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Toxicological information

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Administrative data

Key value for chemical safety assessment

Effects on fertility

Additional information

Read-across approach


Selected endpoints for the human health hazard assessment are addressed by read-across, using a combination of data on the metal cation and the organic acid anion. This way forward is acceptable, since metal carboxylates are shown to dissociate to the organic anion and the metal cation upon dissolution in aqueous media. No indications of complexation or masking of the metal ion through the organic acid were apparent during the water solubility and dissociation tests (please refer to the water solubility and dissociation in sections 4.8 and 4.21 of IUCLID). Once the individual transformation products of the metal carboxylate become bioavailable (i.e. in the acidic environment in the gastric passage or after phagocytosis by pulmonary macrophages), the “overall” toxicity of the dissociated metal carboxylate can be described by a combination of the toxicity of these transformation products, i.e. the metal cation and carboxylate anion according to an additivity approach.


 


2-ethylhexanoic, molybdenum salt is the molybdenum metal salt of 2-ethylhexanoic acid, which readily dissociates to the corresponding molybdenum and 2-ethylhexanoate ions. These ions are considered to represent the overall toxicity of 2-ethylhexanoic, molybdenum salt in a manner proportionate to the free acid and the metal (represented by one of its readily soluble salts). 


 


A detailed justification for the read-across approach is added as a separate document in section 13 of IUCLID.


 


Toxicity for reproduction– effects on fertility


No toxicity data on adverse effects on sexual function and fertility with 2-ethylhexanoic acid, molybdenum salt is available, thus the reproductive toxicity will be addressed with existing data on the dissociation products as detailed in the table below. Further details on the reproductive toxicity of the individual constituents are given below.


 


Table: Summary of toxicity data on adverse effects on sexual function and fertility of 2-ethylhexanoic acid, molybdenum salt and the individual constituents.
























 



Disodium molybdate


(CAS# 7631-95-0)



2-ethylhexanoic acid


(CAS# 149-57-5)



2-ethylhexanoic acid, molybdenum salt
(CAS# 34041-09-3)



Repeated dose toxicity data



No adverse effects on reproductive organs observed up to 60 mg Mo/kg bw/day (90-day study, rat)



See section on repeated dose toxicity



See section on repeated dose toxicity



Two-generation reproductive toxicity study



NOAEL (rat) = >40 mg Mo/kg bw/day


Not classified



NOAEL(rat; F1)
= 100 mg/kg bw/day*

NOAEL(rat; P)
= 300 mg/kg bw/day


 


Not classified



No data


 


Not classified



* Identified as most sensitive endpoint in the registration dossier for 2-ethylhexanoic acid, i.e. has been used for the DNEL derivation of this substance.


 


Disodium molybdate


 





In an OECD Test Guideline 416 multigenerational study (Hoberman, 2017), groups of 24 male and 24 female Sprague-Dawley rats were administered sodium molybdate dihydrate at 0, 5, 17, or 40 mg molybdenum (Mo)/kg bw/day in the drinking water and at 40 mg molybdenum (Mo)/kg bw/day in diet over two generations to assess reproductive toxicity.





No adverse effect on reproductive function was observed at any dose level in either generation as indicated by no significant dose-related effect on oestrus cycles, sperm parameters, mating, fertility, gestation, litter size, pup survival, growth or postnatal development. Serum levels of Mo and copper were increased in a dose-related manner. The No Observed Adverse Effect Levels (NOAEL) are 17 mg Mo/kg bw/day for systemic toxicity and 40 mg Mo/kg bw/day for reproductive toxicity.


 











Earlier, a guideline-conform repeated dose toxicity study (acc. OECD 408, under GLP) in rats with the test item sodium molybdate was modified to include parameters related to reproductive toxicity, such as oestrous cycle and sperm analyses as specified in OECD 416: In that 90-day repeated dose toxicity study (Hoffman, 2011) disodium molybdate was administered to male and female rats at doses of 5, 17 or 60 mg/kg bw/day of Mo (molybdenum in disodium molybdate dihydrate) via feed. In addition to the standard examination parameters, the following examinations were conducted to assess any adverse effects on sexual function and fertility: vaginal cytology, oestrus cycle, qualitative sperm staging (in acc. with OECD 416).





Reduced bodyweight gains were observed in the 60 mg Mo/kg bw/day dose group. The effect was more pronounced in males, which might be due to a slightly reduced food intake. During the recovery phase food consumption in the 60 mg/kg bw/day males and females returned to a value comparable to the control animals. Light microscopic evaluation of control and 60 mg Mo/kg bw/day animals showed test item-related findings in the kidneys (slight diffuse hyperplasia of the proximal tubules) of two 60 mg Mo/kg bw/day females. No such findings were reported for the animals after the 60-day recovery phase.


There were no test substance related changes in the male or female reproductive tissues (testes, epididymis, prostate, seminal vesicles, ovaries, uterus or vagina). There were no test substance-related effects on vaginal cytology and oestrous cycles during weeks 7-9 of the dosing phase (i. e., the period during which vaginal cytology and oestrous cycles were evaluated). No test-item related changes in organ weight of testes or secondary sex organs and no effect on spermatid or sperm counts, motility or morphology were observed. All other recorded microscopic findings were considered incidental and unrelated to administration of disodium molybdate dihydrate. They occurred at similar incidences in the control and test substance treated groups or they were sporadic with no relationship to dose.





 


In this 90-day repeated dose toxicity study the NOAEL for systemic toxicity was determined to be 17 mg Mo/ kg bw/day based on the effects on body weights and kidneys seen at 60 mg Mo/kg bw/day. The NOAEL for effects on reproductive organs, sperm and oestrous cycle is 60 mg Mo/kg bw/day.





Other data:


The registrant, via the REACH Molybdenum Consortium has further conducted an extensive literature/data search and evaluation programme on animal and human toxicity data relating to reproductive/developmental toxicity of molybdenum substances. All data sources were assessed by expert toxicologists for quality and reliability, as well as relevance for regulatory risk assessment under REACH. Besides the study by Hoffmann et al. (2011), no further reliable data on fertility was found. Further relevant, but unreliable data is presented in the technical dossier and in tabular format in the CSR, but not further discussed here.


2-Ethylhexanoic acid


2-Ethylhexanoic acid was administered via drinking water to an unspecified number of male and female rats at 0, 100, 300, or 600 mg/kg bw/day. There were no deaths. The relative epididymal weights in high-dose males were significantly increased, but no histological changes were noted. A slight, but not statistically significant increase in the number of abnormal sperm was noted in the highest two dose groups; however, the incidence per animal was not provided. Treated groups required more time to successfully complete mating, and the mean litter size in high-dose pregnant females was significantly reduced. The mean pup weights in the high-dose group were significantly lower on postnatal day 7 and 14. Mean foetal weight per litter and mean placental weights were significantly reduced in the mid- and high-dose groups. Clubfoot was the only skeletal malformation; changes in skeletal variations were also noted (wavy ribs, reduced cranial ossification, and twisted hind legs). Corrected maternal body weights at termination and weight gains of high-dose females were significantly reduced. Physical development of the eyes, teeth and hair appeared to be slightly later in the pups from the high-dose groups; the significance of this finding is unclear since no data were presented on the length of gestation in treated and control dams. The high-dose of 600 mg/kg bw/day significantly reduced overall water consumption and body weights in female animals. The NOAEL for reproductive effects in parental animals was 300 mg/kg bw/day; this effect occurred in the presence of maternal toxicity. The NOAEL for F1 offspring was 100 mg/kg bw/day. Based on these results, 2-ethylhexanoic acid is not likely to cause effects on fertility but is likely to be a developmental toxicant. The developmental toxicity of 2-ethylhexanoic acid is at least partially related to disruption of Zn metabolism and distribution in the mother, and that higher zinc levels in the mothers leads to lower developmental toxicity in offspring.


2-ethylhexanoic acid, molybdenum salt


Since no toxicity data on adverse effects on sexual function and fertility is available for 2-ethylhexanoic acid, molybdenum salt, information on the individual constituents molybdate and 2-ethylhexanoic acid will be used for the hazard assessment and, when applicable, for the risk characterisation of 2-ethylhexanoic acid, molybdenum salt. For the purpose of hazard assessment of 2-ethylhexanoic acid, molybdenum salt, the point of departure for the most sensitive endpoint of each constituent will be used for the DNEL derivation.


2-ethylhexanoic acid, molybdenum salt is not expected to show adverse effects on sexual function and fertility, since the two constituents molybdate and 2-ethylhexanoic acid have not shown adverse effects on sexual function and fertility in relevant bioassays. Thus, 2-ethylhexanoic acid, molybdenum salt is not to be classified according to regulation (EC) 1272/2008 as reproductive toxicant: fertility impairment. Further testing is not required. For further information on the toxicity of the individual constituents, please refer to the relevant sections in the IUCLID and CSR.



Short description of key information:
2-ethylhexanoic acid, molybdenum salt is not expected to show adverse effects on sexual function and fertility.

Justification for selection of Effect on fertility via oral route:
Information from read-across substances:
animal data for molybdenum: NOAEL(rat) >40 mg Mo/kg bw/day
animal data for 2-ethylhexanoic acid: NOAEL(rat, P)=300 mg/kg bw/day

Effects on developmental toxicity

Description of key information
2-ethylhexanoic acid, molybdenum salt is expected to be a developmental toxicant, based on studies carried out with 2-ethylhexanoic acid.
Additional information

Read-across approach


Selected endpoints for the human health hazard assessment are addressed by read-across, using a combination of data on the metal cation and the organic acid anion. This way forward is acceptable, since metal carboxylates are shown to dissociate to the organic anion and the metal cation upon dissolution in aqueous media. No indications of complexation or masking of the metal ion through the organic acid were apparent during the water solubility and dissociation tests (please refer to the water solubility and dissociation in sections 4.8 and 4.21 of IUCLID). Once the individual transformation products of the metal carboxylate become bioavailable (i.e. in the acidic environment in the gastric passage or after phagocytosis by pulmonary macrophages), the “overall” toxicity of the dissociated metal carboxylate can be described by a combination of the toxicity of these transformation products, i.e. the metal cation and carboxylate anion according to an additivity approach.


 


2-ethylhexanoic, molybdenum salt is the molybdenum metal salt of 2-ethylhexanoic acid, which readily dissociates to the corresponding molybdenum and 2-ethylhexanoate ions. These ions are considered to represent the overall toxicity of 2-ethylhexanoic, molybdenum salt in a manner proportionate to the free acid and the metal (represented by one of its readily soluble salts). 


 


A detailed justification for the read-across approach is added as a separate document in section 13 of IUCLID.


 


Toxicity for reproduction – developmental toxicity


No toxicity data on adverse effects on development of the offspring with 2-ethylhexanoic acid, molybdenum salt are available, thus the reproductive toxicity will be addressed with existing data on the dissociation products as detailed in the table below. Further details on the genetic toxicity of the individual constituents are given below.


 


Table: Summary of toxicity data on adverse effects on development of the offspring of 2-ethylhexanoic acid, molybdenum salt and the individual constituents.
























 



Disodium molybdate


(CAS# 7631-95-0)



2-ethylhexanoic acid


(CAS# 149-57-5)



2-ethylhexanoic acid, molybdenum salt
(CAS# 34041-09-3)



Pre-natal developmental toxicity study



NOAEL(rat; mat.)= 40 mg/kg bw/day


NOAEL(rat; dev) = 40 mg/kg bw/day


Not classified

NOAEL(rat; mat.)= 250 mg/kg bw/day


NOAEL(rat; dev) = 100 mg/kg bw/day *


Category 2, H361d (CLP)



No data


 


Self-classified


Category 2, H361d (CLP)



Two-generation reproductive toxicity study



No data



NOAEL(rat; F1)
= 100 mg/kg bw/day*

NOAEL(rat; P)
= 300 mg/kg bw/day


 


Not classified



No data



* Identified as most sensitive endpoint in the registration dossier for 2-ethylhexanoic acid, i.e. has been used for the DNEL derivation of this substance.


 


 


Disodium molybdate


A guideline-conform prenatal developmental toxicity study (acc. OECD 414, under GLP) in rats with the test item sodium molybdate is available. Exposure was during gestational days 6 through 20 via the diet, in four dose groups (ca. 3, 10, 20 and 40 mg Mo/kg bw/day) and a control group (plain diet). For complete study details, please refer to the endpoint study record in the technical dossier.


There were no treatment or dose-related effects on maternal body weights, weight changes, feed consumption in grams/day or grams/kg, body weight/day, or on maternal clinical observations, pregnancy indices, or maternal organ weights at any dose. There were also no biological or statistical differences among groups for the numbers of ovarian corpora lutea/female, for uterine implantation sites, or for uterine implantation losses per female at any dose. Therefore, the NOAEL for maternal toxicity was established at 40 mg Mo/kg bw/day.


There were no biological or statistical differences among groups for the numbers of foetuses, foetal sex ratios, foetal body weights, foetal external, visceral or skeletal malformations or variations per female at any dose. The incidences of the few foetal malformations and the more common foetal variations observed in the study were comparable to the historical control database of the laboratory on this rat strain and supplier. The foetal effects in this study also did not exhibit any treatment- or dose- related pattern of increased incidences and/or severities. The NOAEL for developmental toxicity is 40 mg Mo/kg bw/day. Although no clear toxic effects were observed in either the dams or the embryos/fetuses, the highest dose tested is equivalent to approximately 20,000 times the average daily general population intake of molybdenum from food and water of about 2 µg/kg bw/day.


Remark on study on prenatal developmental toxicity in a 2nd species: For this substance there is already an endpoint record (Tyl 2013) for an OECD 414 guideline-compliant prenatal developmental toxicity study in the rat, where the results do not meet the criteria for classification. The recently revised ECHA R7a Endpoint Specific Guidance document, published July 2015, now clarifies that ‘for prenatal developmental toxicity studies, testing in two species is a standard information requirement for registrations at 1000 or more tonnes per year’. The Lead Registrant is therefore now taking steps to address this endpoint requirement for a second species.


Other data:


The registrant, via the REACH Molybdenum Consortium has further conducted an extensive literature/data search and evaluation programme on animal and human toxicity data relating to reproductive/developmental toxicity of molybdenum substances. All data sources were assessed by expert toxicologists for quality and reliability, as well as relevance for regulatory risk assessment under REACH. Besides the study by Tyl (2013), no further reliable data on prenatal developmental toxicity was found. Further relevant, but unreliable data is presented in the technical dossier and in tabular format in the CSR, but not further discussed here.


2-Ethylhexanoic acid


2-Ethylhexanoic acid was administered via drinking water to an unspecified number of male and female rats at 0, 100, 300, or 600 mg/kg bw/day. There were no deaths. The relative epididymal weights in high-dose males were significantly increased, but no histological changes were noted. A slight, but not statistically significant increase in the number of abnormal sperm was noted in the highest two dose groups; however, the incidence per animal was not provided. Treated groups required more time to successfully complete mating, and the mean litter size in high-dose pregnant females was significantly reduced. The mean pup weights in the high-dose group were significantly lower on postnatal day 7 and 14. Mean foetal weight per litter and mean placental weights were significantly reduced in the mid- and high-dose groups. Clubfoot was the only skeletal malformation; changes in skeletal variations were also noted (wavy ribs, reduced cranial ossification, and twisted hind legs). Corrected maternal body weights at termination and weight gains of high-dose females were significantly reduced. Physical development of the eyes, teeth and hair appeared to be slightly later in the pups from the high-dose groups; the significance of this finding is unclear since no data were presented on the length of gestation in treated and control dams. The high-dose of 600 mg/kg bw/day significantly reduced overall water consumption and body weights in female animals. The NOAEL for reproductive effects in parental animals was 300 mg/kg bw/day; this effect occurred in the presence of maternal toxicity. The NOAEL for F1 offspring was 100 mg/kg bw/day. Based on these results, 2-ethylhexanoic acid is not likely to cause effects on fertility but is likely to be a developmental toxicant. The developmental toxicity of 2-ethylhexanoic acid is at least partially related to disruption of Zn metabolism and distribution in the mother, and that higher calcium levels in the mothers leads to lower developmental toxicity in offspring. Based on the above given information, 2-ethylhexanoic acid was classified as toxic for reproduction, developmental toxicity category 2 (H361d).


2-ethylhexanoic acid, molybdenum salt


Since no reproductive toxicity study is available for 2-ethylhexanoic acid, molybdenum salt, information on the individual constituents molybdate and 2-ethylhexanoic acid will be used for the hazard assessment and, when applicable, for the risk characterisation of 2-ethylhexanoic acid, molybdenum salt. For the purpose of hazard assessment of 2-ethylhexanoic acid, molybdenum salt, the point of departure for the most sensitive endpoint of each constituent will be used for the DNEL derivation.


Considering the read-across principles as detailed above for 2-ethylhexanoic acid, molybdenum salt based on the toxicological assessment of the individual constituents, it is therefore proposed to also read-across the classification of toxic for reproduction, developmental toxicity category 2 (H361d) of 2-ethylhexanoic acid to 2-ethylhexanoic acid, molybdenum salt.



Justification for selection of Effect on developmental toxicity: via oral route:
Information from read-across substances:
animal data for molybdenum: NOAEL(rat; dev) = 40 mg/kg bw/day
animal data for 2-ethylhexanoic acid: NOAEL(rat, F1)=100 mg/kg bw/day

Justification for classification or non-classification

2-ethylhexanoic acid, molybdenum salt is not expected to show adverse effects on sexual function and fertility, since the two constituents molybdate and 2-ethylhexanoic acid have not shown adverse effects on sexual function and fertility in relevant bioassays. Thus, 2-ethylhexanoic acid, molybdenum salt is not to be classified according to regulation (EC) 1272/2008 as reproductive toxicant: fertility impairment. Further testing is not required.


Considering the read-across principles as detailed above for 2-ethylhexanoic acid, molybdenum salt based on the toxicological assessment of the individual constituents, it is therefore proposed to also read-across the classification of toxic for reproduction, developmental toxicity category 2 (H361d) of 2-ethylhexanoic acid to 2-ethylhexanoic acid, molybdenum salt.

Additional information