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

Endpoint summary

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

no study available

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

An extended one-generation reproductive toxicity study does not need to be conducted because there are no results from available repeated dose toxicity studies that indicate adverse effects on reproductive organs or tissues, or reveal other concerns in relation with reproductive toxicity.

A screening study for reproductive / developmental toxicity does not need to be conducted because a pre-natal developmental toxicity study is available.  

Effects on developmental toxicity

Description of key information

Prenatal developmental toxicity study (GD 6 - 15), oral (gavage), rat (Sprague CD; 25 female/dose); EPA OPP 83-3, GLP; dose levels 0, 100, 300, and 1000 mg a.i./kg bw/day; NOAEL(development) = 1000 mg/kg bw/d; Read-across from partially unsaturated IQAC, DMS quaternised

Link to relevant study records

Reference

Endpoint:

developmental toxicity

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

Route of administration:

oral: gavage

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

10 days, from gd6 through gd15

Frequency of treatment:

once daily

Duration of test:

22 days (till gd21)

Dose / conc.:

100 mg/kg bw/day (actual dose received)

Dose / conc.:

300 mg/kg bw/day (actual dose received)

Dose / conc.:

1 000 mg/kg bw/day (actual dose received)

Clinical signs:

effects observed, non-treatment-related

Description (incidence and severity):

300 mg/kg bw/day dose group:

2 dams exhibited audible respiration during or subsequent to the treatment period.

One dam exhibited swelling in the face, urogenital area wetness, gasping and perinasal and perioral encrustation. This animal was sacrificed due to her moribund condition on gd10. None of these signs were considered to be test substance related due to their absence in the dose range finding study up to doses of 1875 mg/kg bw/day and the lack of any dose relation in the current study.


1000 mg/kg bw/day dose group:

3 dams exhibited audible respiration during or subsequent to the treatment period.

No treatment-related differences in gestational parameters including total number of implantations, number of viable and nonviable implants in any dose group.

Mortality:

mortality observed, non-treatment-related

Description (incidence):

300 mg/kg bw/day dose group:

One female became moribund and was sacrificed on gd10.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

No treatment-related effects on gestational body weights and body weight gain, corrected body weight, corrected body weight gain, absolute and relative liver weight, and gravid uterine weight .

Fetal body weights per litter were not affected by treatment.

Increased food consumption in the 100 mg/kg bw/day dose group was not considered to be related to treatment due to the lack of a dose-relationship.

Gross pathological findings:

effects observed, non-treatment-related

Description (incidence and severity):

One female in the 300 mg/kg bw/day dose group which was sacrificed due to her moribund condition, had gas-filled intestines, mucoid fluid or material in the nose turbinates, abnormal material in the trachea and discolored and consolidated lungs. One further animal in this dose group had no implants in one uterine horn.

Two females in the 1000 mg/kg bw/day dose group contained blood in the uterus (detected with Hemastix reagent strips) One further female had discolored lungs (dark red) in all lobes.

Number of abortions:

no effects observed

Pre- and post-implantation loss:

no effects observed

Total litter losses by resorption:

no effects observed

Early or late resorptions:

no effects observed

Dead fetuses:

no effects observed

Details on maternal toxic effects:

REPRODUCTION DATA OF DAMS (0, 100, 300, 1000 mg/kg bw):

- Corpora lutea:338 (16.1 per dam), 380 (16.5 per dam), 364 (15.7 per dam), 387 (15.5 per dam)

- Implantation sites (Total implants): 340 (15.5 per dam), 379 (16.5 per dam)*, 363 (15.7 per dam)**, 382 (15.3 per dam)

- Resorptions: 10 (0.5 per dam), 7 (0.4 per dam), 12 (0.5 per dam), 53 (2.7 per dam)**

- Early resorptions:13 (0.6 per dam), 21 (0.9 per dam), 17 (0.7 per dam), 14 (0.6 per dam)

- Late resorptions:0 (0 per dam), 1 (0 per dam), 2 (0.1 per dam), 0 (0 per dam)

- Live (Viable) fetuses:327 (14.9 per dam), 356 (15.5 per dam), 343 (14.3 per dam), 367 (14.7 per dam)

* Significantly different from control, p= 0.05 using two-tailed Fisher's exact test
** Significantly different from control, p= 0.01 using two-tailed Fisher's exact test

Key result

Dose descriptor:

NOEL

Effect level:

>= 1 000 mg/kg bw/day

Based on:

act. ingr.

Basis for effect level:

other: maternal toxicity

Key result

Abnormalities:

no effects observed

Fetal body weight changes:

no effects observed

Description (incidence and severity):

No treatment related effects on fetal body weights (all fetuses, male or female)
observed in any group. The statistically significant differences in mean male and female body weights in litters at 100 mg/kg bw/day were not considered to be treatment-related due to the lack of a dose-response relationship.

Reduction in number of live offspring:

no effects observed

Description (incidence and severity):

Live (Viable) fetuses:327 (14.9 per dam), 356 (15.5 per dam), 343 (14.3 per dam), 367 (14.7 per dam)

External malformations:

no effects observed

Description (incidence and severity):

Malformations: none significantly different from Control

External variations: none significantly different from control

Skeletal malformations:

no effects observed

Description (incidence and severity):

Malformations: none significantly different from Control

Skeletal variations:
- Anterior arch of atlas poorly ossified; Statistical significance of affected litters in 1000 mg/kg bw/day dose group; % affected litters (71.4, 87.0, 86.4 96.0*)
- Majority of forelimbs unossified; Statistical significance of affected litters in 300 mg/kg bw/day dose group; % affected litters (38.1, 26.1, 4.5**, 24.0)

* Significantly different from control, p= 0.05 using two-tailed Fisher's exact test
** Significantly different from control, p= 0.01 using two-tailed Fisher's exact test

Visceral malformations:

no effects observed

Description (incidence and severity):

Malformations: none significantly different from Control

Soft Tissue variations:
- Excessive bleeding at umbilicus; Statistical significance of affected litters in 100 mg/kg bw/day dose group; % affected litters (23.8, 0*, 27.3, 40.0)

Key result

Dose descriptor:

NOEL

Effect level:

>= 1 000 mg/kg bw/day

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

other: embryotoxicity

Key result

Abnormalities:

no effects observed

Key result

Developmental effects observed:

no

Conclusions:

Based on read-across, the NOEL for maternal and developmental toxicity is 1000 mg active ingredient/kg bw/day.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

No experimental data on developmental toxicity is available for C1618FA-TEPA-compound. However, a prenatal developmental toxicity study was conductes with tehsource substance partially unsaturated IQAC, DMS quaternised.A justification for read-across is attached to Iuclid section 13.

In a prenatal developmental toxicity study according to EPA OPP 83-3 timed-pregnant CD® (Sprague-Dawley) rats were administered the test item partially unsaturated IQAC, DMS quaternised (75%) by gavage on gestation days (gd) 6 through 15. Twenty-five copulation plug-positive females per group were dosed with undiluted test item at dose levels corresponding to 100, 300, and 1000 mg/kg/day of active ingredient. These dose levels were selected on the basis of results from a dose range-finding study in which no maternal toxicity or evidence of teratogenicity was observed at dose levels as high as 1875 mg/kg/day. An additional 25 females, assigned to the control group, received Milli-Q® water at a dose volume equivalent to that used in the high dose group. Clinical observations were made daily (twice daily during dosing), and maternal body weights were measured on gd 0, 6, 9, 12, 15, 18 and 21. Maternal food consumption was measured at 3-day intervals throughout gestation; gd 0-21. At scheduled sacrifice on gd 21, the dams were evaluated for liver and gravid uterine weights, number of corpora lutea and’ number and status of implantation sites (including early and late resorptions, dead fetuses and live fetuses).

All live and dead fetuses were dissected from the uterus, weighed and examined externally for malformations and variations and gender determinations.

Approximately one-half of the live fetuses in each litter were examined for visceral and craniofacial malformations and variations. The remaining one half of the fetuses were stained with alizarin red S and were examined for skeletal malformations and variations.

The pregnancy rate was equivalent across groups and ranged from 88-100%. No females aborted or delivered early. At scheduled sacrifice, 3 females in the control group; 2 females in the 100 mg/kg/day group and 1 female in the 300 mg/kg/day group were found to be nonpregnant. One female from the control group and 1 female from the 300 mg/kg/day group contained no viable fetuses at scheduled sacrifice. 21 to 25 live litters were available for evaluation from each group.

One female in the 300 mg/kg/day treatment group became moribund and was sacrificed on gd 10. Two to 3 dams in the 300 and 1000 mg/kg/day treatment groups exhibited audible respiration during or subsequent to the treatment period. None of these observations were considered to be test substance related. There were no treatment-related effects on food consumption, gestational body weight and body weight gain, corrected body weight, corrected body weight gain, and gravid uterine weight. No treatment-related differences in gestational parameters including total number of implantations, number of viable and nonviable implants, were observed in any dose group, fetal body weights per litter were not affected by treatment. No treatment-related malformations or variations were observed in this study.

Administration of the test item by gavage to pregnant Charles River CD® rats during organogenesis resulted in no treatment-related maternal toxicity, embryotoxicity, teratogenicity, or developmental delay. In this study, the ‘no observable effect level" (NOEL) for maternal toxicity as well as for developmental toxicity was at least 1000 mg/kg/day.

 

 

 

Justification for classification or non-classification

In conclusion, results of existing studies indicate that C1618FA-TEPA-compound does not need to be classified for effects on toxicity to reproduction (fertility and development) according to GHS Regulation EC No 1272/2008 and therefore labelling is not necessary.