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Diss Factsheets

Administrative data

Description of key information

Key information is based on weight of evidence data from repeated toxicity studies performed with the two main components aminopropanol and gluconate and dated before 2009.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
short-term repeated dose toxicity: oral
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:
according to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Version / remarks:
1998
Deviations:
no
GLP compliance:
yes
Limit test:
no
Specific details on test material used for the study:
Commercial DIPA (CAS 000110-97-4) was obtained from the Dow Chemical Company (Midland, MI).
The purities of four lots of DIPA used for these studies ranged from 98.8% to 99.6%, as determined by GC/FID.
Species:
rat
Strain:
Fischer 344/DuCrj
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories Inc. (Kingston, New York and Raleigh, North Carolina)
- Age at study initiation: approximately 6 weeks of age
- 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: drinking water
Details on oral exposure:
Drinking water formulated with test article to supply 0, 100, 500, or 1000 mg DIPA/kg/day for 13 weeks
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Periodic analyses of DIPA in all dose solutions for all studies ranged from 95% to 105% of target.
Duration of treatment / exposure:
13 weeks (90 days)
Frequency of treatment:
Continuously via drinking water.
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
500 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
10
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: dose levels were based upon the prior 2-week drinking water study.
- Eficiency of the dosing: Water consumption was between 98% and 106% of targeted levels.
- Rationale for selecting satellite groups: assess recovery from any treatment-related effects.
- Post-exposure recovery period in satellite groups: Additional groups of 10 rats/sex were maintained on untreated drinking water for 4 weeks after initially receiving the control or high dose level for 13 weeks.
Positive control:
Not applicable
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
- Cage side observations checked were included.

DETAILED OBSERVATIONS/EXAMINATIONS: Yes
- Time schedule: weekly, detailed (handheld) clinical examinations, body weight, water and feed consumption

OPHTHALMOSCOPIC EXAMINATION: Yes / No / Not specified
- conducted prestudy and during the last week of treatment:

HAEMATOLOGY & CLINICAL CHEMISTRY: Yes
- on blood samples collected at necropsy

URINALYSIS: Yes
on samples collected near the end of each study

NEUROBEHAVIOURAL EXAMINATION: No

IMMUNOLOGY: No

OTHER:
- electrolyte parameters on blood samples collected at necropsy
Sacrifice and pathology:
Histopathologic examination was conducted on an extensive list of organs from all control and high dose level rats along with selected organs from the low- and middle-dose animals
Other examinations:
- selected organ weights
Statistics:
Weekly body weights, feed and water consumption, clinical pathology parameters, terminal body weight, organ weights: Parametric or non-parametric ANOVA, followed by Dunnett’s or Wilcoxon’s test for comparison to controls
Detailed clinical observations: Z-test of proportions according to Bruning and Kintz
Clinical signs:
no effects observed
Description (incidence and severity):
Not significant, only minor effects from treatment.
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
High dose males and females gained 4–5% less body weight than controls after 13 weeks of dosing.
Food efficiency:
no effects observed
Description (incidence and severity):
Rats given 1000 mg/kg/day also consumed slightly less feed than controls (2–3%) and consistently weighed slightly less than controls.
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
Water consumption by high dose males and females decreased 7.5% and 18% relative to controls
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
There were minimal, but statistically identified, differences noted for cholesterol (increased), albumin (decreased) and phosphorus (decreased) for males given 1000 mg/kg/day
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
Consistent with decreased water consumption, rats given 1000 mg/kg/day had increased urine specific gravity and the females had decreased urine volume, which were considered secondary adaptive effects.
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Absolute and relative kidney weights were increased for males and females receiving 500 or 1000 mg/kg/day and the absolute kidney weight also was increased for males given 100 mg/kg/day. Male kidney weights were increased to a greater extent than the females with the mean relative kidney weight of males receiving 1000 mg/kg/day 21% greater than controls, while the females from this dose level were 14% greater than controls. Despite the kidney weight increase, there were no gross or histopathologic findings in kidney tissue related to treatment.
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed
Details on results:
The endpoints affected by DIPA ingestion were examined in additional groups of control and high dose group rats following the 4-week recovery period. Water consumption of the treated rats remained below controls by approximately the same degree as at the end of the dosing period, but all other affected endpoints demonstrated reversibility. Absolute and relative kidney weights of rats previously given DIPA were still above controls, but the differences were about one-half of those immediately following 13 weeks dosing; mean relative kidney weights were increased 11% and 6.6% relative to controls for males and females, respectively. No treatment-related renal histopathological changes were observed.
Key result
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
organ weights and organ / body weight ratios
Dose descriptor:
NOAEL
Effect level:
500 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
organ weights and organ / body weight ratios
Critical effects observed:
yes
Lowest effective dose / conc.:
500 mg/kg bw/day (nominal)
System:
urinary
Organ:
kidney
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
no
Conclusions:
The no observed adverse effect levels (NOAEL) in the DIPA toxicity studies for systemic toxicity were 100 mg/kg/day for males and 500 mg/kg/day for females in the 13-week drinking water study based upon the increased mean kidney weights.
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1995
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 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Deviations:
not specified
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
Animals : 12 males and 12 females - 6 weeks of age
Route : gavage of sodium gluconate in water at a volume of 1ml/100g bw
Satellite groups of 4 rats of each sex were included to determine the plasma concentration of sodium gluconate.
Route of administration:
oral: gavage
Vehicle:
water
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
4 weeks (28 days)
Frequency of treatment:
daily
Dose / conc.:
500 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
Dose / conc.:
2 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
12
Control animals:
yes, concurrent no treatment
Details on study design:
See information already presented.
Positive control:
Not applicable
Observations and examinations performed and frequency:
- Body weights and food consumption were measured on day 1 and every third or fourth day of the study.
- Ophthalmological examinations on all animals at the start of the study and on 6 rats of each sex per group at week 4.
- Haematological and clinical chemical parameters were measured at the end of treatment on blood collected from fasted surviving rats on all animals at necropsy.
- Qualitative and quantitative urinary examinations (pH, protein, ketones and glucose content) on 6 rats of each sex from each group at the end of treatment and water intake was measured over 24 hours.
Sacrifice and pathology:
- Weights of the brain, pituitary, thyroids, salivary glands, thymus, heart, lungs, liver, spleen, kidneys, adrenals, testes, prostate, seminal vesicles, ovaries, and uterus.
- Detailed histopathological examinations on cerebrum, heart, lung, cecum, liver, kidney, testis, epididymis, prostate and eye on all control animals and those receiving 2000 mg/kg bw per day and on all gross lesions.
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):
not specified
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
effects observed, non-treatment-related
Description (incidence and severity):
The qualitative urinary analysis showed increased prevalences of urinary ketone bodies, urobilogen and phosphate sedimentation and increased urinary protein
concentrations in all treated animals justified by interference in the assay.
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:
effects observed, treatment-related
Description (incidence and severity):
Histopathological examination showed a thickening of the limiting of the border of the stomach in 5/12 males at 2000 mg/kg bw per day. No toxic changes associated with the test article were detected. As the limiting ridge is a tissue specific to rodents, this lesion is not toxicologically significant for humans. Other lesions occurred incidentally and were not related to treatment.
Histopathological findings: neoplastic:
not examined
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
histopathology: non-neoplastic
Remarks on result:
other: irrelevant effect for human
Dose descriptor:
NOAEL
Effect level:
2 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
histopathology: non-neoplastic
Remarks on result:
other: irrelevant effect for human
Critical effects observed:
yes
Lowest effective dose / conc.:
2 000 mg/kg bw/day (nominal)
System:
gastrointestinal tract
Organ:
stomach
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
no
Conclusions:
The non-toxic dose of sodium gluconate in rats was estimated to be 1000 mg/kg/day for males and 2000 mg/kg/day for females.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Study duration:
subacute
Species:
rat
Quality of whole database:
Based on a repeated dose toxicity study with propanolamine the effects observed were not relevant for human. No effects were observed in a study with sodium gluconate.

Repeated dose toxicity: inhalation - systemic 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:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
2006-2007
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 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)
Version / remarks:
Organisation for Economic Co-Operation and Development (OECD), 1981. OECD guidelines for testing of chemicals. Section 4, Health Effects, Paris.
Deviations:
no
GLP compliance:
yes
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:
Fischer 344/DuCrj
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories Inc. (Kingston, New York and Raleigh, North Carolina)
- Age at study initiation: approximately 6 weeks of age
- 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
Type of coverage:
occlusive
Vehicle:
water
Remarks:
deionized water
Details on exposure:
0, 100, 500 or 750 mg DIPA/kg/day was applied to an approximately 2 x 2 cm interscapular-dorsal area of groups of five Fischer 344 rats/sex/dose level 5 days/week for 4 weeks. Hence, the actual dosages were: 25, 125 and 187.5 mg/ cm2. Application site skin was clipped free of hair, covered with an occlusive wrap during the dosing period each day, and was reclipped as necessary during the dosing period.
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.
Duration of treatment / exposure:
4 weeks (28 days)
Frequency of treatment:
5 days/week
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
500 mg/kg bw/day (nominal)
Dose / conc.:
750 mg/kg bw/day (nominal)
No. of animals per sex per dose:
5
Details on study design:
- Dose selection rationale: determined from a 4-day dermal irritation probe study in which daily application of 1000 mg/kg/day was determined to be too irritating for prolonged administration.
- Procedure of exposure: Application site skin was clipped free of hair, covered with an occlusive wrap during the dosing period each day, and was reclipped as necessary during the dosing period. The wraps were removed after 6 h and the treated sites were washed by gentle padding with watersoaked gauze.
- Scoring: Skin site of application was graded at the end of each week and the dosing period for erythema and eschar, edema, scaling and fissuring, and presence of scabs
Positive control:
Not applicable
Observations and examinations performed and frequency:
Weekly and terminal body weights, organ weights (absolute and relative), clinical pathology parameters, urine specific gravity
Standard hematologic and clinical chemistry parameters
Sacrifice and pathology:
- A complete necropsy was conducted on all animals.
- The adrenal glands, brain, heart, kidneys, liver, and ovaries or testes were weighed from all animals.
- Representative samples of a complete set of organs were collected and preserved in neutral, phosphate-buffered 10% formalin (NBF).
- Skin specimens were collected from the treated site and an adjacent untreated site in addition to a distant untreated site and histologic examination was made of the skin from treated, untreated adjacent and distal sites from all rats.
- Examination included an extensive set of organs consistent with regulatory guidelines (EPA, 1998), i.e. all organ systems and gonads and secondary sex organs of both sexes were examined histopathologically from the control and high dose animals with the kidneys, liver, lungs, urinary bladder and all gross lesions examined from the remaining rats.
- Tissues were prepared by standard techniques, embedded in paraffin, sectioned approximately 6 lm thick, stained with hematoxylin and eosin, and examined by a veterinary pathologist using a light microscope.
Statistics:
Weekly body weights: Three-way, repeated measures ANOVA, with body weights the repeated measure Dunnett’s test for comparison to controls
Terminal body weight, organ weights (absolute and relative), clinical pathology parameters, urine specific gravity: Two-way ANOVA, separate one-way ANOVA for each sex if sex by dose significant Dunnett’s test for comparison to controls
Clinical signs:
no effects observed
Dermal irritation:
effects observed, treatment-related
Description (incidence and severity):
Slightly to mildly irritating at 500 and 750 mg/kg/day. Over the course of the study from day 12, erythema was noted for all five males and three females treated with 750 mg/kg/day and two males and two females treated with 500 mg/kg/day. The erythema was graded as very slight to slight. During the course of the study after day 18, scabs were noted at the treatment site of one male and two females at 500 mg/kg/day, and of two males and three females at 750 mg/kg/day.
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 examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
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:
effects observed, treatment-related
Description (incidence and severity):
Slight hyperkeratosis of the treated site in all rats given 750 mg/kg/day and very slight hyperkeratosis in two males and two females given 500 mg/kg/day.
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed
Dose descriptor:
NOAEL
Effect level:
>= 750 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
clinical biochemistry
clinical signs
dermal irritation
food consumption and compound intake
gross pathology
haematology
histopathology: non-neoplastic
mortality
organ weights and organ / body weight ratios
urinalysis
Critical effects observed:
no
Conclusions:
The no observed adverse effect level (NOAEL) was >750 mg/kg/day in the 4-week dermal study,
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Study duration:
subacute
Species:
rat
Quality of whole database:
The no observed adverse effect level (NOAEL) for propanolamine was >750 mg/kg/day in a 4-week dermal study.

Repeated dose toxicity: dermal - local effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
2006-2007
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 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)
Version / remarks:
Organisation for Economic Co-Operation and Development (OECD), 1981. OECD guidelines for testing of chemicals. Section 4, Health Effects, Paris.
Deviations:
no
GLP compliance:
yes
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:
Fischer 344/DuCrj
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories Inc. (Kingston, New York and Raleigh, North Carolina)
- Age at study initiation: approximately 6 weeks of age
- 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
Type of coverage:
occlusive
Vehicle:
water
Remarks:
deionized water
Details on exposure:
0, 100, 500 or 750 mg DIPA/kg/day was applied to an approximately 2 x 2 cm interscapular-dorsal area of groups of five Fischer 344 rats/sex/dose level 5 days/week for 4 weeks. Hence, the actual dosages were: 25, 125 and 187.5 mg/ cm2. Application site skin was clipped free of hair, covered with an occlusive wrap during the dosing period each day, and was reclipped as necessary during the dosing period.
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.
Duration of treatment / exposure:
4 weeks (28 days)
Frequency of treatment:
5 days/week
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
500 mg/kg bw/day (nominal)
Dose / conc.:
750 mg/kg bw/day (nominal)
No. of animals per sex per dose:
5
Details on study design:
- Dose selection rationale: determined from a 4-day dermal irritation probe study in which daily application of 1000 mg/kg/day was determined to be too irritating for prolonged administration.
- Procedure of exposure: Application site skin was clipped free of hair, covered with an occlusive wrap during the dosing period each day, and was reclipped as necessary during the dosing period. The wraps were removed after 6 h and the treated sites were washed by gentle padding with watersoaked gauze.
- Scoring: Skin site of application was graded at the end of each week and the dosing period for erythema and eschar, edema, scaling and fissuring, and presence of scabs
Positive control:
Not applicable
Observations and examinations performed and frequency:
Weekly and terminal body weights, organ weights (absolute and relative), clinical pathology parameters, urine specific gravity
Standard hematologic and clinical chemistry parameters
Sacrifice and pathology:
- A complete necropsy was conducted on all animals.
- The adrenal glands, brain, heart, kidneys, liver, and ovaries or testes were weighed from all animals.
- Representative samples of a complete set of organs were collected and preserved in neutral, phosphate-buffered 10% formalin (NBF).
- Skin specimens were collected from the treated site and an adjacent untreated site in addition to a distant untreated site and histologic examination was made of the skin from treated, untreated adjacent and distal sites from all rats.
- Examination included an extensive set of organs consistent with regulatory guidelines (EPA, 1998), i.e. all organ systems and gonads and secondary sex organs of both sexes were examined histopathologically from the control and high dose animals with the kidneys, liver, lungs, urinary bladder and all gross lesions examined from the remaining rats.
- Tissues were prepared by standard techniques, embedded in paraffin, sectioned approximately 6 lm thick, stained with hematoxylin and eosin, and examined by a veterinary pathologist using a light microscope.
Statistics:
Weekly body weights: Three-way, repeated measures ANOVA, with body weights the repeated measure Dunnett’s test for comparison to controls
Terminal body weight, organ weights (absolute and relative), clinical pathology parameters, urine specific gravity: Two-way ANOVA, separate one-way ANOVA for each sex if sex by dose significant Dunnett’s test for comparison to controls
Clinical signs:
no effects observed
Dermal irritation:
effects observed, treatment-related
Description (incidence and severity):
Slightly to mildly irritating at 500 and 750 mg/kg/day. Over the course of the study from day 12, erythema was noted for all five males and three females treated with 750 mg/kg/day and two males and two females treated with 500 mg/kg/day. The erythema was graded as very slight to slight. During the course of the study after day 18, scabs were noted at the treatment site of one male and two females at 500 mg/kg/day, and of two males and three females at 750 mg/kg/day.
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 examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
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:
effects observed, treatment-related
Description (incidence and severity):
Slight hyperkeratosis of the treated site in all rats given 750 mg/kg/day and very slight hyperkeratosis in two males and two females given 500 mg/kg/day.
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed
Dose descriptor:
NOAEL
Effect level:
>= 750 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
clinical biochemistry
clinical signs
dermal irritation
food consumption and compound intake
gross pathology
haematology
histopathology: non-neoplastic
mortality
organ weights and organ / body weight ratios
urinalysis
Critical effects observed:
no
Conclusions:
The no observed adverse effect level (NOAEL) was >750 mg/kg/day in the 4-week dermal study,
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
25 mg/cm²
Study duration:
subacute
Species:
rat
Quality of whole database:
Slightly to mildly irritating at 500 and 750 mg/kg/day.

Additional information

The no observed adverse effect levels (NOAEL) in oral toxicity studies with propanolamine for systemic toxicity were 100 mg/kg/day for males and 500 mg/kg/day for females in the 13-week drinking water study based upon the increased mean kidney weights. This effect was considered to be irrelevant for human exposure. The non-toxic oral dose of sodium gluconate in rats was estimated to be 1000 mg/kg/day for males and 2000 mg/kg/day for females.

The no observed adverse effect level (NOAEL) for propanolamine was >750 mg/kg/day in a 4-week dermal study with slight to mild irritation at > 25 mg/cm2.

Justification for classification or non-classification

Based on weighed evidence, 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 in case of repeated exposure.