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Description of key information

- subacute (28 d) repeated dose toxicity study with additional focus on reproductive organs, oral (gavage), Sprague-Dawley rat, m/f; OECD TG 407; GLP; RL1, dose levels: 0, 100, 300, 500 mg a.i./kg bw/d; NOAEL = 500 mg/kg bw/d; read-across: C8-10 Alkylamidopropyl betaine
- subchronic (90 d) repeated dose toxicity study with additional focus on reproductive organs, oral (gavage), Sprague-Dawley rat, m/f; OECD TG 408; GLP; RL1, dose levels: 0, 75, 150, 300 mg a.i./kg bw/d; NOEL = 300 mg/kg bw/d; read-across: C8-18 AAPB
- subchronic (90 d) repeated dose toxicity study with additional focus on reproductive organs, oral (diet), Wistar rat, m/f; OECD TG 408; GLP; RL1, dose levels: 0, 9.5, 24, 97 and 247 mg a.i./kg bw/day/d; NOEL = 247 mg/kg bw/d; read-across: C8-18 and C18 unsatd. AAPB (Coco AAPB)
- subchronic (90 d) repeated dose toxicity study with additional focus on reproductive organs, oral (gavage), Wistar rat, m/f; OECD TG 408; GLP; RL1, dose levels: 0, 100, 300, 1000 mg a.i./kg bw/day; NOAEL = 1000 mg/kg bw/d; read-across: Formamidopropylbetaine

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
300 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

No experimental data are available for the target substance Undecylenamidopropyl Betaine. However, reliable data on repeated dose toxicity are available from the closely related source substances C8-10 Alkylamidopropyl betaine, C8-18 AAPB, C8-18 and C18 unsatd. AAPB and Formamidopropylbetaine. A justification for read-across is given below.

 

In a subacute toxicity study according to OECD guideline 407 (2008) and EU method B.7 (2008) C8-10 Alkylamidopropyl betaine (34.65% a.i.) was administered to 5Hsd: Sprague Dawley SDrats/sex/dose in purified water by gavage at dose levels of 0 (control), 100, 300 and 500 mg/kg bw/day for 28 consecutive days. Control and high dose groups included 5 additional animals per sex to be sacrificed after 2 weeks of recovery.

No mortality occurred. No clinical signs and no changes were observed at the weekly detailed clinical observations. Neurotoxicity assessment did not reveal any treatment-related effects. No changes on body weight and food consumption were noted.

The lymphocytosis and monocytosis seen in single females dosed at 300 and/or 500 mg/kg bw/day showed reversibility at the end of the recovery period or comparability to control data. No toxicological relevant effects in coagulation and clinical chemistry parameters were observed. No differences were reported in terminal body weights and organ weights between treated and control animals and no treatment-related changes were noted at macroscopic and microscopic observations.

On the basis of the results obtained in this study, the dose level of 500 mg/kg bw/day was considered the NOAEL.

 

In a subchronic toxicity study according OECD guideline 408 (1991), C8-18 AAPB (30.3% a.i.) was administered to 10 male and 10 female Sprague-Dawley rats per dose by gavage at dose levels of 0, 250, 500, 1000 mg/kg bw/day (corresponding to ca. 75, 150, and 300 mg active ingredient/kg bw) for 90 days. The aqueous test item was further diluted with aqua destillata to achieve the scheduled doses. Concentrations in test formulations were analytically verified.

The substance was tolerated without any systemic effects. Up to and including the highest dose tested of 1000 mg/kg bw, there were no compound related effects in mortality, clinical signs, body weight, food consumption, hematology, clinical chemistry, organ weights including weights of ovaries and testes, systemic organ pathology and histopathology including inspection of epididymides, testes, prostate, seminal vesicle, ovaries, mammary gland and uterus.

The only treatment related effect seen in this study was a local inflammatory response at the site of application (forestomach gastritis) most probably caused by an irritant effect of the test item. These appeared in gross pathology findings in form of some stomach ulcer at fundus and cardia region in one male and one female rat at 1000 mg/kg bw/day, and in microscopic findings in form of squamous hyperplasia, submucosal edema, inflammatory cell filtration at a dose level of >= 500 mg/kg bw/day (2/10 male and 2/10 female rats at a dose level of 500 mg/kg bw, and at 1000 mg/kg bw in 6/10 males and 3/10 females). The severity of the forestomach gastritis was judged by the pathologist as minimal to moderate. Forestomach gastritis is a common finding in rat gavage studies on irritative test items. This treatment related finding is generally forced by the gavage exposure regime with constantly repeated bolus ingestion, normally reversible after cessation of treatment and almost missing when the test items are applicated via food or the drinking water. The reversibility of AAPB induced rat forestomach gastritis and its missing when the test item is applicated via food have been proven in a subacute gavage study with recovery group (Cognis, 1991) and in a subchronic feeding study (Unilever, 1994), respectively. A forestomach or a functional correlate to the rat forestomach is missing in humans. The irritative rat forestomach gastritis is judged as not relevant in view of a potential serious health risk for humans due to significant different anatomic situation and exposure probability in humans.

Therefore, the NOEL derived from this study relevant to human DNEL calculation is the NOEL for systemic effects which is the highest tested dose of 300 mg a.i./kg bw/day (= 1000 mg product (a.i. ca. 30%)/kg bw/day.

The LOEL local effects (500 mg/kg bw/day, corresponding to ca. 150 mg active ingredient/kg bw), based on local irritative effects at the site of application (forestomach gastritis), is judged as not relevant to humans due to significant different anatomic situation and exposure probability in humans.

 

In a further subchronic toxicity study according OECD guideline 408, Coco AAPB (a.i. 33.8%) was administered to 12 male and 12 female Colworth Wistar rats per dose via food at dose levels of 0.00 %, 0.04 %, 0.10 %, 0.40 % and 1.00 % (corresponding to 0, 28, 71, 288 and 731 mg product/kg bw (9.5, 24, 97 and 247 mg a.i./kg bw/day)) for 90 days. Additional animals in satellite groups (control and high dose, 5 males and 5 females, each) were kept for further 32 days without treatment to detect recovery from, or persistence of toxic effects. Concentrations in diet formulations were analytically verified and substance intake was calculated from recorded food consumption.

The substance was tolerated without any systemic effects relevant in view of an potential serious health risk for humans. Up to and including the highest dose tested of 1 % in feed (corresponding to 731 mg product/kg bw/day and 247 mg a.i./kg bw/day), there were no dose related effects on mortality, clinical signs, body weight, food consumption, water consumption, haematology, urinalysis and histopathology including inspection of seminal vesicles, prostate, epididymides, testes, mammary glands, ovaries and fallopian tubes, uterus, cervix and vagina.

The only treatment related effects ascertainable at termination of treatment but not after the recovery period were reduced food conversion efficiencies and organ weight changes in the caecum and liver. The enlarged caecum observed at necropsy in some male and female rats fed 0.40 % and 1.00 % test item was reflected in the statistically significant increases recorded in the absolute and relative, full and empty caecal weights for both male and female rats fed 1.00 % test item. These animals fed 1.00 % test item also showed reduced absolute and relative liver weights, reduced abdominal fat depots corresponding to the reduced food efficiency and several possibly associated plasma and serum biochemical changes. There was no histopathological correlate for the organ weight changes in caecum and liver. All alterations were completely reversible in the recovery group after 32 days without treatment.

Enlargement of the rat caecum with or without subsequent effects on caecum weight, food conversion and nutritional status is a common and frequently response to feeding poorly-absorbable or osmotically-active substances, such as xylitol, sorbitol, sucralose or natural sugars like d-ribose, general changes in nutritional diet composition or application of compounds with effects on the caecal microflora. In the absence of histopathological alterations, the rat caecum changes are taken as physiological adaptive responses and considered to be of no toxicological significance. An increase in liver weight without any histopathological correlate is commonly not considered to reflect an adverse effect but should be considered as an adaptive metabolic response which in known to be reversible. As also in this study, the increase in liver weight was without any histopathological correlate and has been proven to be reversible, the liver weight alteration is not considered to be an adverse effect relevant in view of a potential serious health risk for humans.

Therefore, the NOEL derived from this study relevant in view of a potential serious health risk for humans is the highest tested dose of 1 % in feed (corresponding to 731 mg product/kg bw/day and 247 mg a.i./kg bw/day).

The LOEL is 0.4 % in feed (corresponding to 288 mg product/ kg bw/day and 97 mg a.i. /kg bw/day), based on transient effects on food conversion efficiencies and organ weights of caecum and liver, judged as not relevant to humans in view of a potentially serious health risk due to missing histopathological correlate and proved reversibility.

 

In a subchronic toxicity study (according to OECD Guideline 408), Formamidopropylbetaine was administered to 10 Wistar rats/sex/dose by gavage at dose levels of 0, 100, 300 and 1000 mg a.i./kg for 90 consecutive days.

There were no compound related effects in mortality, clinical signs, functional observations, ophthalmoscopy, body weight and weight gain, food consumption and food efficiency, hematology, clinical chemistry, organ weights, gross and histologic pathology or neurobehaviour.

From the results presented in this report a No Observed Adverse Effect Level (NOAEL) of at least 1000 mg a.i./kg was established.

This subchronic toxicity study in the rat is acceptable and satisfies the guideline requirements for a OECD 408 study in rats.

 

Conclusion

The NOEL for systemic effects relevant to human DNEL calculation is derived from the 90 d repeated dose toxicity study with C8-18 AAPB which is the highest tested dose of 300 mg a.i./kg bw/day (= 1000 mg product (a.i. ca. 30%)/kg bw/day.

 

There are no data gaps for the endpoint repeated dose toxicity. No human data are available. However, there is no reason to believe that these results from rat would not be applicable to humans.

 

Justification for read-across

For details on substance identity and detailed toxicological profiles, please refer also to the general justification for read-across given at the beginning of the CSR and attached as pdf document to IUCLID section 13.

 

This read-across approach is justified based on structural similarities. The target and source substances contain the same functional groups. Thus a common mode of action can be assumed.

The only deviation within this group of substances is a variety in their carbon chain length, which obviously does not have a relevant impact on systemic toxicity after repeated exposure as demonstrated by the available data on the source substances.

 

 

Structural similarity and functional groups

The target substance Undecylenamidopropyl Betaine is a monoconstituent substance manufactured from undecylenic acid and N, N-dimethylpropylenediamine (DMAPA) and further reacted with monochloroacetic acid.

The source substance C8-10 Alkylamidopropyl betaine is a UVCB substance manufactured from fatty acids (C8 and C10) and N, N-dimethylpropylenediamine (DMAPA) and further reacted with sodium monochloroacetate.

The source substance C8-18 AAPB is a UVCB substance manufactured from natural fatty acids or oils with N, N-dimethylpropylenediamine (DMAPA) and further reacted with sodium monochloroacetate. As their origin is from natural sources, the used fatty acids may have a mixed slightly varying composition with an even numbered chain length from C8 to C18. Unsaturated C18 amounts may be included.

The source substance C8-18 and C18 unsatd. AAPB is a UVCB substance manufactured from natural fatty acids or oils with N, N-dimethylpropylenediamine (DMAPA) and further reacted with sodium monochloroacetate. As their origin is from natural sources, the used fatty acids may have a mixed slightly varying composition with an even numbered chain length from C8 to C18, including unsaturated C18 chains.

The source substance Formamidopropylbetaine is a monoconstituent substance manufactured from formic acid and N, N-dimethylpropylenediamine (DMAPA) and further reacted with sodium monochloroacetate.

 

Differences

Differences in chemical and other intrinsic properties of the target and source substances could potentially arise from the following facts:

-Different amounts of different carbon chain lengths (carbon chain length distribution):

Higher amounts of higher chain lengths and corresponding lower amounts of lower chain length lead to a rising average lipophilicity as can be seen from the increasing log Kow from Formamidopropylbetaine (log Kow: -3.3), Undecylenamidopropyl Betaine (log Kow: -1.38), C8-10 Alkylamidopropyl betaine (log Kow: 2.2), C12 AAPB (log Kow: 3.54), C8-18 AAPB (log Kow:4.23).

There are clear trends in the physicochemical properties (with regard molecular weight, water solubility, log Kow and surface tension) as demonstrated in detail in the general justification for read-across. As data on developmental toxicity are available for the upper and lower end of this row similarly showing the absence of developmental toxicity, the differences in C chain lengths obviously do not influence the intrinsic toxicity. 

- Different amounts of unsaturated fatty ester moieties:

The source substance C8-18 and C18 unsatd. AAPB contains considerable amounts of unsaturated C18 chains, which represents a worst case with respect tosome toxicological endpoints, mainly local effects (e.g. irritation, sensitisation). But in general, variability in the fatty acid moiety is not expected to be relevant to the intrinsic systemic toxicity of the substances.

 

The provided structural similarities and impurity profiles support the proposed read-across hypothesis with high confidence.

 

Comparison of repeated dose toxicity data

 

Source substances

Target substance

C8-10 Alkylamidopropyl betaine

C8-18 and C18 unsatd. AAPB

C8-18 AAPB

Formamido-propylbetaine

Undecylen-amidopro-pyl Betaine

WoE_ Repeated dose toxicity: 73772-45-9 / 73772-46-0_8.6.1_Evonik_2016_OECD407

 

OECD TG 407, subacute, rat, oral: gavage

 

NOAEL = 500 mg a.i./kg bw/d

No toxicologically relevant effects were observed up to the highest dose level tested

 

Reliability: 1 (reliable without restrictions), GLP

WoE_RA_feeding_Repeated dose toxicity: 61789-40-0_8.6.2_90days_Unilever_A03_FT890785

 

OECD TG 408, subchronic, rat, oral: feed

 

NOEL effects relevant to humans: 247 mg a.i./kg bw/d (highest tested dose, 1 % in feed, 731 mg/kg bw/d based on product (a.i. 33.8 %))

LOEL: 97 mg a.i./kg bw/day) (0.4% in feed, 288 mg/kg bw/d based on product (a.i. 33.8 %))

 

 

Reliability: 1 (reliable without restrictions), GLP

Key_RA_gavage_Repeated dose toxicity: oral: 97862-59-4_ 8.6.2_Goldschmidt_1991_OECD 408


OECD TG 408, subchronic, rat, oral: gavage


NOEL systemic effects: 300 mg a.i./kg bw/d (highest tested dose, 1000 mg/kg bw/d based on product (a.i. ca. 30 %))
LOEL local effects: 150 mg a.i./kg bw/d (500 mg/kg bw/d based on product (a.i. ca. 30 %))
NOEL local effects: 75 mg a.i./kg bw/d (250 mg/kg bw/d based on product (a.i. ca. 30 %))

 

Reliability: 1 (reliable without restrictions), GLP

WoE_RA_Repeated dose toxicity: oral 90-day OECD 408 NOTOX 497622

 

OECD TG 408, subchronic, rat, oral: gavage

 

NOAEL = 1000 mg a.i./kg bw/d

No toxicologically relevant effects were observed up to the highest dose level tested.

 

Reliability: 1 (reliable without restrictions), GLP

No data, read-across

 

The 28 day NOAEL for C8-10 Alkylamidopropyl betaine was 500 mg a.i./kg bw/d (highest tested dose level). No toxicologically relevant treatment related effects were noted.

 

In the subchronic toxicity study (according to OECD Guideline 408) with Formamidopropylbetaine no compound related effects in mortality, clinical signs, functional observations, ophthalmoscopy, body weight and weight gain, food consumption and food efficiency, hematology, clinical chemistry, organ weights, gross and histologic pathology or neurobehaviour were reported. A NOAEL of at least 1000 mg a.i./kg was established.

 

In the studies on C8-18 AAPB and Coco AAPB, up to and including the highest tested doses, no indication of any systemic toxicity of AAPBs relevant in view of a potential serious health risk for humans was found.

The only treatment related effect seen in the gavage studies was a local inflammatory response at the site of application (forestomach gastritis) most probably caused by an irritant effect of the test item.

Reversibility of the forestomach gastritis was shown in the 28-day gavage study.

In the 90 d feeding study transient effects on food conversion efficiencies and organ weights of caecum and liver were observed, but judged as not relevant to humans in view of a potentially serious health risk due to missing histopathological correlate and reversibility.

 

The NOELs derived from the 90-day gavage and the 90-day feeding study relevant in view of a potential serious health risk for humans were the highest tested doses of 300 mg a.i./kg bw/day (corresponding to 1000 mg product (a.i. ca. 30%)/kg bw/day) and 1% in feed (corresponding to 731 mg product/kg bw/day and 247 mg a.i./kg bw/day based on measured food consumption), respectively.

 

Quality of the experimental data of the analogues:

The available data are adequate and sufficiently reliable to justify the read-across approach.

The studies were conducted according to OECD Guideline 407 or 408 and were reliable without restrictions (RL1, GLP).

The test materials used in the respective studies represent the source substance as described in the hypothesis in terms of substance identity and minor constituents.

Overall, the study results are adequate for the purpose of classification and labelling and risk assessment.

 

Conclusion

Based on structural similarities of the target and source substances as presented above and in more detail in the general justification for read across, it can be concluded that the available data from the source substances C8-10 Alkylamidopropyl betaine, C8-18 AAPB, C8-18 and C18 unsatd. AAPB and Formamidopropylbetaine are also valid for the target substance Undecylenamidopropyl Betaine .

 

The source substances were of low systemic toxicity in the available repeated dose toxicity studies. Similarly low systemic toxicity is also expected for the target substance Undecylenamidopropyl Betaine.

 


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
No single key study has been selected, since all available data are used on a weight of evidence approach.

Justification for classification or non-classification

Based on the available data, Undecylenamidopropyl Betaine does not need to be classified for specific organ toxicity after repeated exposure according to regulation (EC) 1272/2008. Thus, no labelling is required.