Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Additional information

In the 28-day and 90-day repeated dose toxicity studies (tested doses up to and including approximately 300 mg a.i./kg bw/d) and developmental toxicity study (tested doses up to and including 1000 mg a.i./kg bw/d) in rats, there were no histopathological changes in reproductive organs (seminal vesicles, prostate, epididymides, testes, mammary glands, ovaries and fallopian tubes, uterus, cervix, vagina) and no effects on reproductive organs weights (testes, ovaries). In developmental toxicity studies AAPBs showed no teratogenic activity and embyotoxic effects were found only at the maternal toxic dose level. Taking into account the overall low toxic activity of the AAPBs, particularly with regard to the missing adverse effects on reproductive organs or tissues in the 28-day and 90 -day studies as well as in the developmental toxicity study, the missing teratogenic activity, the fact that embyotoxic effects were found only at the maternal toxic dose level and the toxicodynamic of AAPBs, which is primarily based on its irritancy, fertility-specific effects are highly unlikely. Therefore, further reproductive toxicity studies donot need to be conducted.

 

In accordance with Annex X column 2 of the REACH Regulation (EC) No 1907/2006, the performance of a two-generation reproductive toxicity study is not required. AAPB is of low systemic toxicity as indicated by a LD50> 2000 mg/kg bw. No indication of any systemic toxicity of AAPBs relevant in view of a potential health risk for humans was found in the sub-chronic studies, including reproductive organs. From developmental toxicity data, there is no evidence for teratogenic effects. AAPBs have no genotoxic properties as proven in the full data set including in vivo data.

The use profile of the substance indicates that relevant exposure to humans occurs via the dermal route. Reliable, relevant and adequate toxicokinetic data from an in vitro study on human skin showed a dermal resorption rate of 0 %.

Based on the above specified toxicological and toxicokinetic data, itcan be proven that the substance is of low toxicological activity and that no systemic absorption occurs via the relevant route of exposure. Therefore, further reproductive toxicity studies do not need to be conducted.

Further, in accordance with Annex XI, section 1.2 of the REACH Regulation (EC) No 1907/2006, the performance of a two-generation reproductive toxicity study is scienftifically unjustified. As indicated above there is no indication of any systemic toxicity of AAPBs relevant in view of a potential health risk for humans, neither from sub-chronic data nor from developmental toxicity data.

In conclusion, further testing on vertebrate animals in a 2-generation reproductive toxicity study, using 2600 animals is unjustified.


Short description of key information:
From the 28-day and 90-day repeated oral dose toxicity studies and developmental toxicity studies in rats there are no indications of any substance-related effects on reproductive organs up to including the highest tested doses of 300 and 1000 mg a.i./kg bw/day, respectively.

Effects on developmental toxicity

Description of key information
A relevant, reliable and adequate developmental toxicity / teratogenicity study on C8-18 AAPB is available. In this study, performed according to OECD TG 414 on CD rats, 330, 990 and 3300 mg/kg bw/day of a 28.9 % aqueous solution of C8-18 AAPB, corresponding to 100, 300, and 1000 mg active substance/kg bw/day, respectively, were applied by gavage. Dose-related maternal toxic effects (reduced food consumption, impaired body weight and necropsy stomach findings) occurred at 990 mg/kg bw/day and above. Embryotoxic effects (reduced mean fetal weight and increased number of resorptions) were found only at the maternal toxic dose level of 3300 mg/kg bw/day. Up to and including the highest tested dose, no external, skeletal or soft tissue malformations and no external variations were found. The NOEL for maternal toxicity was 330 mg/kg bw/day (corresponding to 100 mg active substance/kg bw/day) and the NOEL for developmental toxicity was 990 mg/kg bw/day (corresponding to 300 mg active substance/kg bw). The NOEL for teratogenic effects was the highest tested dose of 3300 mg/kg bw/day, corresponding to the guideline limit dose of 1000 mg active ingredient/kg bw/day.
Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
300 mg/kg bw/day
Additional information

A relevant, reliable and adequate developmental toxicity / teratogenicity studies on C8-18 AAPB is available.

In this study, performed according OECD 414, C8-18 AAPB (28.9 % a. i, 62 % water, and 5.4 % NaCl) was administered to 25 females CD rats/dose at dose levels of 0, 330, 990, 3300 mg from day 5 through 19 of gestation by gavage. The test item dose levels refer to nominal active ingredient of 100, 300, and 1000 mg/kg bw/day. The nominal values were analytically verified in samples taken at study initiation and study termination. The actual concentrations of the samples taken from the aqueous test item carrier mixtures were within the range of 101.9 % to 109.9 % of the nominal C8-18 AAPB concentrations indicating correctly prepared application mixtures and a sufficient stability. Number of evaluated pregnant rats were 20/group (the first 20 animals with pregnancy signs were used). Animals evaluated for maternal toxicity were 20/group except of high dose group in which one additional animal was included due to a premature death of one dam.

Regarding maternal toxicity, the dams of the 990 mg/kg bw/day group showed decreased net body weight change from day 6 onward (= carcass weight minus day 6 body weight), reduced food consumption, thickened/partly thickened stomach mucosa in 4 of 20 animals and in addition ulcers (diameter approximately 1 mm or 0.5 to 1 mm) in 2/4 animals with thickened mucosa. In the 3300 mg/kg bw/day group the dams showed severely reduced food consumption, reduced body weights (absolute, body weight gain on gestation days 3 to 6, 6 to 9, 12 to 15, 15 to 18 and 18 to 20, and net body weight change from day 6 onward), reduced carcass weight and reduced gravid uterus weights. Thickened or partly thickened stomach mucosa (greyish discoloured in two dams) was noted in 20 of 21 dams including one prematurely deceased dam. In addition, in two of these dams a few ulcers were noted in the stomach (diameter up to 1 mm).

The number of early, late and total resorptions was increased in the 3300 mg/kg bw/day group, and the ratio of viable fetuses to implantation sites was decreased compared to the controls. This was due to a total post-implantation loss in two dams in this dose group. In addition, a statistically significant reduction in fetal weights and in the number of viable fetuses as compared to the control was observed. No external, skeletal or soft tissue malformations and no external variations were found.

The NOEL for maternal toxicity was 330 mg/kg bw/day (corresponding to 100 mg active ingredient/kg bw/day).

The NOEL for developmental toxicity was 990 mg/kg bw/day (corresponding to 300 mg active ingredient/kg bw/day).

The NOEL for external, skeletal or soft tissue malformations and variations was the highest tested dose of 3300 mg/kb bw/day (corresponding to the guideline limit dose of 1000 mg active ingredient/kg bw/day.

 

In HERA risk assessment report first edition, 2005 an additional deveopmetal toxicity study is reported as follows:

“One further developmental toxicity study is available with cocamidopropyl betaine (30 % active substance). Female pregnant rats were administered 0, 30, 90 or 300 mg/kg bw on days 6 through 17 of gestation. No treatment-related effects on the incidence of fetal external, visceral, or skeletal malformations or developmental variations were observed among litters from dams in any of the treated groups.

The maternal and developmental no-observed-effect level (NOEL) of this study was 300 mg/kg bw/d, the highest level (Colgate-Palmolive, 2000).”

Justification for classification or non-classification

There is no evidence for an intrinsic toxicity to reproduction of AAPBs from the results of an reliable oral developmental toxicity / teratogenicity study on rats at doses up to and including the guideline limit dose of 1000 mg a. i./kg bw/day and reliable oral subchronic and subacute repeated dose toxicity studies with histopathological examination of the male and female reproductive organs (epididymides, testes, seminal vesicle, prostate, ovaries, fallopian tubes, uterus, vagina, mammary gland).

Therefore no classification is required for toxicity to reproduction according to CLP, EU GHS (Regulation (EC) No 1272/2008) and directive 67/548/EEC.