D-Glucose, reaction products with alcohols C16-18 (even numbered)

Endpoint summary

Description of key information

Subchronic (90-day) study oral (gavage), rat (Sprague-Dawley) m/f (OECD guideline 408, GLP): NOAEL: 1000 mg/kg bw/day (nominal) (male/female)

Read-across from D-Glucopyranose, oligomeric, C10-16-alkyl glycosides

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

27 Jun - 26 Oct 1988

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: GLP - Guideline study with acceptable restriction. No ophthalmological examinations were performed prior to treatment. No information on detailed clinical examinations.

Qualifier:

according to guideline

Guideline:

EU Method B.26 (Sub-Chronic Oral Toxicity Test: Repeated Dose 90-Day Oral Toxicity Study in Rodents)

Deviations:

yes

Remarks:

No ophthalmological examinations were performed prior to treatment; no information on detailed clinical examinations

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

other: Sprague Dawley CD

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River, Sulzfeld; Germany
- Age at study initiation: 5-6 weeks
- Weight at study initiation: 169.6 (m) and 140.9 (f) g (control group); 157 (m) and 140.7 (f) g (250 mg/kg bw/d test group); 161.5 (m) and 138.4 (f) g (500 mg/kg bw/d test group); 166.5 (m) and 138.2 (f) g (1000 mg/kg bw/d test group)
- Housing: animals were housed in groups of 2-3 per sex in Makrolon type III cages with soft wood bedding (ARWI-Center, Essen, Germany)
- Diet: pelleted maintenance diet Altromin 1324 DK (Altromin GmbH, Lage, Germany), ad libitum
- Water: tap water, ad libitum
- Acclimation period: 11 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-23
- Humidity (%): 54-68
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 27.06.1988 To: 29/30.09.1988 (main test groups) and 26.10.1988 (satellite control and test group)

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS: dosing solutions of the test substance in water were prepared daily and just prior to application.

VEHICLE
- Concentration in vehicle: 2.5, 5 and 10% w/v
- Amount of vehicle (if gavage): 10 mL/kg bw

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

90 days

Frequency of treatment:

once daily in the morning, 5 days/week

Remarks:

Doses / Concentrations:
0, 250, 500, 1000 mg/kg bw
Basis:
other: nominal dose

No. of animals per sex per dose:

10 (main study), 5 (satellite control and high dose group)

Control animals:

yes, concurrent vehicle

Details on study design:

- Rationale for selecting satellite groups: satellite groups were used to assess the cumulative toxicity and reversibility of effects.
- Post-exposure recovery period in satellite groups: 27 days

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: animals were checked for mortality and clinical signs twice daily.

BODY WEIGHT: Yes
- Time schedule for examinations: animals were weighed at arrival, on the first day of treatment, and then weekly throughout the treatment period and before necropsy.

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: 1 day before necropsy
- Dose groups that were examined: control and high dose group

HAEMATOLOGY: Yes
- Time schedule for collection of blood: after 6 weeks (interim examination) and at study termination
- Anaesthetic used for blood collection: Yes (ether)
- Animals fasted: No data
- How many animals: all surviving animals
- Parameters listed in Table 1 under "Any other information on materials and methods incl. tables" were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: : after 6 weeks (interim examination) and at study termination
- Animals fasted: No data
- How many animals:
- Parameters listed in Table 1 under "Any other information on materials and methods incl. tables" were examined.

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes (see Table 2 under "Any other information on materials and methods incl. tables)"
HISTOPATHOLOGY: Yes (see Table 2 under "Any other information on materials and methods incl. tables)"

Necropsy included the examination of all major organs, tissues and body cavities. Histopathological examinations were performed on all the animals of the control and high dose groups. The histopathological examination of the proventriculus (target organ) was also performed in animals of the intermediate dose groups and the satellite high dose group.

Statistics:

The following statistical analyses were performed to compare mean values of control and treatment groups:
- t-test: body weights and blood parameters
- t-test followed by Dunnett’s test: biochemical parameters
- U-test: organ weights

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

250 mg/kg bw/d (males): slightly reduced body weights until Week 4 and in Week 7; 500 mg/kg bw/d (males): slightly reduced body weights between Weeks 1-7

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

effects observed, treatment-related

Description (incidence and severity):

1000 mg/kg bw/d: slightly increased

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

1000 mg/kg bw/d: oedema and ulceration of the forestomach

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

500 and 1000 mg/kg bw/d: inflammatory oedema of the submucosa of the forestomach as well as multiple ulcerations; acanthosis and proliferation of forestomach mucosa; 1000 mg/kg bw/d (satellite group): incomplete regeneration of forestomach mucosa

Histopathological findings: neoplastic:

not examined

Details on results:

CLINICAL SIGNS AND MORTALITY
No substance-related mortalities occurred during the study period. Due to mistakes in blood sampling, two males of the group 2 (250 mg/kg bw/d) inadvertently died. One female of group 3 (500 mg/kg bw/day) died as a result of incidental gavage errors.

BODY WEIGHT AND WEIGHT GAIN
The total body weight gain was slightly decreased during Weeks 1-7 of applications in males of groups 2 (250 mg/kg bw/d) and 3 (500 mg/kg bw/d) in comparison to control due to lower initial weight of the above test groups.

FOOD CONSUMPTION AND COMPOUND INTAKE
No substance-related effects on food consumption were observed during the study period.

WATER CONSUMPTION AND COMPOUND INTAKE
During test substance administration, the mean water intake was, probably compound related, slightly increased in test animals of the group 4 (1000 mg/kg bw/d).

OPHTHALMOSCOPIC EXAMINATION
There were no treatment-related changes at the ophthalmological examination.

HAEMATOLOGY
No substance-related effects were observed for haematological parameters at study termination. Slight changes in leukocytes, lymphocytes and thrombocytes were observed at the interim examination (after 6 weeks).

CLINICAL CHEMISTRY
No substance-related changes in clinical chemistry parameters were noted during the study.

ORGAN WEIGHTS
Although a slight reduction in the absolute organ weights of gonads, brain and thymus as well as slight increases in the relative organ weights of adrenal gland and liver occurred, these effects were not considered to be treatment-related since no corresponding changes in histopathology were observed.

GROSS PATHOLOGY
Gross section revealed ulcerations and oedema restricted to forestomach in the group 4 (1000 mg/kg bw/d).

HISTOPATHOLOGY: NON-NEOPLASTIC
Histopathogical evaluation revealed inflammatory oedema of the submucosa as well as multiple ulcerations associated with acanthosis and proliferation of the mucous membrane of forestomach in animals of groups 3 (500 mg/kg bw/d) and 4 (1000 mg/kg bw/d). The test animals of group 2 (250 mg/kg bw/d) did not show substance-related findings in the forestomach.

Dose descriptor:

LOEL

Remarks:

local

Effect level:

500 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: inflammation and ulcerations of mucous membrane of the forestomach due to bolus administration and irritating potential of the test substance (local effect)

Dose descriptor:

NOAEL

Remarks:

systemic

Effect level:

>= 1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no systemic or cumulative effects

Critical effects observed:

not specified

Conclusions:

According to the examinations described daily doses of 1000 mg test substance per body weight do not lead to systemic toxic effects. This dose can be considered as 'no-observable-adverse-effect-level' for rats.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

A reliable 90-day repeated dose study was performed with D-Glucopyranose, oligomeric, C10-16-alkyl glycosides via oral gavage, showing no toxicologically relevant systemic effects up to and including the highest dose level of 1000 mg/kg bw/day.

 

Local irritative effects at the side of application (forestomach gastritis), were judged as not relevant to humans due to significant different anatomic situation and exposure probability in humans.

 

The main difference between source and target substance is the alkyl chain distribution. The justification for read-across is given in the target record. There is supporting information available on repeated dose toxicity of long chain aliphatic alcohols (C6 - C22).The repeat dose toxicity of the category of long chain alcohols with chain lengths ranging from C6 to C22 indicates a low order of toxicity upon repeated exposure.A review of the toxicological database for the category of the LCOH demonstrates that members of the category of the long chain alcohols are of a low order of toxicity upon single or repeated exposure. Overall, the data show an inverse relationship between chain length and toxicity. The shorter chain alcohols tend to induce more pronounced effects when compared to materials with a longer chain length (Veenstra et al. 2009).Taking this supporting information into account, the NOAEL of 1000 mg/kg bw/day as derived for the source substance in a 90-day study in rats can be considered to represent a worst case.

 

No systemic toxicity is expected to occur after repeated oral exposure to D-Glucose, reaction products with alcohols C16-18 (even numbered). Thus, the NOAEL is considered to be ≥1000 mg/kg bw/day.

 

Therefore, based on the considerations above, it can be concluded that the results of the oral sub-chronic repeated dose toxicity study conducted in the rat with the source substance are likely to predict the properties of the target substance and are considered as adequate to fulfil the information requirement of Annex IX, 8.7.2. The dose descriptor obtained from the existing subchronic repeated dose toxicity study performed on the source substance is considered as an appropriate starting point for deriving a DNEL.

 

Justification for classification or non-classification

Based on the available relevant and reliable data, D-Glucose, reaction products with alcohols C16-18 (even numbered) does not need to be classified and labelled according to the CLP Regulation (EC) No 1272/2008.