| Front page | | Contents | | Previous | | Next |

Appendices 1-18 to: Report on the Health Effects of Selected Pesticide Coformulants

101     Summary

101.1     Description

DEGBE is a colourless liquid with a low vapour pressure (0.02 mmHg (2.7 Pa, at 20 °C); it is miscible with water.

101.2     Toxicokinetics

When the acetate (¹⁴C-DEGBEA) of DEGBE was given as a single oral dose (200 or 2000 mg/kg b.w.) to male Sprague-Dawley rats, about 85% of the total ¹⁴C-dose was excreted in the urine, about 2 to 3% in the faeces, and about 5% as carbon dioxide in expired air by 72 hours. The major urinary metabolite was 2-(2-butoxyethoxy)acetic acid, accounting for 53-59% of the total urinary radioactivity. No unchanged DEGBEA or DEGBE was detected and no evidence was found for excretion of 2-butoxyacetic acid.

Following dermal contact to rats (0.2 or 2.0 g/kg of undiluted ¹⁴C-DEGBE or ¹⁴C-DEGBEA, or 0.2 g/kg of a 10% aqueous solution of ¹⁴C-DEGBE) for 24 hours, the excretion in urine at the low dose level was about 40-51% in females and about 27-48% in males. At the high dose, females excreted about 12-18% DEGBE and males about 3-13% DEGBEA. The excretion in faeces was only a few percent (about 0.2-3%). The main urinary metabolite was 2-(2-butoxyethoxy)acetic acid. Trace levels of 2-butoxyacetic acid were present in all 8-hour and 24-hour urine samples following application of DEGBE, but not DEGBEA.

No data regarding the absorption and elimination of DEGBE following inhalation or oral intake, or the distribution of DEGBE have been found.

101.3     Human toxicity

A few case reports of irritation and sensitisation to DEGBE have been reported.

No data on acute and repeated dose toxicity, toxicity to reproduction, mutagenic and genotoxic effects, or carcinogenic effects in humans have been found.

101.4     Animal toxicity

101.4.1     Single dose toxicity

Oral LD₅₀-values for DEGBE ranging from 5080 to 9600 mg/kg b.w. in rats, from 2400 to 6560 mg/kg b.w. in mice, of 2200 mg/kg b.w. in rabbits, and of 2000 mg/kg b.w. in guinea pigs have been reported.

Dermal LD₅₀-values greater than 2000 mg/kg b.w. for rats, and from 2700 to 4120 mg/kg b.w. for rabbits have been reported.

No rats died when exposed for 7 hours to the maximum attainable vapour concentration (estimated to be 122 mg/m³). Also rabbits, cats, guinea pigs, rats, and mice survived an exposure period of 2 hours in a saturated atmosphere. An LC₅₀-value of about 73000 mg/m³ has been reported for rats following exposure for 4 hours to the acetate (DEGBEA) of DEGBE.

In a skin irritation study in rabbits (EU Annex B4), DEGBE was considered to have a non-irritating potential. Other reports have considered DEGBE to have only a very slightly irritating (rabbits) or slightly irritating (rabbits, guinea pigs) potential.

In a primary eye irritation test in rabbits, a concentration of 5% DEGBE did not produce any primary irritant effects. The lowest concentration producing keratitis was 25%, and that causing minor transient conjunctivitis was 10%. Reversible increases in the intraocular tension were observed with concentrations from 1%. Effects were most severe within the first 24 hours and the eye returned to normal within 14 days. Other reports have considered DEGBE to be capable of causing moderate irritating and moderate transient corneal injury to the eyes of rabbits.

DEGBE was not sensitising in the guinea pig maximisation test (EU Annex B6).

101.4.2     Repeated dose toxicity

Wistar rats exposed to DEGBE (0, 100, 350, or 1000 mg/m³, 6 hours/day, 5 days/week for 2 weeks) showed a dose-related decrease in spleen weight (all male exposure groups), increased (but not dose-related) lung weights at the two highest concentrations, and decreased body weight (not significant) at the highest concentration; histopathology revealed perivascular and peribronchial accumulations of granulocytes and activation of alveolar epithelium at all exposure levels. Similarly, another 2-week inhalation study (OECD Guideline 412) in female Wistar rats exposed (head-nose only) to DEGBE (0 or 350 mg/m³, 6 hours/day, 5 days/week) showed decreased body weight gain and slight to moderate multifocal perivascular and peribronchial accumulation of granulocytes and minimal focal bronchiolisation in the lungs in exposed animals. In a 5-week inhalation study in Fisher 344 rats exposed (whole-body) to DEGBE (vapour, 0, 13, 40, 122 mg/m³, 6 hours/day, 5 days/week), only effects on the liver were observed (dose-related decreased relative liver weight in males from 40 mg/m³, dose-related increase in relative liver weight in females from 40 mg/m³ (significant only at 122 mg/m³), and slight paleness of the liver (at 122 mg/m³) and slight hepatocyte vacuolisation at all dose levels). When Wistar rats were exposed (whole-body) to DEGBE (vapour, 0, 13, 40, or 95 mg/m³, 6 hours/day, 5 days/week for 13 weeks, OECD Guideline 413), the only observed effect was a dose-related decreased level of serum aspartate aminotransferase in males of all exposure groups.

In a 6-week oral gavage study in male rats, haematological effects (dose related decrease in haemoglobin, total red cells, MCV, MCH, and MCHC) were observed at dose levels from 1782 mg/kg b.w./day; increased spleen weights (absolute and relative), decreased liver weight, and proteinaceous casts were observed as well. Hyperkeratosis in the stomach was observed in all dosed rats (891 mg/kg b.w./day). A 13-week oral gavage study (0, 65/51, 327/254, or 1630/1270 mg/kg b.w./day in males and females, respectively) in rats revealed haematological effects (females: dose-related decrease in MCHC, and white blood cell and lymphocyte counts at the two lowest dose levels; males: increase in total red cells and haemoglobin content at the mid-dose level); increased liver weights (absolute and relative) in mid- (only males) and high-dose groups) and kidney weight (relative) in high-dose males; decreased spleen weight (relative) in mid-dose males; and decreased food consumption and body weight gain (males) at the highest dose level. Furthermore, a high mortality (88%) was observed at the highest dose level.

The only suggestion of a systemic effect of DEGBE in a 13-week dermal study in rat was a slightly increased incidence of occult blood in the urine of females at dose levels from 600 mg/kg b.w./day; microscopic examination of the urine revealed no urinary casts and no significant numbers of erythrocytes. DEGBE produced skin irritation, which was concentration (2 ml/kg b.w./day of 0, 10, 30 or 100% of DEGBE in water, 6 hours a day, 5 days per week) dependent in incidence, severity, and time of onset and was more severe in females than in males. In another 13-week dermal study in rats, 5/12 females at the highest concentration level (2 ml/kg b.w./day of 100% of DEGBE in water, 6 hours a day, 5 days per week) had scab formation at the treatment site during the study; no other treatment-related clinical findings were noted. FOB and motor activity tests revealed no findings indicative of a neurotoxic effect, and there were no gross or neuropathological treatment-related changes. In a 4-week dermal study in rabbits, haematological changes (decreased eosinophil and monocyte count in males; decreased haemoglobin, erythrocyte, leukocyte and neutrophil count in females) were observed following application of 2 ml/kg b.w./day of 1.5% of DEGBE in water (7 hours a day, 5 days per week); no treatment-related effects on the skin were noted.

101.4.3     Toxicity to reproduction

In a one-generation oral gavage study in rats, the only significant effect observed was a decrease in the weight of the pups at day 14 of lactation in offspring from females administered 1000 mg/kg b.w./day and mated with untreated males; a NOAEL of 1000 mg/kg b.w./day can be considered for reproductive and developmental effects and of 500 mg/kg b.w./day for post-natal effects. Similarly, no reproductive or developmental effects were observed in a one-generation dermal study in rats at a dose level of 2000 mg/kg b.w./day (the only dose level in the study); in contrast to the oral study, no effects were noted in the offspring during the lactation period. A NOAEL of 2000 mg/kg b.w./day can be considered for reproductive, developmental and post-natal effects.

In an oral developmental toxicity study in rats, no developmental effects, including teratogenicity, were observed at dietary dose levels of up to 1% (equal to 633 mg/kg b.w./day, day 0 to 20 of gestation) and in the postnatal period (10 weeks after birth), a high survival rate and good growth of the offspring were noted. Maternal effects (reduced body weight gain) were observed in all exposure groups (equal to 25, 115, or 633 mg/kg b.w./day) during the gestation period. A NOAEL of 633 mg/kg b.w./day can be considered for developmental effects, including teratogenicity, and a LOAEL for maternal effects of 25 mg/kg b.w./day. In mice, no indications for developmental effects were observed at oral (gavage) dose levels of 500 or 2050 mg/kg b.w./day (day 7 to 14 of gestation); 25% of the dams died at the high dose level with no mortality and no effects of body weights being observed at the low dose level. In a dermal teratogenicity study (OECD-guideline 414) in rabbits, a NOAEL of 1000 mg/kg b.w./day (highest dose level in the study) was observed for developmental toxicity, including teratogenicity. All of the dosed (100, 300 or 1000 mg/kg b.w., days 7 to 18 of gestation) dams gained less weight than the controls during gestation (significant only for the mid-dose group) and at the two higher dose levels, skin irritation was observed after about 1 week of treatment and persisted until the dams were sacrificed; a NOAEL of 100 mg/kg b.w./day can be considered for maternal effects.

101.4.4     Mutagenic and genotoxic effects

DEGBE has shown negative results in the following in vitro test systems: in the Ames test (one test in Salmonella typhimurium strains TA98, TA100, TA1535, TA1537, and TA1538), for gene mutation in the HGPRT assay in Chinese Hamster Ovary (CHO) cells, for chromosome aberrations in CHO cells, and for unscheduled DNA synthesis (UDS) in rat hepatocytes. The tests were performed with and without metabolic activation (UDS: only without) and with concentrations up to cytotoxicity. A weak, dose-dependent increase in mutations was seen in the mouse lymphoma test (L5178Y) without, but not with, metabolic activation; there was no increase at non-toxic dose-levels.

Negative results have also been reported in in vivo studies: in the mouse bone marrow micronucleus test (OECD-guideline 474) following oral gavage (0, 330, 1100, or 3300 mg/kg b.w.) and for lethal mutations in the Drosophila sex-linked recessive lethal assay following administration in the feed (11000 ppm, for 3 days) or by a single injection (14000 ppm).

101.4.5     Carcinogenic effects

No data have been found.

| Front page | | Contents | | Previous | | Next | | Top |