Registration Dossier

Administrative data

Description of key information

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

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
200 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Additional information

Justification for grouping of substances and read-across

The PFAE Linear (Polyfunctional Aliphatic Ester) category consists of 16 substances, well-defined mono-constituent substances as well as related UVCB substances, respectively with varying fatty alcohol chain lengths and branching. The distinguishing feature of this category of chemicals is that they are diester derivatives of common dicarboxylic acids: namely adipic (C6), azelaic (C9) and sebacic (C10) acids. The alcohol portion of the diesters generally falls in the C3-C20 carbon number range, including linear and branched, 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 and environmental 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 interpolation 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. In particular, for each specific endpoint the source substance(s) structurally closest to the target substance is/are chosen for read-across, with due regard to the requirements of adequacy and reliability of the available data. Structural similarities and similarities in properties and/or activities of the source and target substance are the basis of read-across.

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

Repeated dose toxicity oral

Repeated dose toxicity inhalation

Repeated dose toxicity dermal

1

6938-94-9 (a)

RA: CAS 105-99-7
RA: CAS 103-23-1

--

--

2

105-99-7

Subacute:

NOAEL  

 1000 mg/kg bw
RA: CAS 103-23-1

--

--

3

110-33-8

RA: CAS 105-99-7
RA: CAS 103-23-1

Subacute:

NOAEC  

1430 mg/m³ air

--

4

1330-86-5

RA: CAS 105-99-7
RA: CAS 103-23-1

--

--

5

123-79-5 (b)

--

--

--

6

103-23-1

Subchronic:

NOAEL = 200 mg/kg bw/day

--

--

7

68515-75-3

Subchronic:

NOAEL male = 1500 mg/kg bw/day,

NOAEL female = 1950 mg/kg bw/day (c)

--

--

8

33703-08-1

--

--

--

9

16958-92-2

RA: CAS 103-23-1

Subacute:

NOAEC  

510 mg/m³ air

Subchronic:

NOAEL  

2000 mg/kg bw/day

10

85117-94-8

--

--

--

11

103-24-2

Subacute:

NOAEL = 300 mg/kg bw/day
RA: CAS 103-23-1

--

--

12

897626-46-9

RA: CAS 103-24-2
RA: CAS 69275-01-0
RA: CAS 103-23-1

--

--

13

7491-02-3

RA: CAS 105-99-7
RA: CAS 103-23-1
RA: CAS 69275-01-0

--

--

14

109-43-3

RA: CAS 105-99-7
RA: CAS 103-23-1
RA: CAS 69275-01-0

--

--

15

122-62-3

RA: CAS 105-99-7
RA: CAS 103-23-1
RA: CAS 69275-01-0

Subchronic:

NOAEC  

250 mg/m³ air (c)

--

16

69275-01-0

Subacute:

NOAEL  

1000 mg/kg bw/day

--

--

(a) Category members subject to the REACh Phase-in registration deadline of 31 May 2013 are indicated in bold font.Only for these substances a full set of experimental results and/or read-across is given.

(b) Substances that are either already registered under REACh or not subject to the REACh Phase-in registration deadline of 31 May 2013 are indicated in normal font. Lack of data for a given endpoint is indicated by “--“.

(c) Original data source is not available and thus not used for read-across.

 

Repeated dose toxicity 

Repeated dose toxicity - oral

Subacute

Diester of Adipic acid

CAS 105-99-7

The subacute oral toxicity of Dibutyl adipate (CAS 105-99-7) was investigated in a study similar to OECD guideline 407 and in conformity with GLP (Hiratsuka, 1996).

Dilutions of the test substance in olive oil were administered once daily via oral gavage to groups of 6 Crj: CD(SD) rats per sex at doses of 20, 140 and 1000 mg/kg bw for a period of 28 days. A similar constituted group received the vehicle and acted as a control. In addition, satellite groups of 6 animals per sex, each for the control and high dose group, were used to investigate the reversibility of effects during a 14-day post-exposure recovery period. No substance-related mortalities occurred during the whole study period. Clinical signs involved slight salivation in males and females at 1000 mg/kg bw/day during treatment. However, this effect disappeared during the 14-day recovery period. Food consumption was similar between treated and control animals and no changes in body and organ weights were noted during the study. No treatment-related alterations in parameters of haematology, clinical chemistry and urinalysis were observed. At gross and histopathological examination, no abnormal findings were reported in treated animals of the whole study.

Based on the results of this subacute toxicity study, the NOAEL of Dibutyl adipate was considered to be ≥

1000 mg/kg bw/day.

 

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 kidney 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 kidney 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.

 

Diester of Azelaic acid

CAS 103-24-2

In a subacute oral toxicity study according to OECD 422 and GLP, male and female Crj:CD(SD)IGS rats were exposed to Bis(2-ethylhexyl) azelate (technical product of CAS 103-24-2; analytical purity 77.2%)at doses of 100, 300 and 1000 mg/kg bw/day (Shirota, 2003).

The test substance in corn oil was administered daily to 13 animals per sex and dose via gavage. Males were treated for a period of 42 days (14 days before mating and 28 days thereafter), whereas females were exposed to the test substance 14 days prior to mating and until Day 3 of lactation (42-53 days). A similar constituted group received the vehicle and acted as a control. No mortality and no clinical signs were observed during the study period. At the end of the study, body weight gain was significantly suppressed in males receiving 1000 mg/kg bw/day compared to controls. However, no effects on food consumption were observed in treated animals. No abnormal findings were noted at gross pathology in any of the treated animals. At 1000 mg/kg bw/day, relative weights of liver and kidney were increased in both sexes. The changes in liver weight were accompanied by an increased incidence of centrilobular hypertrophy and a reduction in the occurrence of periportal fatty change in males treated with 1000 mg/kg bw/day. Haematology did not reveal any treatment-related changes in males, but a non-adverse decrease in white blood cells and a shorter activated partial thromboplastin time were observed in females at 1000 mg/kg bw/day. The analysis of clinical chemistry parameters showed a slight, but statistically significant increase in the ratio of albumin to globulin in males at 1000 mg/kg bw/day and females at ≥ 300 mg/kg bw/day. The increase in ratio of albumin to globulin noted in females at 300 mg/kg bw/day was not considered as an adverse effect because of no accompanying changes in total protein or albumin at this dose. Furthermore, concentrations of creatinine, total protein and calcium in blood were significantly reduced in females at 1000 mg/kg bw/day. Neurobehavioural examination did not reveal any treatment-related effects in the animals compared to controls.

Based on these results, the NOAEL for male and female Crj:CD(SD)IGS rats was established at 300 mg/kg bw/day.

 

Diester of Sebacic acid

CAS 122-62-3

One study investigating peroxisome proliferation in the liver is available, in which 4 male Fischer 344 rats received Bis(2-ethylhexyl) sebacate (CAS 122-62-3) at a concentration of 2% in the diet for 21 consecutive days (Moody et al., 1978).

An additional group of 13 animals was fed the plain diet and served as control. At necropsy, a statistically significant increase in liver weights and hepatic peroxisomal enzyme activities (carnitine acetyltransferase and catalase) was observed in treated animals compared to controls. Furthermore, a statistically significant, but not specified decrease in serum triglycerides compared to controls was reported, whereas serum cholesterol remained unchanged. Since no other examinations were performed at necropsy, the results of this study were not sufficient for an overall assessment of subacute toxicity.

CAS 69275-01-0

To assess the subacute oral toxicity of Bis(2-octyldodecyl) sebacate (CAS 69275-01-0) , a GLP-conform study according to EU method B.7 was performed in Sprague Dawley rats at dose levels of 100, 350 and 1000 mg/kg bw/day (Potokar, 1986). The test substance in oleum arachidis DAB8 or the vehicle alone was administered once daily to groups of 10 animals per sex via oral gavage for a period of 28 days. A satellite group of 5 males and 5 females, each for the control and 1000 mg/kg bw/day dose groups, was included in the study to investigate the reversibility of effects during a 28-day post-exposure recovery period. No mortality occurred during the whole study period. Clinical signs included thin fur, alopecia, chromodacryorrhoe, sporadically slight scrapes and were not considered to be treatment-related. At ophthalmological examination no adverse effects were reported. In the course of the study, a slight to strong increase in body weight gain and food consumption was noted in females at all dose levels compared to controls. At macroscopic and histopathological examination of the animals, no abnormal findings were reported. Haematology and clinical chemistry analysis showed some variations in the parameters analysed, but did not reveal any treatment-related changes. In animals of the satellite group, no substance-related findings were noted at the end of the recovery period.

Based on the study results, a NOAEL of  

1000 mg/kg bw/day was derived for Bis(2-octyldodecyl) sebacate.

 

Subchronic

Diester of Adipic acid

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 was 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-partu and then 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 weight 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 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 suspected of being infertile. Based on the results of this study the NOAEL for systemic toxicity was considered to be at 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 females in the fertility study.

Repeated dose toxicity - dermal

Subchronic

Diester of Adipic acid

CAS 16958-92-2

The subchronic dermal toxicity of Bis(tridecyl) adipate was investigated in a 90-day study similar to OECD guideline 411 and in compliance with GLP (Lane, 1985 and 1986).

The undiluted test substance was applied once daily for 5 days/week to the clipped skin of 10 Sprague Dawley rats per sex and group at dose levels of 800 and 2000 mg/kg bw/day under open conditions. A similar constituted group of animals remained untreated and served as controls. During the study, no treatment-related mortalities and no signs of systemic toxicity were observed. In general, most clinical signs involved local effects from the collars (e.g. lesions around the neck, reddish nasal discharge, chromodacryorrhea) or ocular bleedings (e.g. corneal opacities). Chronic deterioration of the skin (CDS), manifested only as flaking, was observed in males and females treated with 800 and 2000 mg/kg bw. Very slight erythema occurred in animals of both sexes at 2000 mg/kg bw/day and mostly at the beginning of the study. During the first part of the study, scabbing was observed on the backs of most animals of both treatment groups, with males being more affected than females. However, no dose-dependent relationship was apparent in either sex and scabbing was rarely seen later in the study. A slight, statistically significant decrease in body weights compared to controls was noted in treated males from Day 36 to the end of the study at 2000 mg/kg bw/day. Urinalysis revealed a dose-dependent increase in protein concentrations in females during Weeks 5, 9, and 13, and males during Weeks 5 and 9. Furthermore, the concentration of urinary ketone was slightly and dose-relatedly increased in both sexes. No toxicologically relevant changes in parameters of haematology were observed at any sampling interval. At study termination, a dose-dependent (correlation at a 95% confidence level) and statistically significant increase in clinical chemistry parameters was only seen in serum globulin concentration in females. Relative to body weight, the livers were mildly enlarged (p<0.05) in exposed rats of both sexes at 2000 mg/kg bw/day and in males at 800 mg/kg bw/day. The mean absolute kidney weight was slightly increased in males and females at 2000 mg/kg bw/day and in males at 800 mg/kg bw/day. A statistically significant increase in relative kidney weights was observed in both sexes and at both dose levels. In treated females, relative thymus weights were significantly decreased, whereas the decrease in relative thymus weight was not significant in males. Since no concomitant changes in histopathology were observed in liver, kidney and thymus, the effects on organ weights in the animals were considered to be non-adverse and adaptive responses (kidney, liver) to treatment with the test substance. Microscopic examination revealed mild hyperplasia of sebaceous glands of both sexes at 2000 mg/kg bw/day. No further treatment-related lesions were observed at gross and histopathological examination.

Based on the results of this study, the systemic NOAEL for subchronic dermal toxicity in Bis(tridecyl) adipate was considered to be  

2000 mg/kg bw/day.

 

Repeated dose toxicity - inhalation

Subacute

Diester of Adipic acid

CAS 110-33-8

The subacute inhalation toxicity of Dihexyl adipate (CAS 110-33-8) was investigated in male and female Sprague Dawley rats in a study similar to OECD guideline 412 (Rusch, 1979).

Groups of 10 animals per sex were exposed daily 5 days/week to the test substance at analytical concentrations of 0.015, 0.13 and 1.43 mg/L (15, 130 and 1430 mg/m³ air; MMAD<=3.5) for a period of 4 weeks using a whole body exposure sytem. A further group of 20 animals per sex was sham-exposed and served as control group. No mortalities were observed up to the end of the study. During the study, several animals in all groups exhibited rales, but this was not considered unusual for this type of exposure. Some animals also showed nasal discharge, while 1 animal exposed to 15 mg/cm³ air exhibited red nasal discharge. Reduced activity and excessive lacrimation were observed in 1 animal treated with 130 mg/m³ air and a red stain around the mouth was observed in 1 animal exposed to 1430 mg/m³ air. However, none of these clinical signs were considered to be treatment-related. No changes in body weights and clinical chemistry parameters were observed in treated animals compared to controls. After treatment, slight statistically significant changes in haematology parameters (clotting time, haemoglobin and haematocrit) occurred at the lower concentrations (15 and 130 mg/m³ air). However, these were within the normal biological limits, and thus not considered to be treatment-related. Mild proteinuria was observed randomly throughout the control and treatment groups, and was thus not considered treatment-related. Statistically significant changes in organ weight were observed for adrenals and lungs of animals exposed to 130 and 1430 mg/m³ air, respectively. Furthermore, the adrenal to brain ratios were also elevated in the 130 mg/m³ air group, and to a lesser degree also in the other exposure groups. Since no corresponding histopathological alterations were observed, changes in adrenal and lung weights were considered to be non-adverse. However, neither finding was considered to have toxicological significance. All other organ weights were considered to be within the normal biological ranges and not remarkably changed. No gross pathology and histopathology changes were observed in any of the treated animals compared to controls.

Based on the results of this study, the NOAEC for Dihexyl adipate was established at  

1430 mg/m³ air.

CAS 16958-92-2

The subacute inhalation toxicity of Bis(tridecyl) adipate (CAS 16958-92-2) was investigated in a range-finding study similar to OECD guideline 412 for a period of 14 days (Dalbey, 1989).

Groups of 10 Sprague Dawley rats per sex were exposed 6 h daily for 5 days per week to nominal concentrations of the test aerosol of 0.25 and 0.51 mg/mL (250 and 510 mg/m³ air; MMAD<=1.1) using a whole body exposure system. In addition, 10 control animals per sex were sham-exposed. No mortalities and no clinical signs of toxicity were observed in any of the animals during the study period. Body and organ weights of the liver, kidneys, thymus, and right middle lung lobe were not affected by treatment. At gross pathology, no abnormalities were noted and histopathological examination did not reveal any substance-related changes in nasal turbinates, lung, tracheobronchial lymph nodes, kidney, or liver.

Based on these results, the NOAEC for Bis(tridecyl) adipate was established at  

510 mg/m³ air.

 

Subchronic

Diester of Sebacic acid

CAS 122-62-3

In a subchronic inhalation toxicity study with Bis(2-ethylhexyl) sebacate (CAS 122-62-3), 12 Fischer 344 rats per group were exposed for 4 h daily on 5 days/week to concentrations of 0, 25 and 250 mg/m³ air over periods of 1, 7 or 13 weeks (HPV, 2010). No adverse systemic or lung effects were observed after exposure to the test substance. However, the original study report is not available and the secondary source provided only limited details on test conditions and results and was thus not suitable for risk assessment.

 

Conclusion for repeated dose toxicity

Oral toxicity after repeated exposure was investigated in eight studies. Subacute oral administration of two representative substances of the PFAE linear category, namely Dibutyl adipate (CAS 105-99-7) and Bis(2-octyldodecyl) sebacate (CAS 69275-01-0) showed no adverse systemic effects, resulting in NOAELs of >=1000 mg/kg bw/day. Adverse effects have been reported in oral studies (21 to 90 days) for the category members with 2-ethylhexanol as alcohol portion of the diester, namely Bis(2-ethylhexyl) adipate (CAS 103-23-1), -azelate (CAS 103-24-2) and –sebacate (CAS 122-62-3). The NOAEL for subacute oral toxicity of the category member Bis(2-ethylhexyl) azelate in rats was established at 300 mg/kg bw/day. In subacute to subchronic oral toxicity studies with Bis(2-ethylhexyl) adipate a systemic NOAEL of 200 mg/kg bw/day was identified.

Reduced body weight gain, increased liver weight associated with centrilobular hypertrophy, and a reduction in the grade of periportal fatty change were main findings after repeated oral exposure to Bis(2-ethylhexyl) dicarboxylic acid esters. These effects are attributed to the strong rodent specific activation of 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 Di (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.

Data on repeated dose toxicity via the dermal route are available for one category member. Subchronic dermal application of Bis(tridecyl) adipate (CAS 16958-92-2) did not reveal any adverse effects up to a dose level of 2000 mg/kg bw/day. In a parallel experiment, dermal absorption of Bis(tridecyl) adipate was measured to be approximately 10% in rats (Yang, 1985), thus indicating low systemic availability of the test substance via the dermal route.

Inhalation toxicity after repeated exposure was investigated in three studies within the category. Studies on the subacute inhalation toxicity of Dihexyl adipate (CAS 110-33-8) and Bis(tridecyl) adipate (CAS 16958-92-2) did not indicate any adverse effects up to and including the concentrations of 1430 and 510 mg/m³ air, respectively. Additionally, subchronic exposure to Bis(2-ethylhexyl) sebacate (CAS 122-62-3) via the inhalation route did not reveal any treatment-related effect up to the maximum applied concentration of 250 mg/m³ air.

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

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


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
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.

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 linear 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) 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.