developmental LOAEL was 250 mg/kg and the developmental NOAEL was 150 mg/kg.
Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The source substance is the main constituent of the target substance. It shares common functional groups with the other two betaines present, differing only in the alkyl chain length.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Source: Cetyl betaine [EC 211-748-4]
Target: Betaines, C12-16 (even numbered)-alkyldimethyl. Composition information per section 1.2

3. ANALOGUE APPROACH JUSTIFICATION
The Cosmetic Ingredient Review Expert Panel reviewed the product use, formulation and safety data of eleven alkyl betaines, as used in cosmetics. (Final report issued 2014-04-04)
The Panel concluded that the common core chemical structure, similar functions and concentrations in cosmetics, and the predicted physicochemical properties enabled grouping these ingredients and
reading across the available toxicological data to support the safety assessment of each individual compound in the entire group.
Therefore it is assessed that it is acceptable to apply the results of the study on cetyl betaine to the C12-16 betaine.

4. DATA MATRIX
Source: betaines, C12-14 (even numbered) -alkyldimethyl [EC 931-700-2]: OECD TG 414, NOAELdev = 150 mg/kg bw/d
Target: betaines, C12-16 (even numbered) -alkyldimethyl [EC 947-036-1, CAS n/a]: no data
Reason / purpose for cross-reference:
read-across source
Frequency of treatment:
daily
Dose descriptor:
LOAEL
Effect level:
50 mg/kg bw/day
Based on:
act. ingr.
Basis for effect level:
body weight and weight gain
Abnormalities:
no effects observed
Dose descriptor:
LOAEL
Effect level:
250 mg/kg bw/day
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: developmental effects
Dose descriptor:
NOAEL
Effect level:
150 mg/kg bw/day
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: developmental effects
Abnormalities:
no effects observed
Developmental effects observed:
yes
Lowest effective dose / conc.:
250 mg/kg bw/day
Treatment related:
not specified
Relation to maternal toxicity:
developmental effects as a secondary non-specific consequence of maternal toxicity effects
Dose response relationship:
yes
Relevant for humans:
not specified

In the fetuses, no significant differences between the control and treated groups were evident with respect to number of corpora lutea, total implantations, post implantation loss, viable fetuses, and fetal body weights. Fetal malformation in the treated groups was not significantly different from that of the controls. Reduced or absent ossification of the skull, sternebrae #5 and/or #6, and other sternebrae occurred more frequently in the 250 mg/kg dose group. These effects were considered to be biologically significant as they were observed in conjunction with reduced maternal body weight gains.

No other developmental variations were noted.

Conclusions:
In oral reproductive and developmental toxicity studies of cetyl betaine in rats, the LOAEL for the dams was 50 mg/kg due to decreased body weight gain and a maternal NOAEL could not be calculated. The developmental LOAEL was 250 mg/kg and the developmental NOAEL was 150 mg/kg.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
150 mg/kg bw/day
Species:
rat
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available

Justification for classification or non-classification

In the OECD 414 study effects in pups were seen only at levels above the onset of maternal toxicity. Classification is not required.

Additional information