Fatty acids, C16-18 (even numbered), reaction products with tetraethylenepentamine, acetates (salts)

Endpoint summary

Description of key information

Subchronic 91 d study, oral (feed), rat (Sprague-Dawley; 20/sex/dose), OECD guideline 408, GLP; dose levels 0, 10, 100 and 1000 mg/kg bw/day; NOEL = 100 mg/kg bw/d, LOAEL = 1000 mg/kg bw/d based on decreased absolute and relative liver weights, lower total serum protein, higher SGPT and SGOT concentrations without correlating microscopic lesions; read-across from partially unsaturated IQAC, DMS quaternised

 

The reported no observed effect level has been recalculated for the derivation of an acceptable DNEL longterm oral, departing from the highest dose as the LOAEL to arrive at a realistic basis for DNEL derivations, resulting in the recalculated NOAEL of 300 mg/kg bw/day.

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
This read-across is based on the hypothesis that source and target substances have similar toxicological and ecotoxicological properties because
• they are manufactured from similar precursors under similar conditions
• they share structural similarities and common functional groups
• the analytical descriptors show comparable results
• the metabolism pathway leads to comparable products (amine backbone and long chain fatty acids) and non-common products predicted to have no toxicological effects (long chain fatty acids).

This read-across hypothesis corresponds to scenario 2 - different compounds have qualitatively and quantitatively the same type of effects - of the read-across assessment framework i.e. properties of the target substance C1618FA-TEPA-compound are predicted to be similar to those of the source substances Partially unsaturated IQAC, DMS quaternised and oleic acid based IQAC, DMS quaternised.

Based on the available experimental data, the read-across strategy is supported by close structural analogy as well as similar toxicological profiles.

Therefore, read-across from the existing sub-chronic toxicity studies and pre-natal developmental toxicity as well as ecotoxicological studies on the source substance is considered as an appropriate adaptation to the standard information requirements of the REACH Regulation for the target substance, in accordance with the provisions of Annex XI, 1.5 of the REACH Regulation.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Please refer to detailed Justification for read-across attached to Iuclid section 13

3. ANALOGUE APPROACH JUSTIFICATION
Please refer to detailed Justification for read-across attached to Iuclid section 13

4. DATA MATRIX
Please refer to detailed Justification for read-across attached to Iuclid section 13

Reason / purpose for cross-reference:

read-across: supporting information

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Route of administration:

oral: feed

Duration of treatment / exposure:

13 weeks

Dose descriptor:

NOEL

Effect level:

100 mg/kg bw/day (nominal)

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

other: Reduced liver weight and minor serum enzymes changes in males at 1000 mg/kg bw/day

Dose descriptor:

NOAEL

Effect level:

300 mg/kg bw/day (nominal)

Based on:

other: act. ingr. (recalculated)

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Critical effects observed:

no

Endpoint conclusion

Endpoint conclusion:

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 repeated dose toxicity studies with C1618FA-TEPA-compound are available. A read-across from the source substance partially unsaturated IQAC, DMS quaternised is used to assess repeated dose toxicity. A justification for read-across is attache dto Iuclid section 13.

 

Oral repeated dose toxicity studies

In a subchronic toxicity study comparable to OECD guideline 408 (1981), the partially unsaturated IQAC, DMS quaternised (tallow fatty acid based; CAS-no. 68122-86-1) was administered to 20 Sprague-Dawley rats/sex/dose by oral feed at dose levels of 0, 10, 100 and 1000 mg/kg bw/day (active ingredient). No satellite group was included to assess the reversibility of any potentially adverse effects.

The active ingredient in diet was analysed in all preparations and actual test material consumption closely resembled theoretical values (males 94 to 95 % and females 86 to 93 %).

There were no treatment related clinical signs observed, no animal died or was sacrificed during the study. Body weights and weight gains were in a normal range. No significant differences in food consumption were detected for any treated male group. Food consumption in the 10 and 100 mg/kg bw/day female groups were significantly increased during some weeks during the study. There were no consistent differences in food efficiencies.

Decreased values of absolute and relative liver weights in the male high dose group were probably treatment related and were accompanied by lower total serum protein and higher SGPT and SGOT concentrations for this treatment level. Correlating microscopic lesions were not detected. A dose dependency for these effects was not found.

No other treatment related effects on organ weights, hematological or clinical chemistry parameters were observed. All macroscopic observations and microscopic lesions were considered incidental and not treatment related. Microscopic examinations revealed no treatment related changes.

The histological examination of the reproductive organs (testes, epididymis, prostate, seminal vesicle, ovary, uterus and vagina) did not reveal any treatment related abnormalities.

A pretest health examination, conducted on 10 animals/sex, showed five animals with positive background endoparasites or viral titers.

The NOEL was 100 mg/kg bw/day.

The study suffers, however, from the excessively wide dose spacing, which would not be the standard for present day testing protocols. Considering the overall toxicological profile, there is no evidence for a potential serious health risk for humans upon ingestion of members of this chemical structure family. As a consequence, the reported NOEL has been recalculated for the derivation of an acceptable DNEL longterm oral, departing from the highest dose as the LOAEL to arrive at a realistic basis for DNEL derivations, resulting in the recalculated NOAEL of 300 mg/kg bw/day.

 

A 28 day repeated dose toxicity study with dose levels of4, 40 and 400 mg/kg bw/dayis reported by NICNAS. However, other than reporting a NOEL, no other details of the study have been submitted (FSQSC 1988). The NOEL from this study was 400 mg/kg bw/d based onminor changes in serum enzymes (male/female) and in bilirubin (female) at 400 mg/kg bw/d.

 

Dermal repeated dose toxicity studies

In a repeat dose dermal study, rabbits, 5/sex, received topical application of 2 mL/kg bw/day of Varisoft 475 at dose levels of 3 or 27 mg active compound/kg bw/d for 13 weeks (91 days). Animals at both doses had slight to moderate erythema, oedema and desquamation. There were no treatment related changes in body weight. No treatment related changes were observed in clinical pathology, bone marrow smears, organ weights, microscopic changes in skin or histopathological changes to internal organs. The reported NOEL for systemic toxicity was 27 mg active compound/kg bw/d. In other repeat dose studies of 14 day or 91 day duration (no other details provided), no effects other than skin irritation were reported for Varisoft 475. The NOELs from the studies on Varisoft 475 are tabulated below.

 

Exposure Duration	Highest Dose Tested	NOEL (systemic effects)
14 days 7 hours, 5 days/week	600 mg/kg bwt	600 mg/kg bwt/day
91 days 7 hours, 5 days/week	27 mg/kg bwt	27 mg/kg bwt/day
91 days 7 hours, 5 days/week	300 mg/kg bwt	300 mg/kg bwt/day
91 days 7 hours, 5 days/week	400 mg/kg bwt	400 mg/kg bwt/day

 

Summary

In the 91-day oral study in male rats, absolute and relative liver weight decrease, a slight decrease in serum albumin concentration and higher SGPT and SGOT concentrations were observed in highest dose group (1000 mg/kg bw/day). Correlating histopathological lesions were not detected. A dose dependency for these effects was not found.

Minor effects on liver enzyme serum levels in both genders and on serum bilirubin levels in female animals at 400 mg/kg bw/day, the highest dose tested, were reported in the 28 days study, while in the subchronic study decreased relative and absolute liver weights, a slight decrease in protein concentration and minor increases in serum enzyme levels (SGOT and SGPT) were reported for the male high dose group (1000 mg/kg bw/day), only. Findings were without histopathological correlate. These observations are in accordance with the mild and obviously not dose related and potentially reversible effects observed, the practically absent acute oral toxicity for this substance class and its low bioavailability upon ingestion as determined in the toxicokinetic studies (cf. 7.1 Summary and discussion of toxicokinetics).

The repeated dose toxicity studies, also reported by NICNAS for the oral route, are significant in showing that in consequence there is no evidence for a potential serious health risk for humans upon ingestion of members of this structure family. The studies suffer, however, from the wide dose spacing, which would not be the standard for present day testing protocols. As a consequence, the reported NOELs have been recalculated for the derivation of an acceptable DNEL longterm oral, departing from the highest dose as the LOAEL to arrive at a realistic basis for DNEL derivations.

Furthermore, no effects on reproductive organs have been reported in the oral sub-chronic study up to the highest dose of 1000 mg/kg bw/day.

No reliable, sufficiently documented dermal repeated dose toxicity studies are available. Thus, the derivation of an acceptable DNEL longterm dermal for systemic effects the NOAEL obtained from the oral repeated dose toxicity study will be used as starting point.

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 classification or non-classification

The available data do not indicate the need for a classification for repeated dose toxicity for C1618FA-TEPA-compound according to GHS Regulation EC No 1272/2008 and therefore labelling is not required.