Alcohols, C16-18, reaction products with D-glucose

Endpoint summary

Description of key information

NOAEL (subacute, rat) ≥ 1000 mg/kg bw/day, based on read-across
NOAEL (subchronic, rat) ≥ 1000 mg/kg bw/day, based on read-across

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:

migrated information: read-across based on grouping of substances (category approach)

Adequacy of study:

key study

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:

REPARATION 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:
250, 500 and 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.

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: all surviving 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 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 classified 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

Quality of whole database:

The available information comprises an adequate and reliable study (Klimisch score 2) from a reference substance with similar structure and intrinsic properties.

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

There are no studies available on the repeated dose toxicity of D-Glucose, reaction products with alcohols C16-18 (even numbered) (excess). In order to fulfil the standard information requirements set out in Annex IX, 8.6, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006, read-across from structurally related substance is conducted.

A detailed justification for the grouping of chemicals and read-across is provided in the technical dossier (see IUCLID Sections 7.1 and 13).

Oral

Subacute

No data is available on the subacute toxicity of D-Glucose, reaction products with alcohols C16-18 (even numbered) (excess). Based on an analogue approach, a 28-day toxicity study with the fatty alcohol octadecan-1-ol (CAS 112-92-5), which is a major constituent of the substance to be registered, is used to cover this endpoint (Henkel, 1999). According to OECD guideline 407, 10 animals per sex and dose received the test substance at doses of 100, 500 and 1000 mg/kg bw/day in olive oil or the vehicle alone via gavage. To study the reversibility of effects, 5 male and 5 female animals received the test substance at the high dose and served as satellite group during a post-exposure period of 28 days. No substance-related mortalities occurred during the study period. Minor changes in clinical chemistry and haematological parameters as well as body and organ weights were not attributed to treatment with the test substance. Based on the results of the subacute toxicity study with that test substance, the NOAEL for rats was considered to be ≥1000 mg/kg bw/day for that substance.

Subchronic

No information exists on the subchronic toxicity of D-Glucose, reaction products with alcohols C16-18 (even numbered) (excess), but there are reliable studies available from the structurally related substances hexadecan-1-ol (CAS 36653-82-4), octadecan-1-ol (CAS 112-92-5) and D-Glucopyranose, oligomeric, C10-16-alkyl glycosides, the latter also being a member of the category. The fatty alcohols are no members of the category, but they are used for an analogue approach.

A subchronic oral toxicity study with D-Glucopyranose, oligomeric, C10-16-alkyl glycosides was performed in Sprague Dawley CD rats according to EU method B.26 and in conformity with GLP (Henkel, 1989). Aqueous solutions of the test substance were administered daily to groups of 10 male and 10 female rats at doses of 250, 500 and 1000 mg/kg bw/day for 13 weeks via gavage. A similarly constituted group of 10 males and 10 females received water as vehicle and acted as a control. In addition, satellite groups of 5 males and 5 females each for the control and high dose group were used to investigate reversibility of effects in a 27-day post-exposure recovery period. No substance-related mortalities occurred during the study period. 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. Due to bolus administration and the irritating potential of the test substance, inflammation and ulcerations of mucous membrane of the forestomach were observed. Based on the results of the subchronic study with D-Glucopyranose, oligomeric, C10-16-alkyl glycosides, the systemic NOAEL for rats was considered to be ≥ 1000 mg/kg bw/day.

For the fatty alcohol octadecan-1-ol, a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test in male and female Wistar rats according to OECD guideline 422 is available (National Food Agency Denmark, 1992). Twelve animals per sex and group received the test substance via feed at concentrations of 1500, 7500 and 30000 ppm (corresponding to approx. 100, 500 and 2000 mg/kg/bw/day) for 7 days/week over a period of 45 (males) and 54 (females) days. Control animals were given plain diet. No adverse effects on the animals were observed during study. Based on these results, the NOAEL for rats was considered to be ≥ 2000 mg/kg bw/day for males and females, respectively, for that substance.

In a subchronic toxicity study with hexadecan-1-ol, which followed no specific guideline, male and female rats were orally administered the test substance at concentrations of 1%, 2.5% and 5-10% in the diet for 7 days/week over a period of 13 weeks (Biological Research Division, 1966). The corresponding doses based on food consumption and body weight were 723, 1822 and 4257 mg/kg bw/day for males and 875, 2064 and 4567 mg/kg bw/day for females. Since no adverse toxic effects were observed up to the highest dose, a NOAEL of 4257 mg/kg bw/day for males and 4567 mg/kg bw/day for females was derived for hexadecan-1-ol.

 

Due to the strong structural similarities with these substances, no toxicity is expected to occur after repeated exposure to D-Glucose, reaction products with alcohols C16-18 (even numbered) (excess), either.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Hazard assessment is conducted by means of read-across based on a category approach. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties between source and target substance and overall assessment of quality, duration and dose descriptor level (refer to the endpoint discussion for further details).

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
No study required since the substance has a low vapour pressure and is marketed in granules of a size excluding the possibility of inhalation; experience demonstrates that no dust formation occurs upon handling. Therefore, human exposure to vapours or dusts is not to be expected.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
No study required since the substance has a low vapour pressure and is marketed in granules of a size excluding the possibility of inhalation; experience demonstrates that no dust formation occurs upon handling. Therefore, human exposure to vapours or dusts is not to be expected.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
No study required since data from structurally related substances according to Regulation (EC) No 1907/2006, Annex XI, article 1.5 demonstrate a lack of acute toxicity via the dermal route and negligible dermal absorption through human skin in vitro.

Justification for selection of repeated dose toxicity dermal - local effects endpoint:
No study required since data from structurally related substances according to Regulation (EC) No 1907/2006, Annex XI, article 1.5 demonstrate a lack of acute toxicity via the dermal route and negligible dermal absorption through human skin in vitro.

Justification for classification or non-classification

The available data on the repeated dose toxicity via the oral route of substances structurally related to D-Glucose, reaction products with alcohols C16-18 (even numbered) (excess)according to the criteria laid down in Regulation (EC) No 1907/2006, Annex XI, 1.5do not meet the criteria for classification according to Regulation (EC) No 1272/2008 or Directive 67/548/EEC; in conclusion, D-Glucose, reaction products with alcohols C16-18 (even numbered) (excess) does not meet the criteria for classification, either, and the available data are therefore conclusive but not sufficient for classification.