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EC number: 218-218-1 | CAS number: 2082-81-7
Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test (oral, gavage, Sprague dawley rats, OECD 422, GLP) including neurotoxicity assessment with 1,4 -Butanediol dimethacrylate did not show any neurotoxic effects up to 1000 mg/kg b: NOAEL(neurotoxicity) = 1000 mg/kg bw/d
No indication of neurotoxicity was found in a Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test according to OECD Guideline 422 (22 March 1996) which included a Functional Observation Battery, examination of grip strength and sensory reactivity to stimuli as well as motor activity assessment. The neurotoxicity seen with 1,4-butanediol and its metabolite γ-hydroxybutyic acid (NTP, 1996) has not been observed with 1,4-BDDMA up to the highest dose tested (1000 mg/kg/d ester is equivalent to approx. 390 mg/kg/d γ-hydroxybutyic acid). This might be explained by differences in toxicokinetics between the two studies.
1,4-BDDMA (90% a.i.) was administered to 10 Hsd: Sprague Dawley rats/sex/dose orally by gavage at dose levels of 0 (control), 100, 300 and 1000 mg/kg bw/d. The treatment schedule included 2 weeks before pairing, during pairing, post coitum and post partum periods up to day 3 post partum. Animals were administered for approximately 5 and 8 weeks for males and females, respectively.
Observation of animals at removal from the cage and in an open arena (neurotoxicity assessment) did not reveal changes attributable to the test item. No relevant differences were noted in motor activity and sensory reaction to stimuli between control and treated groups.
On the basis of the results obtained in the study, the NOAEL for neurotoxicity was 1000 mg/kg bw/d (males/females).
No human data are available for neurotoxicity. However, there is no reason to believe that these results from rat would not be applicable to humans.
NTP Summary Report on the Metabolism, Disposition, and Toxicity of 1,4-Butanediol, (CAS No. 110-63-4). Toxicity Report Series No. 54, NIH Publication 96-3932S
Justification for selection of effect on neurotoxicity via oral route endpoint: OECD guideline 422 study including neurotoxicity assessment, no deviations, GLP
Early investigations of 1,4-butanediol (Sprince et al., 1966) indicated a pronounced pharmacologic effect on the central nervous system (CNS). Administration of 496 mg/kg 1,4-butanediol to male Sprague-Dawley or Holtzman rats caused CNS depression and induced a state resembling sleep or anesthesia characterized by loss of righting reflex, struggle response, and voluntary motor activity, but retention of the ability to respond to pain and tactile stimuli (Sprince et al., 1966). Very similar neuropharmacologic responses were observed after administration of -hydroxybutyric acid, except that sleep induction time and sleeping time were longer after administration of 1,4-butanediol than after administration of γ-hydroxybutyric acid (Sprince et al., 1966). After administration of γ-butyrolactone, the γ-lactone of γ-hydroxybutyric acid, sleep induction was similar to that observed with γ-hydroxybutyric acid but sleeping time was more similar to that observed with 1,4-butanediol. Since previous work (Giarman and Roth, 1964; Roth and Giarman, 1966; Roth et al., 1966) had indicated that the CNS depressant effects of γ-butyrolactone were due to its metabolism to γ hydroxybutyric acid, it was suggested that the CNS depressant activity of 1,4-butanediol was the result of biotransformation to γ-hydroxybutyric acid (Sprince et al., 1966; Menon et al., 1973; Snead et al., 1982).
γ -Hydroxybutyric acid is a naturally occurring chemical found in the brain and peripheral tissue (Roth, 1970; Roth and Giarman, 1970). In the brain, acid is present in micromolar concentrations. In peripheral tissues (liver, heart, kidney), acid concentrations are 5 to 10 times higher than in the brain; however, neither the source (precursors) nor physiological function of acid in the peripheral tissues is known with certainty (Mamelak, 1989; Cash, 1994). acid readily crosses the blood-brain barrier, and oral, intraperitoneal, or intravenous administration elicits characteristic neuropharmacologic responses. Current evidence suggests it may function as a neuromodulator (Mandel et al., 1987; Vayer et al., 1987). γ-hydroxybutyric acid is synthesized and released in specific neuronal pathways (Rumigny et al., 1981; Maitre et al., 1983) and its actions are mediated by a set of specific, high affinity receptors which are heterogeneously distributed within the cerebral cortex and hippocampus (Hechler et al., 1992).
Administration of exogenous acid induces a state described as behavioral arrest characterized by specific dose-dependent changes in the electroencephalogram which have been well characterized in the rat, cat, and monkey (Snead, 1992). Administration of low doses (12.5 mg/kg) of acid to male Wistar rats had no effect on behavior or on the electroencephalogram (Godschalk et al., 1977). At doses of 150 mg/kg or greater, acid induces a state characterized by behavioral arrest, facial myoclonus, vibrissal twitching, and loss of righting reflex
More direct evidence that γ -hydroxybutyric acid is responsible for the CNS action of 1,4-butanediol was obtained by Roth and Giarman (1968), who found that the length of sleeping time in rats administered 1,4-butanediol was proportional to the concentration of γ -hydroxybutyric acid in brain tissue. Within 15 minutes after intravenous administration of 520 mg 1,4-butanediol per kilogram body weight to Sprague-Dawley rats, blood and brain concentrations of γ -hydroxybutyric acid (determined using gas chromatography) were significantly increased, and these concentrations continued to increase to a maximum that occurred approximately 60 minutes (blood) or 90 minutes (brain) after administration. This increase in γ hydroxybutyric acid blood and brain concentrations was accompanied by sleep onset 30 minutes after administration, and sleep continued until the acid concentration returned to normal (approximately 150 minutes after administration).
Zabic et al. (1974) examined the dose response for behavioral effects of 1,4-butanediol in male Sprague-Dawley rats. Spontaneous motor activity was reduced at doses as low as 50 mg/kg with 100% cessation of motor activity at 300 mg/kg. Rotorod performance was unaffected at 100 mg/kg, but was significantly impaired at 200 mg/kg, while loss of righting reflex occurred at 300 mg/kg.
γ -Butyrolactone, in the form of an unhydrolyzed, cyclic ester, does not produce behavioral arrest or spike wave discharge in the electroencephalogram of male Sprague-Dawley rats (Snead, 1991, 1992). However, the pharmacologic activity of γ -butyrolactone is essentially identical to that of 1,4-butanediol and γ -hydroxybutyric acid (Giarman and Roth, 1964; Sprince et al., 1966; Snead, 1992) after metabolic conversion to γ -hydroxybutyric acid. γ -Butyrolactone is rapidly hydrolyzed by an enzyme found in the blood and liver to γ -hydroxybutyric acid. γ -Butyrolactone has a half-life (t 1/2) of less than 1 minute in this conversion (Roth and Giarman, 1965; Fishbein and Bessman, 1966).
Vree et al. (1978) determined the concentration of γ -hydroxybutyric acid in the blood of dogs, monkeys, and humans after intravenous administration of sodium γ -hydroxybutyric acid, γ -hydroxybutyric acid ethyl ester, or 1,4-butanediol. Conversion of 1,4-butanediol to γ -hydroxybutyric acid was rapid in all species, but was most rapid in humans. γ -Hydroxybutyric acid blood levels peaked and began to decay within 2 minutes of intravenous administration of 15 or 30 mg/kg 1,4-butanediol to humans. Equal doses of 1,4-butanediol or γ -hydroxybutyric acid yielded nearly superimposable decay curves in humans indicating essentially 100% conversion of 1,4-butanediol to γ -hydroxybutyric acid.
As 1,4-butanediol is rapidly absorbed and metabolized to γ-hydroxybutyric acid in animals and humans, neurotoxic effect of 1,4-butanediol such as depression of central nervous system is considered to be caused by the metabolite, γ-hydroxybutyric acid.
No indication of neurotoxicity was found in a Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test according to OECD Guideline 422 (22 March 1996) which included a Functional Observation Battery, examination of grip strength and sensory reactivity to stimuli as well as motor activity assessment.
The alcohol metabolite of 1,4-BDDMA, 1,4-Butanediol (1,4-BD), is known for its neurotoxic properties and labeled accordingly as an inducer of drowsiness (H phrase H336). The neurotoxicity of 1,4-BD is strongly related to the neuromodulating properties of the subsequent metabolite γ-Hydroxybutyric acid (GHB; complete metabolism of 1,4-BDDMA see Category document). GHB is structurally closely analogous to the naturally occurring neurotransmitter γ-aminobutyric acid (GABA). Both, GHB and GABA have the same subsequent metabolism (namely, being converted to succinate and processed through the tricarboxylic acid cycle). Typical neurotoxic effects of 1,4-BD and GHB were CNS depression and sleep/ anesthesia characterized by loss of righting reflex, struggle response, and voluntary motor activity, but retention of the ability to respond to pain and tactile stimuli (summarized by NTP 1996).
For substances with such a concentration-sensitive functionality like naturally occurring neurotransmitters it can be expected that even small variations in concentrations of closely analogous substances can have a strong impact on the effect strength – or even its absence, when below relevant physiological limits.
In the case of 1,4-BDDMA, no relevant signs of neurotoxicity have been observed up to the highest tested dose of 1000 mg/kg/d (corresponding to 4.4 mmol/kg/d). The only related observation was a slightly reduced grip strength at the second attempt was observed in high dose males, which was considered by the study authors as of no toxicological significance. However, in the light of the metabolic transformation of 1,4-BDDMA to the neuromodulator γ-Hydroxybutyric acid, this finding can be interpreted as indication for systemic uptake of 1,4-BDDMA and confirmation of the proposed metabolic pathway. For subsequent comparison reasons it should be outlined that no relevant, adverse clinical signs were observed in this study which could be related to neurotoxicity. Thus, the neurotoxicity related NOAEL in this study is≥4.4 mmol/kg/d for 1,4-BDDMA. Furthermore, this is the result of a fully reliable guideline study, although being a screening study by nature.
In contrast, for the alcohol metabolite 1,4-butanediol, CNS related clinical signs were seen not only in a comparable OECD 422 screening study with 1,4-butanediol in rats (without neurofunctional battery) at the lowest dose of 200 mg/kg/ bw in rats but also in an OECD 414 developmental toxicity study in mice at the medium dose 300 mg/kg/ bw. In the OECD SIDS 2000, these effects were considered as adverse although being transient, leading to a LOAEL = 2.2 mmol/kg/d in the OECD 422 screening study and a NOAEL of 1.1 mmol/kg/d in the OECD 414 study. Thus, neurotoxicity related clinical signs appear in the alcohol at significantly lower concentration when compared to the parent ester 1,4-BDDMA.
This can be explained by differences in toxicokinetics: In the mentioned alcohol studies, 1,4-BD was applied as a bolus application. In contrast, in studies with 1,4-BDDMA the kinetics of the primary metabolite is expected to be different due to the complex, multi-step metabolic pathway leading from 1,4-BDDMA to GHB. Comparable dose regime effects were observed in another alcohol of the category, ethylene glycol: in a large set of developmental studies presented in chapter184.108.40.206 of the category document, there is a clear pattern that bolus dosing causes much stronger developmental toxicity when compared to rather continuous dosing (drinking water).
Based on the available data 1,4 -BDDMA does not need to be classified for neurotoxicity according to Directive 67/548/EEC as well as CLP, EU GHS (Regulation 1272/2008/EC) and therefore labelling is not necessary.
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