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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

Description of key information

Key information is based on weight of evidence data from a developmental toxicity study performed with diisopropanolamine, an analogue of one of the main components, aminopropanol.

Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
The study is performed with diisopropanolamine (DIPA) as analogue for aminopropanol with the amine as common functional group. Similar breakdown products are expected involving various processes including oxidation and conjugation. DIPA, as amino- propanol, is used as water-soluble emulsifier and neutralizer in cosmetic products at concentrations up to 1%. As reviewed by CIR, DIPA is of low acute systemic toxicity, with an oral LD50 of 4765 mg/kg to rats and a dermal LD50 of >1000 mg/kg for rabbits, but, like 3-amino-propanol, it is irritating to both skin and eye (Cosmetics Ingredient Review, 1987. Final report on the safety assessment of diisopropanolamine, triisopropanolamine, isopropanolamine, and mixed isopropanolamine. J. Am. Coll. Toxicol. 6, 53–76).
Reason / purpose for cross-reference:
read-across source
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
yes
Remarks:
Testing laboratory: The Dow Chemical Company, 1803 Building, Midland, MI 48674, United States
Specific details on test material used for the study:
Source: obtained from The Dow Chemical Company (Midland, MI).
Puritie: 98.8% to 99.6%
Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Time-mated female CRL:CD(SD) rats were obtained from Charles River Laboratories Inc. (Portage, MI).
- Age at study initiation: adults
- Weight at study initiation: not specified
- Fasting period before study: not specified
- Housing: not specified
- Diet: ad libitum LabDiet#5002 Certified Rodent Diet (PMI Nutrition International, St. Louis, MO)
- Water: ad libitum
- Acclimation period: yes

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21–25
- Humidity (%): 45–60%
- Air changes (per hr): 12–15 room air changes/h
- Photoperiod (hrs dark / hrs light): 12 h photocycle
Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
Groups of 25 time-mated female Sprague–Dawley rats were given 0, 100, 300, or 1000 mg DIPA/kg/day on gestation days 6 through 20 by oral gavage.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Periodic analyses of DIPA in all dose solutions ranged from 95% to 105% of target.
Details on mating procedure:
time-mated females
Duration of treatment / exposure:
gestation days 6 through 20
Frequency of treatment:
daily
Duration of test:
21 days
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
300 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
25 females
Control animals:
yes
Details on study design:
- Dose selection rationale: dose levels were determined from a probe toxicity study in which 1000 mg/kg/day given to pregnant rats did not cause maternal toxicity or embryotoxicity
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DETAILED OBSERVATIONS/EXAMINATIONS: Yes
- Time schedule: weekly, detailed (handheld) clinical examinations, body weight, weight gain, and feed consumption
- On gestation day 21, all rats were euthanized, examined grossly, and the weights of the liver, kidneys and gravid uterus were collected. The number of corpora lutea, uterine implantations, resorptions and live/dead fetuses were determined.

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY & CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

IMMUNOLOGY: No
Ovaries and uterine content:
on day 21 of gestation by CO2 inhalation and gross pathologic examination was conducted.
The weights of the kidneys, liver and gravid uteri were obtained and the kidneys, liver and all gross lesions were preserved in 10%NBF.
A detailed examination of the reproductive tract was conducted which included the number and position of all implants, viable fetuses, dead fetuses, resorptions, and the number of ovarian corpora lutea. Uteri lacking visible implantations were stained with a 10% aqueous solution of sodium sulfide for evidence of early resorptions.
Fetal examinations:
- Sex ratio and body weight
- External examinations: Yes, all per litter
- Soft tissue examinations: Yes, one-half of the fetuses from each litter were randomly selected for a visceral examination, conducted by dissection under a low power stereomicroscope
- Skeletal examinations: Yes, Fetuses not selected for visceral examination were skinned, eviscerated, preserved in alcohol, double stained with Alcian Blue and Alizarin Red S, cleared and evaluated for skeletal changes
- Head examinations: Yes, heads of the fetuses used in soft tissue examination were placed in Bouin’s fixative and subsequently serially sectioned for examination of the eyes, brain, nasal passages and tongue
Statistics:
- Maternal body weight, weight gain, feed consumption, organ weights and fetal body weights: Parametric or non-parametric ANOVA, followed by Dunnett’s or Wilcoxon’s test for comparison to controls
- Pre- and post-implantation loss: Censored Wilcoxon’s test Haseman and Hoel
- Corpora lutea, implantations and litter size: Non-parametric ANOVA followed by Wilcoxon’s test
- Pregnancy rates: Fisher exact probability test
- Fetal sex ratios: Binomial distribution test
Indices:
Not specified
Historical control data:
Not specified
Clinical signs:
no effects observed
Dermal irritation (if dermal study):
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Changes in number of pregnant:
no effects observed
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
changes in number of pregnant
changes in pregnancy duration
clinical signs
dead fetuses
dermal irritation
early or late resorptions
effects on pregnancy duration
food consumption and compound intake
gross pathology
mortality
necropsy findings
number of abortions
organ weights and organ / body weight ratios
pre and post implantation loss
total litter losses by resorption
Fetal body weight changes:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Description (incidence and severity):
A statistically identified shift in sex ratio vs. binomial distribution of the control pups, but this was considered as not toxicologically significant.
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Description (incidence and severity):
The small number of alterations observed in fetuses from dams given DIPA either occurred at low frequencies and/or not in a dose-related manner.
Visceral malformations:
no effects observed
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reduction in number of live offspring
changes in sex ratio
fetal/pup body weight changes
changes in litter size and weights
external malformations
skeletal malformations
visceral malformations
Abnormalities:
no effects observed
Developmental effects observed:
no
Conclusions:
The present oral development toxicity study with diisopropanolamine in rats resulted in no observed adverse effect levels (NOAEL) >1000 mg/kg/day for both maternal and fetal effects.
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
Secondary litterature but described in sufficient detail in a recognised International Organisation report. Acceptable for assessment.
D-gluconate is one of the main constituents of Reaction mass of 3-hydroxypropan-1-aminium D-gluconate and N-(3-hydroxypropyl)-D-gluconamide at a molar ratio of 1:1. The process used is a pseudo acid – base reaction in water that leads always to a mixture of the “amide” and the “salt” part. Both entities are required for the applications performances. With the manufacturing process used here it is not possible to separate the amide and salt part from the water phase. D-gluconate is the anion of the salt part.
Principles of method if other than guideline:
SIDS testing requirements regarding reproductive toxicity were satisfied with histopathology of the reproductive organs in repeat dose studies on sodium gluconate and with developmental toxicity studies on glucono-delta-lactone.
GLP compliance:
not specified
Specific details on test material used for the study:
Not specified.
Species:
mouse
Strain:
ICR
Details on test animals or test system and environmental conditions:
Not specified.
Route of administration:
oral: unspecified
Duration of treatment / exposure:
Exposure period: from day 6 to day 15 of gestation
Frequency of treatment:
daily
Duration of test:
10 days
Dose / conc.:
1 000 mg/kg bw/day (nominal)
Dose / conc.:
4 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
Not specified.
Details on study design:
GDL was administered orally to female nulliparous mice for 10 days and the fetuses were observed by laparotomy on dams on pregnancy day 18. Several dams in each group wereallowed to deliver spontaneously, and the offspring wereobserved until
postnatal day 21.
Maternal examinations:
general condition, body weight change and food consumption
Ovaries and uterine content:
number of implantations and dead fetuses
Fetal examinations:
Survival, external, visceral and skeletal examinations.
Statistics:
Not specified.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Changes in number of pregnant:
not specified
Dose descriptor:
NOAEL
Effect level:
>= 4 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
changes in pregnancy duration
clinical signs
dead fetuses
early or late resorptions
effects on pregnancy duration
food consumption and compound intake
mortality
number of abortions
pre and post implantation loss
total litter losses by resorption
Fetal body weight changes:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
not specified
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
>= 4 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reduction in number of live offspring
fetal/pup body weight changes
changes in litter size and weights
changes in postnatal survival
external malformations
skeletal malformations
visceral malformations
Developmental effects observed:
no
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
Secondary litterature but described in sufficient detail in a recognised International Organisation report. Acceptable for assessment.
D-gluconate is one of the main constituents of Reaction mass of 3-hydroxypropan-1-aminium D-gluconate and N-(3-hydroxypropyl)-D-gluconamide at a molar ratio of 1:1. The process used is a pseudo acid – base reaction in water that leads always to a mixture of the “amide” and the “salt” part. Both entities are required for the applications performances. With the manufacturing process used here it is not possible to separate the amide and salt part from the water phase. D-gluconate is the anion of the salt part.
Principles of method if other than guideline:
SIDS testing requirements regarding reproductive toxicity were satisfied with histopathology of the reproductive organs in repeat dose studies on sodium gluconate and with developmental toxicity studies on glucono-delta-lactone.
GLP compliance:
not specified
Specific details on test material used for the study:
Not specified.
Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
No details
Route of administration:
oral: unspecified
Duration of treatment / exposure:
Exposure period: from day 6 to day 15 of gestation
Frequency of treatment:
daily
Duration of test:
10 days
Dose / conc.:
1 000 mg/kg bw/day (nominal)
Dose / conc.:
4 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
Not specified
Details on study design:
GDL was administered orally to female nulliparous rats for 10 days and the fetuses were observed by laparotomy on pregnancy day 21. Several dams in each group were allowed to deliver spontaneously, and the offspring were observed until postnatal day 21.
Maternal examinations:
general condition, body weight change or food consumption
Ovaries and uterine content:
number of implantations/dead fetuses
Fetal examinations:
Survival, mean body weight, external appearance, visceral and skeleton examination.
Statistics:
Not specified.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not examined
Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Changes in number of pregnant:
no effects observed
Details on maternal toxic effects:
Observation of the dams allowed to deliver spontaneously, protraction of the duration of pregnancy or abnormalities at birth were not observed
Key result
Dose descriptor:
NOAEL
Effect level:
>= 4 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
changes in number of pregnant
changes in pregnancy duration
clinical signs
dead fetuses
early or late resorptions
effects on pregnancy duration
food consumption and compound intake
mortality
number of abortions
pre and post implantation loss
total litter losses by resorption
Fetal body weight changes:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
not specified
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Dose descriptor:
NOAEL
Effect level:
>= 4 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reduction in number of live offspring
fetal/pup body weight changes
changes in litter size and weights
changes in postnatal survival
external malformations
skeletal malformations
visceral malformations
Developmental effects observed:
no
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Species:
other: rat and mouse
Quality of whole database:
Studies included a guideline study and two studies referred to in SIDS Initial Assessment Report for SIAM 18.
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

SIDS testing requirements regarding reproductive toxicity were satisfied with histopathology of the reproductive organs in repeat dose studies on sodium gluconate and with developmental toxicity studies on glucono-deltalactone. Indeed no changes were observed on the reproductive organs in 28 days oral studies with sodium gluconate (dosage up to 4400 mg/kg bw) and developmental toxicity studies on glucono-deltalactone on different species were all negative. An oral development toxicity study with diisopropanolamine in rats resulted in no observed adverse effect levels (NOAEL)  >1000 mg/kg/day for both maternal and fetal effects.

Justification for classification or non-classification

Based on weighed evidence from various developmental toxicity and repeated dose studies, there is no indication that Reaction mass of 3-hydroxypropan-1-aminium D-gluconate and N-(3-hydroxypropyl)-D-gluconamide meets the criteria for classification as toxic for reproduction.

Additional information