Registration Dossier

Administrative data

Description of key information

In conclusion, no human hazard for systemic toxicity after repeated oral exposure was identified for the PFAE fumarate category members.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

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 data on the substance are available for the assessement of the repeated oral toxicity, thus data from a category substance and a structurally analogue substance are used. The available studies providing information on the human health hazard assessment within the PFAE fumarates category were conducted with the category member Didodecyl fumarate (CAS 2402-58-6). This substance was selected for testing, because it represents the category member with the shortest fatty alcohol side chain, and consequently with the lowest molecular weight, which is regarded as worst-case approach in terms of hazard assessment of the PFAE fumarates for the local as well as for systemic effects. Furthermore, the category is supported by another polyfunctional aliphatic ester, namely Bis(2-ethylhexyl) adipate (CAS 103-23-1). The read across of Bis(2-ethylhexyl) adipate (CAS 103-23-1) to the PFAE fumarate category is justified due to the similar structural and physico-chemical properties, as well as their toxicological, and ecotoxicological profiles. A detailed justification for the grouping of chemicals and read-across is provided in the technical dossier (IUCLID Section 13) and within Chapter 5.1 of the CSR.

 

Repeated dose toxicity oral

Subacute

CAS 103-23-1

In a study according to OECD 407, Bis(2-ethylhexyl) adipate (CAS 103-23-1) in corn oil was administered daily via oral gavage to 10 Crj: CD(SD) rats per sex and group at dose levels of 40, 200 and 1000 mg/kg bw/day (Miyata et al., 2006). After 28-day treatment with the test substance, no treatment-related mortalities were observed in the animals. The relative organ weight of kidneys was significantly increased in males and females at 1000 mg/kg bw/day. At the same dose level, increased relative adrenal weights in females and increased relative liver weights in both sexes were observed. The changes in kidney weights at 1000 mg/kg bw/day were accompanied by clear spotty pattern in kidneys of 2 male rats as well as increased eosinophilic bodies (7/10 males) and hyaline droplets (8/10 males) at microscopic examination. These kidney effects are specific to male rats (alpha-2 micro globulin nephropathy syndrome) and of no concern to man. Further findings at histopathology involved increased ovarian follicle atresia in 4/10 females at 1000 mg/kg bw/day. Examination of vaginal smears revealed prolongation of the estrous stage in 2/10 females of the 1000 mg/kg bw/day dose group. No substance-related effects were observed on sperm parameters and histopathology of reproductive organs in males.

Based on the results of this study, the NOAEL for male and female Crj:CD(SD) rats was established at 200 mg/kg bw/day.

Subchronic

CAS 2402-58-6

A Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test in the Han Wistar Rat is available (Senn, 2013). The study was conducted according to OECD test guideline 422 and under GLP conditions to investigate the toxicological effects resulting from repeated oral-gavage administration of the test item Didodecyl fumarate (CAS 2402-58-6). 12 animals per sex and dose were administered the test material in corn oil as vehicle at dosages of 100, 300, and 1000 mg/kg body weight/day. The controls received the vehicle only. Didodecyl fumarate was administered to male rats for 48 days and to female rats for 14 days prior to pairing, through the pairing and gestation periods until the F1 generation reached day 4 post-partum. In males at 1000 mg/kg bw/day, slightly higher levels of alanine aminotransferase were observed. Although a relationship to treatment cannot be excluded, the values were well within the normal range of the rat strain used. Therefore, these differences were not considered as adverse. Furthermore, increased liver weights were observed and minor morphological alterations in the liver of males. This consisted of a minimal degree of diffuse, midzonal/centrilobular hepatocellular hypertrophy. This finding may be considered as adaptive in nature, within physiological limits and not a manifestation of frank toxicity. None of these observations were recorded at females. In males at 300 mg/kg bw/day, the alanine aminotransferase levels were also slightly higher but no other liver alterations were recorded at this dose level. No test item-related effects were observed in female rats at any dose level. Neither clinical signs nor effects on mean food consumption or mean body weight were noted at any dose level. Based on these results, the NOAEL (No Observed Adverse Effect Level) for general toxicity was considered to be 1000 mg/kg body weight/day.

CAS 103-23-1

A subchronic oral toxicity study similar to OECD 408 was performed with Bis(2-ethylhexyl) adipate (CAS 103-23-1) in Fischer 344 rats and B6C3F1 mice at dose levels of 1600, 3100, 6300, 12500 and 25000 ppm for a period of 90 days (NTP, 1982). Ten animals per sex and dose received the test substance daily via diet, whereas a similar constituted control group was administered the plain diet. No signs of toxic effects and no mortality were observed in any of the animals during the study period. In mice, an adverse decrease in body weight gain compared to controls was noted starting at 3100 ppm in males and at 6300 or 25000 ppm in females, respectively. In rats, body weight gain was adversely reduced in males at 12500 and 25000 ppm. Average food consumption was not altered between treated and control groups of both genders and species. No adverse effects were noted at histopathological examination in rats and mice. Clinical chemistry and haematological parameters were not reported in this study. Based on these results, a NOAEL of 1600 ppm was derived for male B6C3F1 mice, corresponding to an actual ingested dose of 200 mg/kg bw/day. In male rats, the NOAEL was set at 6300 ppm, which is equivalent to a dose of 630 mg/kg bw/day. In female rats, the NOAEL was set at 25000 ppm, which was equivalent to a dose of 2187 mg/kg bw/day.

The effect of Bis(2-ethylhexyl) adipate (CAS 103-23-1)on the fertility of Alpk:APfSD (Wistar-derived) rats was investigated in a GLP-conform study similar to OECD guideline 415 (Tinston, 1988). Groups of 15 male and 30 female parental animals were exposed daily to the test substance at dietary concentrations of 300, 1800 or 12000 ppm, corresponding to mean achieved dose levels of 52, 178 and 2102 mg/kg bw/day for males and 61, 203 and 2399 mg/kg bw/day for females, respectively. Male and female rats were continuously treated 10 weeks prior to mating and throughout mating. Male rats were sacrificed after mating. Treatment of female rats was continued until Day 36 post-partum when the animals were sacrificed. A similar constituted group of animals received the plain diet and served as controls. There was no evidence for any clear effect on bodyweight or food consumption. An increase in absolute and relative liver weights was observed in both male and female rats receiving dietary levels of 12000 ppm. No treatment-related findings were observed at gross pathology, except for accentuated lobular pattern in the livers of two female rats fed diets containing 12000 ppm of the test substance. No histological changes were noted in the reproductive organs of those males and females suspected of being infertile. Based on the results of this study the NOAEL for systemic toxicity was considered to be 1800 ppm, equivalent to dose levels of 178 and 203 mg/kg bw/day in males and females, respectively. Based on the study results, a NOAEL of 178 mg/kg bw/day was derived for Bis(2-ethylhexyl) adipate based on the effects seen in males in the fertility study.

Conclusion for repeated dose toxicity

There is one study available which was conducted with Didodecyl fumarate (CAS 2402-58-6) addressing the repeated dose toxicity of dicarboxylic esters with fumaric acid. Furthermore, oral toxicity after repeated exposure with the analogue substance Bis(2-ethylhexyl) adipate (CAS 103-23-1) was investigated in four studies.

In a subchronic oral toxicity study with Didodecyl fumarate (CAS 2402-58-6) in rats, a systemic NOAEL of 1000 mg/kg bw/day was identified. No adverse effects were observed up to the highest dose tested.

In subacute to subchronic oral toxicity studies with Bis(2-ethylhexyl) adipate in rats and mice systemic NOAELs of 178 and 200 mg/kg bw/day were identified.

Reduced body weight gain and increased liver weight were main findings after repeated oral exposure to Bis(2-ethylhexyl) adipate. These effects are attributed to the strong rodent specific activation of the peroxisome proliferation, predominantly via the peroxisome proliferator activated receptor (PPAR) alpha pathway (Reddy et al., 1986; Keith et al., 1992). Marked species differences have been observed for PPAR alpha activation. While rodents are very susceptible to hepatic peroxisome proliferation, guinea pigs and marmosets did not respond to Bis(2-ethylhexyl) adipate exposure with a marked increase in hepatic PPAR alpha activity (Cornu et al., 1992). This is supported by the finding that Bis(2-ethylhexyl) adipate metabolism in marmosets in contrast to rats does not lead to the formation of significant amounts of 2-Ethylhexanoic acid, a known PPAR alpha agonist (Elcombe, 1986). Thus, the observed effects after oral application are considered to be not relevant for humans.

In conclusion, no human hazard for systemic toxicity after repeated oral exposure was identified for the PFAE fumarate category members.

A detailed reference list is provided in the technical dossier (see IUCLID, section 13) and within CSR.

Justification for classification or non-classification

According to Article 13 of Regulation (EC) No. 1907/2006 "General Requirements for Generation of Information on Intrinsic Properties of substances", information on intrinsic properties of substances may be generated by means other than tests e.g. from information from structurally related substances (grouping or read-across), provided that conditions set out in Annex XI are met. Annex XI, "General rules for adaptation of this standard testing regime set out in Annexes VII to X” states that “substances whose physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity may be considered as a group, or ‘category’ of substances. This avoids the need to test every substance for every endpoint". Since the group concept is applied to the members of the PFAE fumarate category, data will be generated from representative reference substance(s) within the category to avoid unnecessary animal testing. Additionally, once the group concept is applied, substances will be classified and labelled on this basis.

Therefore, based on the group concept, all available data on repeated dose toxicity do not meet the classification criteria according to Regulation (EC) No. 1272/2008, and are therefore conclusive but not sufficient for classification.