D-Gluconic acid, δ-lactone, reaction products with propanolamine

Repeated dose toxicity: dermal

Administrative data

Endpoint:

short-term repeated dose toxicity: dermal

Type of information:

experimental study

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. 3-aminopropan-1-ol is one of the 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. The 3-aminopropan-1-ol is the kation of the salt part.

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

2007

Materials and methods

Test guideline

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

Test material

Test material information

Constituent 1

Reference substance name:

1,1'-iminodipropan-2-ol

EC Number:

203-820-9

EC Name:

1,1'-iminodipropan-2-ol

Cas Number:

110-97-4

Molecular formula:

C6H15NO2

IUPAC Name:

1,1'-iminodipropan-2-ol

Specific details on test material used for the study:

Source: obtained from The Dow Chemical Company (Midland, MI).
Puritie: 98.8% to 99.6%

Test animals

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

Administration / exposure

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

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

100 mg/kg bw/day (nominal)

Doses / concentrations 2

Dose / conc.:

500 mg/kg bw/day (nominal)

Doses / concentrations 3

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

Examinations

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

Results and discussion

Results of examinations

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

Effect levels

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

Target system / organ toxicity

Critical effects observed:

no

Applicant's summary and conclusion

Conclusions:

The no observed adverse effect level (NOAEL) was >750 mg/kg/day in the 4-week dermal study,