Butyl (S)-2-hydroxypropionate

Neurotoxicity

Description of key information

Butyl-S-lactate is not considered to be neurotoxic, based on evaluation of neurotoxicity studies on the primary hydrolysis product n-butanol and one sub-chronic neurotoxicity study with n-butyl acetate which rapidly hydrolyzes to n-butanol.

Key value for chemical safety assessment

Effect on neurotoxicity: via oral route

Link to relevant study records

Reference

Endpoint:

neurotoxicity

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Justification for type of information:

For details and justification of read-across please refer to the report attached in section 13 of IUCLID.

Reason / purpose for cross-reference:

read-across source

Remarks on result:

other: no adverse neurotox effects were observed based on a weight-of-evidence assessment of available data

Neurotoxicity of n-butanol

Human data:

No data related to chronic toxic encephalopathy were found. From studies among workers exposed to butanol isomers, it can be concluded that irritation of the eyes seems to be the critical effect. Other effects reported were headache, vertigo and Meniere or Meniere-loke vertigo. However, causal relationships with exposure to n-butanol per se or relationships with exposure levels could not be established (Health Council, 1994b).

Animal data, single exposure:

In a pilot experiment preceding a teratology study, exposure to 24000 mg/m³ (8000 ppm) caused narcosis in 3/6 rats, while no such effect was seen at 18000 mg/m³ (6000 ppm) or less. In mice, no effects occurred at expsoure to levels up to 10000 mg/m³ (3300 ppm) for 7 hours, while CNS effects (giddiness, prostartion, narcosis) were observed at 20000 mg/m³ (6600 ppm) (Health Council, 1994b).

Neurobehavioural toxicity following acute inhalation exposure was tested in mice using the so-called "behavioural despair" swimming test. This assay is absed on the finding that rodents that are forced to swim in a restricted space exhibit vigorous escape-directed activity during the first minutes, than a transient period of swimming activity and immobility and after 3 minutes a state of complete immobility. A dose-related decrease in the duration of immobility, measured over a 3 -minutes period, was observed for the 4 -hour exposure range tested. The ID₅₀, the concentration responsible for 50 % decrease in immobility (compared to controls) was calculated to be 617 ppm or 1850 mg/m³ (De Ceaurriz et al., 1983). Single oral administration of doses of 1000 or 2000 mg/kg bw to mice caused a dose-dependent transient impairment of rotarod performance. No such effects were seen with a dose of 500 mg/kg bw (Maickel and Nash, 1985). A single dose of 1200 mg/kg bw impaired the performance of rats on an inclined plane test, 1-butanol being 6.3 times as potent as ethanol on an equimolar basis (Wallgren, 1960). The ED₅₀for narcosis in rabbits was 815 mg/kg bw (Munch, 1972).

Following i.p. injection, the threshold dose for inducing ataxia in rats was 400 mg/kg bw (McCreery and Hunt, 1978); the ED₅₀for righting refelx in mice was 1053 mg/kg bw (Lyon et al., 1981). In addition to these data, the results of a study investigating the effects on the nervous system following acute exposure to 1-butyl acetate vapours are available. Since this acetate ester is readily hydrolysed into n-butanol, these results are considered to be useful for the evaluation.

Four groups of 20 rats (10/sex) were exposed to 0, 7200, 14400 and 28800 mg/m³ for 6 hours. Deaths and clinical signs were not noted. During exposure, reduced activity and reduced response to stimuli (tapping on the chamber) were observed in all dose groups ranging from minimal in the low dose group to minor to moderate in the high dose group. These observations were subjective and incomplete, since they include only those animals that were visible through the inhalation chamber windows. Motor activity measured in 10-minute intervals during a 60-minute period was transiently reduced in the mid- and high-dose group. The functional observational battery examinations showed no eefect on motor activity in the open field. Effects were observed directly after exposure only and included slightly unkempt hair coat in the high dose group and increased forelimb grip strength for the females of the mid dose group (Bernard and David, 1994).

Repeated exposure:

No relevant data on the potential nervous sytem effects of 1-butanol following repeated exposure were found (see also Health Council, 1994b). However, a 13-week neurotoxicity study was performed with 1-butyl acetate and the results are considered to be relevant for the evaluation of the neurotoxicity of 1-butanol.

Male and female Sprague Dawley rats (n = 30–40/group) were exposed to 0, 2640, 7200 and 14400 mg/m³, 6 hours/day, 5 days/week for 13 to 14 weeks. Endpoints were functional observational battery (FOB) and motor activity (during week 1–13 in 10–15 animals/sex(group), neuropathology (gross and microscopic examination of sections from the brain, spinal cord, dirasl and ventral spinal roots, dorsal root ganglia, sciatic nerve and tibial nerve at study termination in 5 animals/sex/group) and scheduled-controlled operant behaviour (SCOB). Body weights were recorded regularly. Clinical observations were made through the inhalation chamber windows during exposure and further before and after exposure and during performing FOB. In the ad libitum-fed animals of the 7200 and 14400 mg/m³ groups, treatment caused reduced activity of of minor to minimal severity were recorded. No treatment-related effects indicative of neurotoxicity were seen in the FOB, motor activity, SCOB and gross and microscopic examinantions in any of the exposure groups (Bernard et al., 1996; David et al., 1998).

Conclusions:

Based on the data presented in the review report, no data were found where effects on the nervous system were related to exposure to n-butanol per se.

Executive summary:

In conclusion, based on the data presented in the review report, no data were found where effects on the nervous system were related to exposure to n-butanol per se.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Effect on neurotoxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

neurotoxicity: sub-chronic inhalation

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Justification for type of information:

For justification of read-across please refer to the read-across report attached to IUCLID section 13.

Reason / purpose for cross-reference:

read-across source

Clinical signs:

not specified

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

For further details, see section below "details on results"

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Neuropathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Details on results:

No mortality occurred during the study.
Neurotoxicity was evaluated in ad libitum-fed animals using FOB and quantitative measurement of MA during weeks 1, 4, 8 and 13 and NP at termination. SCOB testing was conducted daily in food-restricted male rats. Prior to n-butyl acetate exposure, rats were trained to obtain food rewards by pressing a lever 20 times and after a 120 seconds interval. The animals were then tested on a schedule of 4 x FR20 and 2x FI120 in 47 min sessions (1x/d, 5d/wk) during weeks 1 -13 of exposure and weeks 14 and 15 following cessation of exposure. Animals exposed to 1500 ppm and higher had minor reduction in activity levels. There was no evidence of a cumulative effect on the severity of the reduced activity. Control and 500 ppm animals appeared normal during exposure. There were no other apparent differences in the clinical condition of FOB/MA/NP and SCOB animals. Mean body weights and body weight gains of the 3000 ppm male and female ad libitum-fed rats were significantly lower than in controls. At 1500 ppm, there was still some decreased body weight gain among ad libitum-fed females. Mean body weight gains for the 500 ppm ad libitum-fed animals were comparable to controls throughout the study. No differences in body weight were noted among the male SCOB rats. There was no evidence of neurotoxicity during FOB examinations. Mean total MA at 3000 ppm was significantly higher in males than controls during week 4. Mean total MA counts for all male groups were closer to baseline values during weeks 8 and 13 and no significant differences were observed among groups. No time-treatment interactions were observed in total ambulation’s for male groups, and no significant MA differences were present in female rats. No significant differences were seen in SCOB at any air concentration. No treatment related changes were detected during gross necropsy examinations of male and female FOB/MA/NP rats exposed to the test substance. Microscopic evaluations of sections from the brain, spinal cord, dorsal and ventral spinal roots, dorsal root ganglia, sciatic nerve and tibial nerved of animals in the control and 3000 ppm groups did not reveal any treatment-related effects.

Key result

Dose descriptor:

NOAEL

Effect level:

14 500 mg/m³ air (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

behaviour (functional findings)

neuropathology

Remarks on result:

other: no adverse neurotoxic effects observed

Critical effects observed:

no

Conclusions:

The neurotoxic potential of n-butyl acetate was investigated in Sprague-Dawley rats using a functional observational battery, motor activity, neurohistopathology, and schedule-controlled operant behaviour (SCOB) as indicators of neurotoxicity. Animals were exposed to concentrations of 0, 500, 1500, or 3000 ppm (equivalent to 0, 2400, 7200 and 14500 mg/m³) of n-butyl acetate for 6 hours per day for 65 exposures over 14 weeks. Based on the results, the NOAEL for subchronic neurotoxicity to n-butyl acetate can be considered to be 3000 ppm (14500 mg/m³).

Executive summary:

The neurotoxic potential of n-butyl acetate was investigated in Sprague-Dawley rats using a functional observational battery, motor activity, neurohistopathology, and schedule-controlled operant behaviour (SCOB) as indicators of neurotoxicity. Animals were exposed to concentrations of 0, 500, 1500, or 3000 ppm (equivalent to 0, 2400, 7200 and 14500 mg/m³) of n-butyl acetate for 6 hours per day for 65 exposures over 14 weeks. Functional observational battery and motor activity values for ad libitum-fed male and female rats were measured during Weeks -1, 4, 8, and 13. SCOB testing of food-restricted animals, using a multiple fixed ratio/fixed interval schedule, was conducted daily prior to each exposure to maintain the operant behaviour; the data from Weeks -1, 4, 8, and 13 were evaluated for evidence of neurotoxicity. 

Transient signs of sedation and hypoactivity were observed only during exposure to the 1500 and 3000 ppm concentrations. The only signs of systemic toxicity were reduced body weights for the 3000 ppm ad libitum-fed groups and occasionally for the female 1500 ppm ad libitum-fed group. No evidence of neurotoxicity was seen during the functional observational battery examinations. Motor activity for the 3000 ppm male group was significantly (p < or = 0.05) higher than for the control group only during Week 4. No significant differences were observed among groups for Weeks 8 and 13. No significant differences in motor activity values were observed for female rats. No significant differences were seen in operant behaviour at any test vapor concentration. Microscopic evaluations of sections from the brain, spinal cord (cervical and lumbar regions), dorsal and ventral spinal roots, dorsal root ganglia, sciatic nerve, and tibial nerve of animals in the control and 3000 ppm groups did not indicate any treatment-related effects. In conclusion, there was no evidence of cumulative neurotoxicity based on the functional observational battery, motor activity, neurohistopathology, and schedule-controlled operant behaviour endpoints. Thus, the NOAEL for subchronic neurotoxicity to n-butyl acetate can be considered to be 3000 ppm (14500 mg/m³). The data presented here are relevant to the neurotoxicity risk assessment of n-butanol due to the rapid hydrolysis of n-butyl acetate in vivo.

This information is used in a read-across approach in the assessment of the target substance. For justification of read-across please refer to the read-across report attached to IUCLID section 13.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Effect on neurotoxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

No evidence for a potential to induce neurotoxicity was seen in a sub-acute repeated dose toxicity study in rats exposed to Butyl-S-lactate (target substance) via inhalation. No adverse clinical signs of toxicity were observed.

Due to the rapid, enzymatically catalysed, hydrolysis of Butyl-S-lactate into n-butanol and L-lactic acid, the toxicology of Butyl-S-lactate can be understood in terms of the toxicology of n-butanol and L-lactic acid. Lactic acid is an ubiquitous and integral element of mammalian metabolism and therefore of minor toxicological relevance compared to n-butanol which is, as an alcohol, more important for the toxicological assessment. Thus, available data from n-butanol and n-butyl acetate (source substances) were used in a read-across approach to assess the neurotoxic potential of Butyl-S-lactate.

In a well-designed behavioural teratology study, no behavioural effects were found in the offspring of parental and maternal animals treated with n-butanol during gestation or before mating. The offspring of both cohorts were observed during postnatal days 10–90 for signs of developmental neurotoxic effects by measuring ascent on a wire mesh screen, rotarod and running wheel performance, open-field and photoelectrically-monitored activity, avoidance conditioning and operand conditioning. In a pre-natal developmental toxicity study (see IUCLID section 7.8.2; Nelson, 1982), in one half of maternal animals treated during gestation narcosis was observed at 8000 ppm. No effects were detected in rats exposed to 6000 and 3500 ppm.

In the review paper prepared by TNO, 1999 available data on butyl acetate are presented (David, 1998). Since butyl acetate is – like butyl-S-lactate – readily hydrolysed into n-butanol, the results of these studies are useful for the evaluation of the potential neurotoxicity of n-butyl-S-lactate. In a 13 -week inhalation study, male and female Sprague Dawley rats (n = 30–40/group) were exposed to 0, 2640, 7200 and 14400 mg/m³, 6 hours/day, 5 days/week for 13 to 14 weeks. Endpoints were functional observational battery (FOB) and motor activity (during week 1–13 in 10–15 animals/sex(group), neuropathology (gross and microscopic examination of sections from the brain, spinal cord and ventral spinal roots, dorsal root ganglia, sciatic nerve and tibial nerve at study termination in 5 animals/sex/group) and scheduled-controlled operant behaviour (SCOB). No effects were seen in the functional observational battery, motor activity, scheduled-controlled operant behaviour, gross and histopathological examinations of the brain at concentrations up to 14500 mg/m³, the highest level tested. However, during exposure, transient reduced activity of minor to minimal severity was observed in the animals exposed to 7200 and 14500 mg/m³. Based on the available data, no classification of the target substance for neurotoxicity is warranted.

This conclusion is supported by the conclusion of the ECETOC review (2003) on n-butanol, in which it is stated that "n-butanol does not show selective or cumulative neurotoxicity in experimental animals”.

Justification for classification or non-classification

Based on the available data, Butyl-S-lactate does not warrant classification for neurotoxicity.