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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1998-10-14 till 1999-02-11
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: This robust study summary is based on a Klimisch-1-rated chronic toxicity study with the structural analog on undecylenic acid.
Cross-reference
Reason / purpose for cross-reference:
reference to other study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1999
Report date:
1999

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Reference substance name:
Sodium undec-10-enoate
EC Number:
222-264-8
EC Name:
Sodium undec-10-enoate
Cas Number:
3398-33-2
IUPAC Name:
sodium undec-10-enoate
Constituent 2
Reference substance name:
sodium salt of undecylenic acid
IUPAC Name:
sodium salt of undecylenic acid
Details on test material:
- Name of test material (as cited in study report): Undecylenic Acid Sodium Salt, Undecylenate de Sodium
- Substance type: salt
- Physical state: translucent yellow liquid (33% aqueous solution w/w)
- Composition of test material, percentage of components: 33% aqueous solution w/w
- Expiration date of the lot/batch: Jan. 1999
- Storage condition of test material: at RT
- Analytical purity: 98.5%
- Lot No. 2202K

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
-Cesarian obtained, barrier-sustained, virus antibody free
- Source: Charles River, Ste-Aubain-les-Elbeuf, France
- Age at study initiation: 6 weeks
- Weight at study initiation: 188-217g (males) 160-193g (females)
- Housing: suspended wire mesh cages, 2/cage (same sex)
- Diet (e.g. ad libitum): ad lib., pelleted
- Water (e.g. ad libitum): ad lib. 0.22 um-filtered tap water
- Acclimation period: 8 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21+/-2
- Humidity (%): 50+/-20
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: 1998-10-14 To: 1999-02-11

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
weekly, used up to 9 days; stored light protected at RT
stirred continously under light protection during administration

VEHICLE
- Concentration in vehicle: 1.67, 5, 15 and 30 mg/ml
- Amount of vehicle (if gavage): 6 ml/kg BW/day
- Purity: 98.5
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
by GC-FID; weeks 1,4,8, and 13
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
daily; half of the dose twice a day (3-4 h interval between)
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
20 mg/kg bw
Basis:
actual ingested
Remarks:
Doses / Concentrations:
60 mg/kg bw
Basis:
actual ingested
Remarks:
Doses / Concentrations:
180/360 mg/kg BW (180 mg/kg BW up to day 50, afterwards 360 mg/kg)
Basis:
actual ingested
No. of animals per sex per dose:
10 (plus additional 10 animals per sex added to control and high dose group for recovery period)
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: dose-finding study (14 d)
- Rationale for animal assignment (if not random): random by body weight
- Post-exposure recovery period in satellite groups: 4 weeks
Positive control:
no

Examinations

Observations and examinations performed and frequency:
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once daily


BODY WEIGHT: Yes
- Time schedule for examinations: allocation, day 1 of treatment, afterwards weekly


FOOD CONSUMPTION):
- Food consumption for each cage determined and mean daily diet consumption calculated as g food/animal/day: Yes


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: Yes


WATER CONSUMPTION: Yes
- Time schedule for examinations: weekly basis


OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: before treatment, end of treatment
- Dose groups that were examined: control and high dose


HAEMATOLOGY: Yes
- Time schedule for collection of blood: end of study
- Anaesthetic used for blood collection: Yes (isofluran)
- Animals fasted: Yes (overnight during urine collection)
- How many animals: first 10 surviving animals/sex/group
- Parameters checked in table 1 were examined.


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood:end of study
- Animals fasted: Yes (overnight during urine collection)
- How many animals:first 10 surviving animals/sex/group
- Parameters checked in table 1 were examined.


URINALYSIS: Yes
- Time schedule for collection of urine:end of study
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes (overnight)
- Parameters checked in table 1 were examined.

Sacrifice and pathology:
GROSS PATHOLOGY: Yes (see table2)
HISTOPATHOLOGY: Yes (see table2)
Statistics:
see attached statistics13weeks.doc

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Details on results:
CLINICAL SIGNS AND MORTALITY
dose-dependent observation of ptyalism, loud breathing/respiratory difficulties and poor clinical condition

BODY WEIGHT AND WEIGHT GAIN
reduced body weight gain in males of the high dose group, especially after dose increase starting day 50

FOOD CONSUMPTION
slightly reduced in males of the high dose group after dose increase starting day 50

FOOD EFFICIENCY
no effects

WATER CONSUMPTION
no effects (minor, not dose-related)

OPHTHALMOSCOPIC EXAMINATION
no effects (minor, within historical control)

HAEMATOLOGY
no effects (slight, within historical control)

CLINICAL CHEMISTRY
high dose group:
reduced glucose plasma levels in females, reversible in treatment-free period
reduced triglyceride-levels in females, not reversible in the treatment-free period

URINALYSIS
no effects

ORGAN WEIGHTS
no effects

GROSS PATHOLOGY
no effects

HISTOPATHOLOGY: NON-NEOPLASTIC
cardiomyopathie in the highest dose group exclusively (control: 2/20, low dose: 3/20, inter dose: 3/20, high dose: 11/23), myocardial degeneration/monocellular aggregation which was reversible during treatment free period in the highest dose group; minimal liver steatosis, not considered treatment related; one animal in high dose group cerebrellar changes, not considered of relevance; two animals of the high dose group forestomach oedema/inflammatory cell infiltration;

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
60 mg/kg bw/day (actual dose received)
Sex:
male/female
Dose descriptor:
LOAEL
Effect level:
180 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: see 'Remark'

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Under the experimental conditions, the 13 week oral toxicity study derived a LOAEL of 180 mg/kg BW for undecylenic acid sodium salt. Therefore it is suggested that there is no classification of the target chemical methyl-10-undecenoate as to its repeated dose toxicity properties (see also discussion in "executive summary").
Executive summary:

In this study, the potential of the test substance, undecylenic acid sodium salt, to induce toxicity under subchronic repeated oral treatment conditions was investigated in rats according to OECD guideline 408. Male and female Sprague-Dawley rats were treated with the test substance by oral gavage on a daily basis over a period of 90 days. The doses applied were 20, 60, and 180/360 mg/kg bw/day. In addition, a satellite group was included that was allowed to recover during a 4 week treatment-free period.

Animals were examined for mortality, clinical signs, food/water consumption, food efficiency and body weight gain throughout the study. At the end of the study, the animals were sacrificed and haematology/clinical chemistry was performed from blood and/or urine. Furthermore, animals were subjected to detailed macroscopic and microscopic pathological investigation.

Treatment with the test substance did not result in mortality, but in dose-dependent observation of clinical signs. The observed signs included ptyalism, loud breathing/respiratory difficulties and poor clinical condition. Body weight gain and food consumption were reduced in males of the high dose group, especially after dose increase starting day 50 of the study. Reduced glucose plasma levels and reduced triglyceride-levels were found in females of the high dose group, the first being reversible and the latter not reversible in the treatment-free period. Histopathology revealed cardiomyopathy in some animals of the highest dose group (myocardial degeneration/monocellular aggregation) which was reversible during treatment free period. Forestomach oedema/inflammatory cell infiltration was observed in the high dose group. There were no treatment related effects in the low and intermediate dose-groups.

Under the experimental conditions, the 13 week oral toxicity study derived LOAEL for the source chemical sodium salt of undecylenic acid was 180 mg/kg BW. Therefore it is suggested that there is no classification of the target chemical methyl-10-undecenoate as to its repeated dose toxicity properties according to either EU directive and CLP.

Justification for read-across (see endpoint summary):

This study performed with undecylenic acid sodium salt is used for read-across to evaluate methyl 10 -undecenoate. This read-across is based on the following justification.

Referring to ECHA's "Guidance on information requirements and chemical safety assessment - Chapter R.6: QSARs and grouping of chemicals", endpoint information is read-across from a structural analogue. A structural analogue is a source chemical whose physico-chemical and toxicological properties are likely to be similar to the target chemical as a result of structural similarity. The similarity may be based on a common precursor and/or breakdown product, that results via physical or biological processes (metabolic pathway similarity). This is used to examine related chemicals, such as acid/ester/salt.

Since the target chemical methyl-10-undecenoate is the methyl ester of the source chemical undecylenic acid, read-across between the two substances based on structural analogy therefore technically is possible. The scientific justification for the read-across of the study on oral repeat dose toxicity from undecylenic acid to methyl-10 –undecenoate is based on the similiar behaviour of the two substances observed during the six in-vivo studies on acute effects (see following table). 

 

Methyl-10-undecenoate

(methyl ester of undecylenic acid)

Undecylenic acid

 

Acute toxicity: oral

Acute Oral 4 / Xn R22

LD 50 = 1563 mg/kg

No classification

(LD 50 > 2000 mg/kg)

Acute toxicity: dermal

No classification

No classification

Acute toxicity: inhalation (4h)

Acute Inhal. 4 / Xn R20

Waived

Skin sensitisation

No classification

No classification

Skin irritation in vivo

No classification

Skin Irrit. 3, H316 (UN-GHS only)

No classification under CLP

Eye irritation in vivo

No classification

Eye irrit. Cat. 2A / Xi R36

Repeat dose toxicity oral (90 d subchronic)

No classification proposed

Read-across from undecylenic acid

No classification

 

- Acute oral toxicity: methyl-10 -undecenoate is classified as category 4, which is the lowest toxicity category. Since the LD50 of methyl-10 -undecenoate (1563 mg/kg) still is in the same order of magnitude compared to the LD50 of undecylenic acid (> 2000 mg/kg), the observed slight differences of the acute oral toxic effect should be insignificant in a repeated dose toxicity study.

- Acute dermal toxicity, and skin sensitization: both substances with the same results "not classified".

- Acute inhalative toxicity: methyl-10 –undecenoate is classified as category 4, which is the lowest toxicity category in CLP. This rather small inhalative toxic effect should be insignificant for the oral-application-based repeated dose toxicity study (note: for the undecylenic acid this study was waived, since undecylenic acid is a solid).

- Skin irritation: Undecylenic acid is classified as Xi R38 in the old EU classification system. This would translate to Skin Irrit. 3 (H316) in the UN-GHS system, but not in the EU-GHS (CLP), which has only category 1 and 2 for skin irritation. Therefore the skin irritating potential of the acid can be seen as negligible.

- Eye irritation: In contrast to methyl-10 -undecenoate, undecylenic acid is classified as Eye Irrit. 2. That the acid is somewhat more locally irritating than the methyl ester can be expected. Still, this effect should be insignificant when it comes to in-vivo studies which are based on oral test item applicatio

 

Conclusion: Even though the two substances were showing minor discrepancies in the in-vivo acute and local toxicity studies, a pH hydrolysis study has shown that methyl-10 -undecenoate undergo rapid hydrolysis (around 2 hours at 37°C) to undecylenic acid under gastric pH (1.2) (Report reference: 09/ANA/14891/NFS-CPA, 2009), therefore, the read-across for the repeated dose toxicity endpoint is relevant.

It should also be noted that only some relatively minor toxic effects were being observed, not exceeding category 4 for acute toxicity (methyl-10-undecenoate) or category 2 for eye irritation (undecylenic acid), indicating the generally limited hazardous effects exhibited by the two substances. Since furthermore the physical-chemical properties of source and target substance mostly are comparable as well, to accepting the above suggested read-across is being proposed. 

 

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