2-ethylhexanoic acid, manganese salt

Endpoint summary

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

Species:

other: rat and mice

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

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, manganese salt is the manganese metal salt of 2-ethylhexanoic acid, which readily dissociates to the corresponding divalent manganese cation and 2-ethylhexanoic acid anions. The manganese cation and the 2-ethylhexanoic acid anion are considered to represent the overall toxicity of 2-ethylhexanoic, manganese 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.

 

Repeated dose toxicity

No repeated dose toxicity study with 2-ethylhexanoic, manganese salt is available, thus the repeated dose toxicity will be addressed with existing data on the dissociation products manganese and 2-ethylhexanoic acid as detailed in the table below.

 

Table: Summary of repeated dose toxicity data of 2-ethylhexanoic, manganese salt and the individual constituents.

	Manganese sulfate (CAS# 7785-87-7)	2-ethylhexanoic acid (CAS# 149-57-5)	2-ethylhexanoic, manganese salt (CAS#15956-58-8)
Repeated dose oral toxicity	NOAEL(chronic, rat)=200 mg MnSO4/kg bw/day   NOAEL(chronic, rat)= 72.8 mg Mn/kg bw/day*	NOAEL(rat;90d)= 300 mg/kg bw/day   NOAEL(mice;90d)= 200 mg/kg bw/day	No data
Repeated dose inhalation toxicity	respirable IOELV= 0.05 mg/m³   inhalable IOELV=0.2 mg/m³   STOT RE 2 (H373), neurological effects	No data	No data   Self-classified STOT RE 2 (H373), neurological effects

* The registration dossier for manganese sulfate, the DNEL(dermal,systemic) was derived by route to route extrapolation form inhalation to dermal. This extrapolation is not justified, since (i) according to ECHA guidance R.8 preference should be given to experimental data in animals, instead of using occupational exposure limits as DNEL replacement, since this approach does not cover the extended exposure of the general population (ii) a relevant and reliable chronic repeated dose toxicity/carcinogenicity study in rats and mice is available for manganese sulfate (iii) the most sensitive endpoint for the inhalation route is neurotoxicity, which does not occur after oral or dermal exposure, hence the extrapolation from inhalation to the dermal route would be a serious overestimate of the underlying hazard. For the derivation of the DNEL(dermal, systemic), the NOAEL of 72.8 mg Mn/kg bw/day was used as point of departure.

 

Manganese sulfate, oral data (information taken from IEH, 2004)

The effects of 13 weeks of dietary administration of manganese sulphate to F344/N rats (at 1600, 3130, 6250, 12500 or 25 000 ppm) and B6C3F1 mice (3130, 6250, 12 500, 25 000 or 50 000 ppm) have been reported by NTP (1993). In rats, inclusion levels equated to overall doses of 110 to 1700 mg/kg bw/day in males and 115 to 2000 mg/kg/day in females. Treatment was generally well tolerated in the rats although some reduction in weight gain (up to 11%) occurred in females at 6250 ppm or above. No clearly treatment-related changes in haematology or histopathology were noted. However, liver weight (absolute and relative to body weight) was reduced in males and females given 25 000 ppm, as was lung weight in treated female groups. In mice, achieved doses ranged from 330 to 7400 mg/kg bw/day in males and 390 to 6900 mg/kg/day in females. Although food intake was essentially unaffected, growth performance was impaired in all treated male groups, particularly at 50 000 ppm (65% reduction). Female mice at the highest level showed a 36% reduction in weight gain. Other effects in mice were limited to the 50 000 ppm group, where reduced liver weight was noted in males and changes suggestive of microcytic anaemia (i.e., reduced haematocrit, haemoglobin and mean erythrocytic volume) were noted for both sexes. At this level 3/10 males also showed epithelial hyperplasia and hyperkeratosis of the forestomach.

 

In addition to assessing the carcinogenicity of manganese sulphate, a 2-year study by the NTP provided detailed information on a range of non-neurological endpoints following long-term dietary exposure (NTP, 1993). In the study, F344/N rats and B6C3F1 mice were fed diets containing manganese sulphate at 1500, 5000 or 15 000 ppm for 2 years. Achieved dosages were, for rats, 60, 200 or 615 mg/kg bw/day in males and 70, 230 or 715 mg/kg/day in females and, for mice, 160, 540 or 1800 mg/kg/day in males and 200, 700 or 2250 mg/kg/day in females. Endpoints considered included survival, general signs of toxicity, growth performance, clinical pathology, metal content of some tissues, and pathology. In rats, reduced survival, associated with increased severity of nephropathy and renal failure, was noted in males given 15 000 ppm from week 93. Males of this group also showed a slightly (5%) lower body weight until week 80, after which the difference between treated and control animals increased to approximately 10%. Other treated rats were not thus affected, and the food intakes of all groups were similar. Hepatic iron levels were reduced at 9 and 15 months for rats given 5000 ppm or above, while renal copper levels were increased in males at 9 months and females at 9- and 15-months. Secondary to the increased nephropathy in high dose males, increased incidences of mineralisation of blood vessels and glandular stomach, parathyroid hyperplasia, and fibrous osteodystrophy were noted. A somewhat different picture was seen in the mice. Overall, despite similar food intakes, body weights were reduced by 6, 9 and 13% in female mice given 1500, 5000 or 15 000 ppm, respectively; males were not thus affected. Haematology and clinical chemistry were unaffected, although hepatic iron levels were lower at 9 and 15 months in females and at 15 months in males given 5000 or 15 000 ppm. Non-neoplastic effects of treatment were restricted to increased incidences of thyroid follicular dilatation and hyperplasia, in mice given 15 000 ppm, and of focal epithelial hyperplasia, in males given 15 000 ppm and all groups of treated females. The NOAEL for repeated dose toxicity was determined to be 5000 ppm MnSO4, corresponding to 200 mg/kg bw/day MnSO4 and 72.8 mg/kg bw/day Mn.

 

Manganese, inhalation data (information taken from SCOEL, 2011)

Because of the heterogeneity of the data (different types of industry, different manganese compounds and particle sizes, different study designs and different neurofunctional measurements), and the inherent limitations of every individual study, it is not possible to identify one single critical study that would be the best basis for setting the IOELVs. Some studies identified a LOAEL, other a NOAEL. Some studies relied on the respirable fraction; other on the inhalable or “total” (thoracic) fraction. A global approach using the most methodologically-sound studies, as used in the IEH Criteria document (2004) and a number of additional good quality studies published since this review was therefore considered to be the most robust and reliable approach. The studies by Roels et al. (1992), Gibbs et al. (1999), Myers et al. (2003b), Young et al. (2005), Bast-Pettersen et al. (2004) and Ellingsen et al. (2008) as well as Lucchini et al. (1999) in HC (2008) which showed adverse neurological effects and identified a point-of-departure (POD) in the dose-effect/response relationship may offer a basis for recommending an IOELV.

Thus, a reasonable respirable IOELV of 0.05 mg/m³ can be recommended, and a reasonable inhalable IOELV of 0.2 mg/m³ is also recommended. While recommending these values, SCOEL recognises that the overall systemic absorption of coarser particles (> respirable) is probably substantially lower than for the respirable fraction. Thus, SCOEL recommends both a respirable and an inhalable IOELV which would need to be observed conjointly.

 

2-Ethylhexanoic acid

In a 90-day repeated dose toxicity study in rats and mice with 2-ethylhexanoic acid, adiet containing 0.5% 2-ethylhexanoic acid caused no adverse effect in rats in a 13 week feeding study (dose levels were 0, 0.1, 0.5, or 1.5%, calculated NOAEL ca. 300 mg/kg bw/day). No adverse effect was observed in mice receiving a diet containing 0.5 % 2-ethylhexanoic acid in a 13 week feeding study (dose levels were 0, 0.1, 0.5, or 1.5%). The NOAEL was calculated to be 200 mg/kg bw/day. Both NOAELs were based on reduced food consumption and a decreased rate of body weight gain in the high dose groups. For further information on the toxicity of 2-ethylhexanoic acid, please refer to the relevant sections in the IUCLID and CSR.

 

2-ethylhexanoic acid, manganese salt

Since no repeated dose toxicity study is available specifically for2-ethylhexanoic acid, manganese salt, information on the individual constituents manganese and 2-ethylhexanoic acid will be used for the hazard assessment and when applicable for the risk characterisation of 2-ethylhexanoic acid, manganese salt.

 

Considering the read-across principles as detailed above for 2-ethylhexanoic acid, manganese salt based on the toxicological assessment of the individual constituents, it is therefore proposed to also read-across the classification of Specific target organ toxicity-repeated exposure, category 2 based on neurological effects (H373) of manganese sulfate to 2-ethylhexanoic acid, manganese salt.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Information from read-across substances:
animal data for manganese: NOAEL(rat)=72.8 mg Mn/kg bw/day
animal data for 2-ethylhexanoic acid: NOAEL(mouse)=200 mg/kg bw/day

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
Read-across information.

Justification for classification or non-classification

Considering the read-across principles as detailed above for 2-ethylhexanoic acid, manganese salt based on the toxicological assessment of the individual constituents, it is therefore proposed to also read-across the classification of Specific target organ toxicity-repeated exposure, category 2 based on neurological effects (H373) of manganese sulfate to 2-ethylhexanoic acid, manganese salt.