Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises an adequate and reliable study (Klimisch score 2) from a reference substance with similar structure and intrinsic properties. Read-across is justified based on common functional group(s), common precursors/breakdown products and similarities in physicochemical and toxicological properties (refer to endpoint discussion for further details). The selected study is thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.6, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Justification for grouping of substances and read-across

The PFAE fumarates (Polyfunctional Aliphatic Ester) category consists of seven members, which are either well-defined mono-constituent substances or related UVCB substances, with varying fatty alcohol chain lengths. The distinguishing feature of this category of chemicals is that its members are diester derivatives of fumaric acid (CAS 110-17-8). The alcohol moiety of the dicarboxylic esters generally falls in the C12-C22 carbon number range, including linear, even and odd numbered alcohols. 

In order to avoid the need to test every substance for every endpoint, the category concept is applied for the assessment of environmental fate, environmental toxicity and human health hazards. Thus where applicable, environmental and human health effects are predicted from adequate and reliable data for source substance(s) within the group by inter- or extrapolation to the target substances in the group (read-across approach) applying the group concept in accordance with Annex XI, Item 1.5, of Regulation (EC) No 1907/2006. Structural similarities and similarities in properties and/or activities of the source and target substances in the category are the basis of read-across.

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 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. Additionally, experimental data is available from the category member Di-C12-15 Alkyl Fumarate.

Furthermore, the category is supported by another polyfunctional aliphatic ester, namely Bis(2-ethylhexyl) adipate (CAS 103-23-1). This supporting chemical is used to cover toxicological endpoints, exclusively. 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 (see IUCLID Sections 7.1 and 13) and within Chapter 5.1 of the CSR.

Endpoint specific data matrix:

ID#

CAS

Toxicity to reproduction (fertility)

1

2402-58-6

Experimental result:

NOAEL (fertility, P, rat, m/f) ≥ 1000 mg/kg bw/day

2

10341-03-4

RA: CAS 2402-58-6

RA: CAS 103-23-1

3

no CAS / List No. 938-575-3

RA: CAS 2402-58-6

RA: CAS 103-23-1

4

no CAS / Di-C12-15 Alkyl Fumarate

--

5

no CAS / List No. 938-576-9

RA: CAS 2402-58-6

6

1187576-41-5

RA: CAS 2402-58-6

7

68921-53-9

RA: CAS 2402-58-6

RA: CAS 103-23-1

8

103-23-1

Experimental result:

NOAEL (fertility, P, rat, m/f) ≥ 2102/2399 mg/kg bw/day

 

Discussion:

Within the PFAE fumarate category a study is available assessing toxicity to reproduction which was conducted with Didodecyl fumarate (CAS 2402-58-6). Furthermore, there is a reliable study for the structurally related substance Bis(2-ethylhexyl) adipate (CAS 103-23-1)available.

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. Neither clinical signs nor effects on mean food consumption, mean body weight, reproduction or breeding were noted at any dose level. Based on these results, the NOAEL (P) for reproduction was considered to be ≥ 1000 mg/kg body weight/day.

CAS 103-23-1

Toxicity to reproduction of Bis(2-ethylhexyl) adipate (CAS 103-23-1) has been investigated in a one-generation reproduction toxicity study similar to OECD 415.

The effect of Bis(2-ethylhexyl) adipate 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. A similar constituted group of animals received the plain diet and served as controls. After 10 weeks of treatment the animals were mated to produce a single litter (F1), which were reared until Day 36 post-partum. Male parent animals were killed after completion of mating and female parent animals were killed after weaning their litter. There was no evidence for any clear effects on bodyweight or food consumption during the premating phase of the study apart a marginal reduction in bodyweight gain for female rats in the 12000 ppm test group. This decrease in body weight continued through gestation in the female animals of the highest dose group compared to controls. There were no treatment-related effects on pre-coital interval, length of gestation, or on male and female fertility. Offspring weight gain, total litter weight and litter size in the 12000 ppm test group were reduced compared to controls, but there was no effect on the number of pups born live or on their survival at any dose level. An increase in absolute and relative liver weights was observed in both male and female parent animals receiving dietary levels of 12000 ppm. No treatment-related findings were observed at gross pathology, except for accentuated lobular pattern in the liver 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 which failed to breed and were thus suspected of being infertile. Based on the results of this study the NOAEL for fertility was set at ≥ 12000 ppm in the diet, which corresponds to mean achieved dose levels of 2102 and 2399 mg/kg bw/day in males and females, respectively. The NOAEL for systemic toxicity for parental animals (P) and offspring (F1) was considered to be at 1800 ppm, equivalent to dose levels of 178 and 203 mg/kg bw/day in males and females, respectively.

In summary, the NOAEL for fertility from the one-generation reproduction toxicity study of Bis(2-ethylhexyl) adipate was set at ≥ 12000 ppm in the diet, which corresponds to mean achieved dose levels of ≥ 2102 and ≥ 2399 mg/kg bw/day in males and females, respectively.

 

Conclusion for toxicity to reproduction

There is one study available which was conducted with Didodecyl fumarate (CAS 2402-58-6) addressing the endpoint toxicity to reproduction of dicarboxylic esters with fumaric acid. Furthermore, toxicity to reproduction of the analogue substance Bis(2-ethylhexyl) adipate (DEHA; CAS 103-23-1) was assessed in various studies. In an OECD 422 study with Didodecyl fumarate (CAS 2402-58-6) in rats, a NOAEL of ≥ 1000 mg/kg bw/day was identified for the parental generation. No adverse effects on fertility were observed up to the highest dose tested in either males or females. Adverse effects on fertility in females (prolonged estrous stage) have been observed with the analogue substance Bis(2-ethylhexyl) adipate (CAS 103-23-1) in a subacute repeated dose toxicity study according to OECD 407 (dose levels: 40, 200 and 1000 mg/kg bw/day) where findings at histopathology and in vaginal smears examinations revealed increased ovarian follicle atresia and prolongation of the estrous stage in 4/10 and 2/10 females at 1000 mg/kg bw/day, respectively. No substance-related effects were observed on sperm parameters and histopathology of reproductive organs in males (Miyata et al., 2006). In contrast, a one-generation toxicity study with the same test substance (Bis(2-ethylhexyl) adipate, CAS 103-23-1) did not result in any adverse effects on fertility up to a maximum dietary dose level of 12000 ppm, which corresponds to 2102 and 2399 mg/kg bw/day in males and females, respectively.  In rats Bis(2-ethylhexyl) adipate (DEHA) is hydrolysed to adipic acid and 2-ethylhexanol, the latter of which is oxidized to ethylhexanoic acid (EHA) (Takahashi et al., 1981). As EHA is a known reproductive toxicant, read-across from Bis(2-ethylhexyl) adipate (DEHA) can be considered as a worst case approach for the assessment of reproductive/ developmental toxicity within the category. In female rats delayed estrous cycle has been observed when treated with EHA (Pennanen et al., 1993), an effect also observed in the subacute study with Bis(2-ethylhexyl) adipate. However, fertility was not affected in a one-generation study with Bis(2-ethylhexyl) adipate, the study with the longest treatment duration. The overall NOAEL for reproduction toxicity was set at ≥ 1000 mg/kg bw/day, indicating no hazard for reproduction toxicity within the PFAE fumarate category.

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


Short description of key information:
No hazard for reproductive toxicity was identified for the members of the PFAE fumarate category.

Justification for selection of Effect on fertility via oral route:
Hazard assessment is conducted by means of read-across. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties and overall quality assessment (refer to the endpoint discussion for further details).

Effects on developmental toxicity

Description of key information
No hazard for developmental toxicity was identified for the members of the PFAE fumarate category. 
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises an adequate and reliable study (Klimisch score 2) from a reference substance with similar structure and intrinsic properties. Read-across is justified based on common functional group(s), common precursors/breakdown products and similarities in physicochemical and toxicological properties (refer to endpoint discussion for further details). The selected study is thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.6, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.
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

Justification for grouping of substances and read-across

The PFAE fumarates (Polyfunctional Aliphatic Ester) category consists of seven members, which are either well-defined mono-constituent substances or related UVCB substances, with varying fatty alcohol chain lengths. The distinguishing feature of this category of chemicals is that its members are diester derivatives of fumaric acid (CAS 110-17-8). The alcohol moiety of the dicarboxylic esters generally falls in the C12-C22 carbon number range, including linear, even and odd numbered alcohols. 

In order to avoid the need to test every substance for every endpoint, the category concept is applied for the assessment of environmental fate, environmental toxicity and human health hazards. Thus where applicable, environmental and human health effects are predicted from adequate and reliable data for source substance(s) within the group by inter- or extrapolation to the target substances in the group (read-across approach) applying the group concept in accordance with Annex XI, Item 1.5, of Regulation (EC) No 1907/2006. Structural similarities and similarities in properties and/or activities of the source and target substances in the category are the basis of read-across.

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 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. Additionally, experimental data is available from the category member Di-C12-15 Alkyl Fumarate.

Furthermore, the category is supported by another polyfunctional aliphatic ester, namely Bis(2-ethylhexyl) adipate (CAS 103-23-1). This supporting chemical is used to cover toxicological endpoints, exclusively. 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 (see IUCLID Sections 7.1 and 13) and within Chapter 5.1 of the CSR.

Endpoint specific data matrix:

ID#

CAS

Toxicity to reproduction – Developmental Toxicity

1

2402-58-6

Experimental result:

NOAEL (F1) ≥ 1000 mg/kg bw/day

2

10341-03-4

RA: CAS 2402-58-6

RA: CAS 103-23-1

3

no CAS / List No. 938-575-3

RA: CAS 2402-58-6

RA: CAS 103-23-1

4

no CAS / Di-C12-15 Alkyl Fumarate

--

5

no CAS / List No. 938-576-9

RA: CAS 2402-58-6

6

1187576-41-5

RA: CAS 2402-58-6

7

68921-53-9

RA: CAS 2402-58-6

RA: CAS 103-23-1

8

103-23-1

Experimental result:

NOAEL developmental ≥ 1080 mg/kg bw/day

NOAEL maternal = 170 mg/kg bw/day

 

Discussion:

Within the PFAE fumarate category a study is available assessing developmental toxicity which was conducted with Didodecyl fumarate (CAS 2402-58-6). Furthermore, there is one reliable study on the structurally related substance Bis(2-ethylhexyl) adipate (CAS 103-23-1), which is used for read-across based on the analogue approach.

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. Neither clinical signs nor effects on mean food consumption, mean body weight or pup development were noted at any dose level. Based on these results, the NOAEL (P) for development was considered to be ≥ 1000 mg/kg body weight/day.

CAS 103-23-1

In a prenatal developmental toxicity study according to OECD guideline 414, the effects of Bis(2-ethylhexyl) adipate (CAS 103-23-1) on mated female Alpk:APfSD (Wistar derived) rats were investigated during Days 1 to 22 of gestation (Hodge, 1988). Groups of 24 females received the test substance at dietary concentrations of 300, 1800 and 12000 ppm, which approximately corresponded to dose levels of 28, 170 and 1080 mg/kg bw/day. A further group of 24 mated females received the plain diet and served as controls. On Day 22 of gestation, dams were sacrificed and maternal as well as foetal examinations were performed. Maternal toxicity occurred at 12000 ppm and involved a small, but statistically significant decrease in body weight gain compared to controls. This effect was accompanied by slight, statistically significant reduction in food consumption between Days 2 to 18 of gestation. No treatment-related clinical signs were observed during the study and no adverse findings were noted at macroscopic examination of dams. There was no effect at any dose level on fetal weight, litter weight, gravid uterus weight, numbers of intra-uterine deaths or numbers of external abnormalities. At 12000 ppm, a minimal increase of pre-implantation loss associated with a decrease in litter size was observed. Six major abnormalities (in five fetuses) were seen in the treated groups and eight in the control group (of which seven consisted of multiple minor skull defects in one litter). There was no evidence that the type or distribution of these abnormalities was related to test substance treatment. Overall, minor skeletal defects were increased in a dose-related manner at 1800 and 12000 ppm, while skeletal variants (as a percentage of fetuses affected) were increased at 12000 ppm only. These findings indicated slightly poorer ossification at dose levels of 1800 and 12000 ppm. However, the slightly poorer ossification is not considered as an adverse effect. There was no evidence at any dose level, that the test substance was teratogenic in rats. 

Based on the results of the study, the NOEL for developmental toxicity in Alpk:APfSD (Wistar derived) rats was set at 300 ppm, which corresponded to approximately 28 mg/kg bw/day. The NOAEL for developmental toxicity in Alpk:APfSD (Wistar derived) rats was ≥ 12000 ppm, which is equivalent to ca. ≥ 1080 mg/kg bw/day. The NOAEL for maternal toxicity in Alpk:APfSD (Wistar derived) rats was 1800 ppm, which is equivalent to ca. 170 mg/kg bw/day.

Conclusion for developmental toxicity/teratogenicity

Members of the PFAE fumarate category are hydrolysed to fumaric acid and fatty alcohols (C8-C22). The alcohol and the dicarboxylic acids are expected to feed into metabolic pathways. There is one study available which was conducted with Didodecyl fumarate (CAS 2402-58-6) addressing the endpoint toxicity to reproduction of dicarboxylic esters with fumaric acid. No effects onpup developmentwere noted at any dose level. Based on these results, the NOAEL (P) for development was considered to be ≥ 1000 mg/kg body weight/day. Furthermore, one study investigating the developmental toxicity via the oral route is available for the analogue substance Bis(2-ethylhexyl) adipate (CAS 103-23-1, DEHA). Like fumaric acid diesters, DEHA is hydrolyzed to give the corresponding fatty acid and the alcohol, i.e. adipic acid and 2-ethylhexanol. The latter of which is oxidized to ethylhexanoic acid (EHA) which is a known to be a potent developmental toxicant. Therefore the read-across from Bis(2-ethylhexyl) adipate based on an analogue approach should be considered a worst case approach for the assessment of reproductive/ developmental toxicity within the PFAE fumarate category. Due to the absence of adverse effects, the NOAEL for developmental toxicity of Bis(2-ethylhexyl) adipate was set at ≥ 1080 mg/kg bw/day.

Therefore, no hazard for developmental toxicity was identified for the members of the PFAE fumarate category.

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


Justification for selection of Effect on developmental toxicity: via oral route:
Hazard assessment is conducted by means of read-across. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties and overall quality assessment (refer to the endpoint discussion for further details).

Justification for classification or non-classification

Based on read-across from category members and from structurally similar substances, the available data on the toxicity to reproduction/developmental toxicity do not meet the classification criteria according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.