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
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 short chain methyl esters category (SCAE Me) covers fatty acid esters of methanol. The category contains both mono-constituent substances, with fatty acid C-chain lengths ranging from C6 to C18 and UVCB substances, composed of single methyl esters in variable proportions. 

The available data allows for an accurate hazard and risk assessment of the category and the category concept is applied for the assessment of environmental fate, 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.

Table: Endpoint toxicity to reproduction

CAS No.

NOAEL [mg/kg bw/day]

111-82-0 (a)

1000 (m,f)

67762-38-3 (b)

1000 (m,f)

111-62-6 (c)

5500 (m,f)

123-95-5 (c)

6000 (m,f)

 

(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)   Surrogate substances are either chemicals forming part of a related category of structurally similar fatty acid esters or precursors/breakdown products of category members (i.e. alcohol and fatty acid moieties). Available data on these substances are used for assessment of (eco )toxicological properties by read-across on the same basis of structural similarity and/or mechanistic reasoning as described below for the present category.

 

Discussion

CAS 111-82-0

The substance methyl dodecanoate (CAS 111-82-0) was studied for oral toxicity in rats in an OECD 422 combined repeat dose and reproductive/developmental toxicity screening test under GLP conditions (JECDB 2000). 12 male and female Crj:CD (SD) rats per dose were administered doses of 0, 250, 500 and 1000 mg/kg/day by gavage. The animals were mated. The test material was administered to females from 14 days before mating until day 3 of lactation and to males for 45 days. Terminal kill was on day 45 for males and on day 4 of lactation for females. There were no effects of the test substance on the estrous cycle, copulation index, fertility index, gestation length, number of corpora lutea or implantations, implantation index, delivery index or parturition. The NO(A)ELs for reproductive performance of males and females, as well as pup development are considered to be 1000 mg/kg/day in each case.

 

 

CAS 67762-38-3

The substance Fatty acids, C16-18 and C18-unsatd., Me esters (CAS 67762-38-3) was studied for oral toxicity in rats in an OECD 422 combined repeated dose and reproductive/developmental toxicity screening test under GLP conditions (Allan, 2010). A total of 80 (40 males and 40 females) Sprague-Dawley rats were allocated to four groups, three of which received the test item at doses of 100, 300 and 1000 mg/kg bw/day while the other group received the vehicle (corn oil) by oral route (gavage) once daily at 5 mL/kg. Animals were dosed for 2 weeks prior to pairing, during pairing, during gestation and until at least day 4 post-partum for females or until sacrifice for non-pregnant females and until necropsy for males following 4 weeks of treatment. No substance-related effects were observed. Therefore, the NO(A)ELs for reproductive performance of males and females are considered to be 1000 mg/kg/day in each case.

 

CAS 111-62-6

A 90-day oral feeding study (Bookstaff, 2004) was performed with ethyl oleate (CAS 111-62-6) according to the 1993 FDA draft "Redbook II" guidelines (Toxicological Principles for the Safety Assessment of Direct Food Additives and Color Additives Used in Food). The study was performed equivalent to OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents) with additional assessment of oestrus cycle and sperm parameters. The purpose of the study was to determine the safety of ethyl oleate (EO) in a 91-day feeding study in Sprague-Dawley rats. EO was mixed into AIN-93G purified diet at levels of approx. 0, 1900, 3800 and 6000 mg/kg bw/day. All diets were calorie- and fat-matched using high oleic safflower oil (HOSO) as the control fat. There were 20 male and 20 female rats per group. EO in the diet was well-tolerated and there were no toxicologically significant findings in any of the measured parameters (clinical observations, body weight gains, appearance of the faeces, ophthalmic examinations, haematology, clinical chemistry, urinalysis, organ weights, histopathology, or male and female reproductive assessments). Based on the absence of abnormalities concerning oestrus cycle, sperm characterization and histopathologic evaluations the subchronic 90-day oral NOAEL for fertility in rats for ethyl oleate was found to be approx. 6000 mg/kg bw/day.

 

CAS 123-95-5

For butyl stearate (CAS 123-95-5), a reproduction/developmental toxicity screening test comparable to OECD Guideline 421 (Smith, 1953; summarized by Elder, 1985) was performed.20 male and female Sprague-Dawley rats received butyl stearate at a concentration of 6.25% in diet, corresponding to approx. 6000 mg/kg bw/day for a period of 10 weeks. 12 male and female negative control animals were concurrently fed basal diet. After 10 weeks animals were mated. Successfully mated pregnant female were housed individually in breeding cages. The date of parturition and the number of youngs in each litter were recorded. Litters were weaned 21 days postpartum and the weight of the weanlings determined. From each of the three groups of weanlings (those on the test material and the controls), 24 males and 24 females were chosen at random and for the next 21 days, these youngs were fed the same 6.25% diet as had been ingested by their parents. Diet intake and body weights were recorded daily; 21 days after weaning, the rats were sacrificed and necropsies were performed.

Based on reproduction, fertility index, litter size, survival index/viability index of offspring and necropsy at day 21 after weaning the NOAEL for parental fertility as well as for offspring development was found to be 6000 mg butyl stearate/kg bw/day.

 

In summary, all reliable studies consistently showed no treatment-related effects on toxicity to reproduction.

 

A two-generation reproductive study is therefore scientifically unjustified taking into account the low toxicological activity (no evidence of toxicity seen in any of the relevant route of exposure).

 

Conclusions:

In summary, all available data do not indicate any reproductive toxicity and the NOAEL for reproduction toxicity is considered to be above 1000 mg/kg bw/day (m, f).

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


Short description of key information:
All available data on reproduction toxicity resulted in NOAELs of greater than 1000 mg/kg bw/day.

Effects on developmental toxicity

Description of key information
Developmental or teratogenic effects were not observed in any of the available studies which consistently resulted in NOAELs of greater than 1000 mg/kg bw/day.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
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 short chain methyl esters category (SCAE Me) covers fatty acid esters of methanol. The category contains both mono-constituent substances, with fatty acid C-chain lengths ranging from C6 to C18 and UVCB substances, composed of single methyl esters in variable proportions. 

The available data allows for an accurate hazard and risk assessment of the category and the category concept is applied for the assessment of environmental fate, 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.

Table: Endpoint developmental toxicity

CAS No.

NOAEL [mg/kg bw/day]

111-82-0 (a)

1000

67762-38-3 (b)

1000

91031-48-0 (c)

1000

22047-49-0 (c)

1000

123-95-5 (c)

6000

(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)   Surrogate substances are either chemicals forming part of a related category of structurally similar fatty acid esters or precursors/breakdown products of category members (i.e. alcohol and fatty acid moieties). Available data on these substances are used for assessment of (eco )toxicological properties by read-across on the same basis of structural similarity and/or mechanistic reasoning as described below for the present category.

Discussion

CAS 111-82-0

The substance methyl dodecanoate (CAS 111-82-0) was studied for oral toxicity in rats in an OECD 422 combined repeat dose and reproductive/developmental toxicity screening test under GLP conditions (JECDB 2000). 12 male and female Crj:CD (SD) rats per dose were administered doses of 0, 250, 500 and 1000 mg/kg/day by gavage. The animals were mated. The test material was administered to females from 14 days before mating until day 3 of lactation and to males for 45 days. Terminal kill was on day 45 for males and on day 4 of lactation for females. There were no effects of the test substance on the estrous cycle, copulation index, fertility index, gestation length, number of corpora lutea or implantations, implantation index, delivery index or parturition. The NO(A)ELs for reproductive performance of males and females, as well as pup development are considered to be 1000 mg/kg/day in each case.

CAS 67762-38-3

The substance Fatty acids, C16-18 and C18-unsatd., Me esters (CAS 67762-38-3) was studied for oral toxicity in rats in an OECD 422 combined repeat dose and reproductive/developmental toxicity screening test under GLP conditions (Anonymous, 2010). A total of 80 (40 males and 40 females) Sprague-Dawley rats were allocated to four groups, three of which received the test item at doses of 100, 300 and 1000 mg/kg bw/day while the other group received the vehicle (corn oil) by oral route (gavage) once daily at 5 mL/kg. Animals were dosed for 2 weeks prior to pairing, during pairing, during gestation and until at least day 4 post-partum for females or until sacrifice for non-pregnant females and until necropsy for males following 4 weeks of treatment. No substance related effects were observed. Therefore, the NO(A)ELs for reproductive performance of males and females are considered to be 1000 mg/kg/day in each case.

 

CAS 91031-48-0

A Prenatal Developmental Toxicity Study was performed with fatty acids, C16-18, 2-ethylhexyl esters (CAS 91031-48-0) according to OECD Guideline 414 (Pittermann, 1994). Groups of 24 female Sprague-Dawley rats received daily oral gavage doses of the test substance at concentrations of 0, 100, 300 and 1000 mg/kg bw/day during gestation days 6 to 15. On day 20 of gestation the animals were euthanized and examined for maternal and foetal parameters. Based on the number of implantations, number of total litter losses by resorption, mortality, clinical signs, body weight, gross pathology and organ weights of maternal animals the NOAEL for maternal toxicity was found to be 1000 mg/kg bw/day. Examination of foetus litter size and weights, offspring viability (number alive and number dead), sex ratio, grossly visible abnormalities, external, soft tissue and skeletal abnormalities and head examinations showed no abnormalities and no indication for teratogenic effects. Therefore, the NOAEL for embryo-/foetotoxicity and teratogenicity in rats for fatty acids C16-18, 2-ethylhexyl esters was found to be 1000 mg/kg bw/day.

 

CAS 22047-49-0

The developmental toxicity of 2-ethylhexyl stearate (CAS 22047-49-0) was investigated according to OECD Guideline 414 und GLP conditions (Aulmann, 2000). Groups of 24 female Sprague-Dawley rats received daily oral gavage doses of the test substance at dose lvels of 0, 100, 300 and 1000 mg/kg bw/d during gestation days 6 to 15. On day 20 of gestation the animals were euthanized and examined for maternal and foetal parameters. Based on the number of implantations, number of total litter losses by resorption, mortality, clinical signs, body weight, gross pathology and organ weights of maternal animals the NOAEL for maternal toxicity was found to be 1000 mg/kg bw/d. Examination of foetus litter size and weights, offspring viability (number alive and number dead), sex ratio, grossly visible abnormalities, external, soft tissue and skeletal abnormalities and head examinations showed no abnormalities and no indication for teratogenic effects. Therefore, the NOAEL for embryo-/foetotoxicity and teratogenicity in rats for 2-ethylhexyl stearate was found to be 1000 mg/kg bw/day.

 

CAS 123-95-5

A reproduction/developmental toxicity screening test was performed with butyl stearate (CAS 123-95-5) similarly to OECD Guideline 421 (Smith, 1953; summarized by Elder, 1985). 20 male and female Sprague-Dawley rats received butyl stearate at a concentration of 6.25% in diet, corresponding to ca. 6000 mg/kg bw/day for a period of 10 weeks. 12 male and female negative control animals were concurrently fed basal diet. After 10 weeks animals were mated. The date of parturition and the number of youngs in each litter were recorded. Litters were weaned 21 days postpartum and the weight of the weanlings determined. From each of the three groups of weanlings (those on the test material and the controls), 24 males and 24 females were chosen at random and for the next 21 days, these youngs were fed the same 6.25% diet as had been ingested by their parents. Diet intake and body weights were recorded daily; 21 days after weaning, the rats were sacrificed and necropsies were performed. No gross pathologic changes were found among the young rats during necropsy at the end of the 21-day post-weaning period. Based on the study results a developmental NOAEL for butyl stearate of 6000 mg/kg bw/day could be determined.

 

In summary, all reliable studies consistently showed no treatment-related effects on maternal and developmental toxicity.

 

Conclusions:

Five studies investigating the developmental toxicity are available within the SCAE Me category. The studies with the category members methyl dodecanoate (CAS 111-82-0) and Fatty acids, C16-18 and C18-unsatd., methyl esters (CAS 67762-38-3) did not show treatment-related effects on development toxicity up to 1000 mg/kg bw/day. Also the studies from the surrogate substances Fatty acids, C16-18, 2-ethylhexyl esters (CAS 91031-48-0), 2-ethylhexyl stearate (CAS 22047-49-0) and butyl stearate (CAS 123-95-5) did not show treatment-related effects up to the highest tested dose level. Thus, no hazard for developmental toxicity was identified.

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 SCAE Me category, data will be generated from data for reference source substance(s) 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, the available data on reproduction toxicity and 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.