Acetic acid, 2-[(5-chloro-8-quinolinyl)oxy]-, 1-methylhexyl ester

Endpoint summary

Description of key information

Short description of key information on bioaccumulation potential result: 
In rats there was no sex difference in excretion, tissue residues or metabolism.  The major metabolite was identified as CGA153433.  Neither dose level nor repeated dosing had any effect on excretion, tissue residues or metabolism.  Cloquintocet-mexyl is a safener for clodinafop-propargyl; pre-treatment with or co-administration of clodinafop-propargyl had no effect on the metabolism, excretion or tissue distribution of cloquintocet-mexyl.
There were low residues of cloquintocet-mexyl in the milk and tissues of lactating goats and the eggs and tissues of laying hens.  CGA153433 was the major metabolite identified in both goats and hens.
Short description of key information on absorption rate: 
The in-vitro dermal absorption of [14C]-cloquitocet-mexyl was determined using rat and human epidermis.  Absorption was inversely proportional to dose.  Absorption was higher through rat epidermis than when human epidermis was used.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Rat

Male and female rats were given single oral doses of 50 mg/kg [¹⁴C]-cloquintocet-mexyl (Mathies, 1989). Urine and faeces samples were collected for up to 3 days after dosing; liver, kidney and residual carcass were retained at necropsy on day 3. There was no sex difference in either excretion or tissue residues. Approximately 95% of the dose was excreted in 24 hours after dosing; 60% was in faeces with 35-39% in urine. Residues in liver, kidney and carcass 3 days after dosing accounted for <0.3% of the dose. Metabolite profiles were determined in urine and faecal extracts; in both sexes, there was major metabolite accounting for approximately 95% of the radioactivity and two minor fractions. The major metabolite was identified as CGA153433 (see attached metabolic pathway).

Five groups of male and female rats were given oral doses of [¹⁴C]-cloquintocet-mexyl, doses were either a single dose of 0.5 or 100 mg/kg [¹⁴C]-cloquintocet-mexyl or 14 daily doses of 0.5 mg/kg unlabelled cloquintocet-mexyl followed by a single dose of 0.5 mg/kg [¹⁴C]-cloquintocet-mexyl (Stewart, 1990). In addition two groups of bile duct cannulated rats received a single dose of either 0.5 or 100 mg/kg [¹⁴C]-cloquintocet-mexyl. Samples or urine, faeces, expired air/volatiles, bile, blood, tissues and residual carcasses were retained. Radioactivity in urine and bile samples indicated that at least 40% of the dose was absorbed. Approximately 30% of the dose was excreted in urine with the remainder in faeces; no radioactivity was detected in expired air/volatiles. Biliary secretion accounted for approximately 15% of the dose. The rate and route of excretion were unaffected by sex, dose level or repeated dosing.

Metabolite profiles were determined in urine, faeces and bile samples from the above study (Mathies, 1990). There was no sex difference in the metabolite profiles; pre-treatment, dose level and biliary cannulation also had no effect on the observed metabolite profile. All samples contained one major metabolite accounting for between 82.7 and 94.6% of the radioactivity in the individual samples. Minor unidentified metabolites were present in urine and bile accounting for between 0.1 and 0.7% of the dose. The identity of the major metabolite was confirmed as CGA153433 using mass spectroscopy and NMR (Kriemler & Winkler, 1987).

When used as a safener, cloquitocet-mexyl is formulated with clodinafop-propargyl; the effect of co-administration on metabolite profiles was investigated in male and female rats (Mathies, 1997). Two groups of rats were given 14 daily doses containing 40 mg/kg clodinafop-propargyl and 10 mg/kg cloquintocet-mexyl followed by a single dose of either [¹⁴C]-clodinafop-propargyl (50 mg/kg) or [¹⁴C]-cloquintocet-mexyl (100 mg/kg). The metabolite profiles were compared with those from an additional two groups given single doses of either 0.5 mg/kg each of [¹⁴C]-clodinafop-propargyl and cloquintocet-mexyl or 0.5 mg/kg each of [¹⁴C]-cloquintocet-mexyl and clodinafop-propargyl. 

Pre-treatment or co-administration with clodinafop-propargyl had no effect on the metabolism, excretion or tissue distribution of [¹⁴C]-cloquintocet-mexyl in either sex.

Pre-treatment increased the renal excretion of [¹⁴C]-clodinafop-propargyl in male rats; 93% of the dose was excreted in urine in 7 days compared with about 66% without pre-treatment. Residues in tissues at 7 days after dosing were correspondingly lower after pre-treatment. There was no effect in females. Co-administration of cloquintocet-mexyl had no effect on the metabolism, excretion or tissue residues of [¹⁴C]-clodinafop-propargyl in either sex.

Goats

Lactating goats were given 10 daily oral doses of [¹⁴C]-Cloquintocet-mexyl equivalent to 5 ppm in feed. Milk and excreta were collected daily and selected tissues were retained at necropsy 24 hours after the final dose. Radioactivity was recovered in urine (62.04% of dose), faeces (20.81% of dose), milk (0.097% of dose) and tissues (0.075% of dose). 

Concentrations of radioactivity in milk reached a plateau (<0.002 ppm) by 48 hours after the first dose with no accumulation throughout the remainder of the study. Maximum concentrations of radioactivity in plasma (0.127 ppm) occurred at 12 hours after the first dose and fell to <0.019 ppm within the next 12 hours indicating rapid clearance of radioactivity from plasma. There was no accumulation of radioactivity in plasma throughout the 10 day dosing period. The highest concentrations of radioactivity detected in tissues were in kidney (0.024 ppm) and liver (0.010 ppm); all remaining tissues contained <0.004 ppm (Powles, 1990).

Urine contained one major metabolite (see attached metabolic pathway) identified as CGA153433 (66%); the remainder of the radioactivity was separated into 5 unidentified radioactive fractions. Radioactivity extractable from tissues ranged from 50% in liver to 74% in kidney. The major metabolite present in kidney and milk was also identified as CGA153433; residues in muscle and liver were too low for metabolite identification (Muller, 1992).

In a second study (Close et al., 2003), lactating goats were given a higher oral dose of [¹⁴C]-Cloquintocet-mexyl equivalent to 127 ppm in feed for 4 days; excreta, milk and tissue samples were analysed for radioactivity. Radioactivity was recovered in urine (52.2%), faeces (12.3%), milk and tissues (<0.4%) and gastrointestinal tract (22.8%).

Concentrations of radioactivity in milk (0.120-0.576 ppm) were greatest 6 hours after the final dose. Tissue concentrations were muscle, 0.009-0.024 ppm; fat, 0.013-0.060 ppm; liver, 0.104-0.323 ppm and kidney, 2.276-3.537 ppm.

Greater than 72% of the radioactivity in urine, faeces and bile was present as CGA153433 with <1.1% present as unchanged [¹⁴C]-Cloquintocet-mexyl. Additionally, two further metabolites were identified as the cyclic compound M2 (5.5%) and it’s glucuronic acid conjugate, M1 (12.2%). Compounds identified in milk and tissues were unchanged [¹⁴C]-Cloquintocet-mexyl (1.8-9.5%), CGA153433 (48.1-80.2%), MI (0.8-11.1%) and M2 (2.2-4.8%).

Hens

Laying hens were given 14 daily oral doses of [¹⁴C]-Cloquintocet-mexyl equivalent to 5 ppm in feed (Stewart, 1991). Eggs and excreta were collected daily; tissue samples were retained at necropsy 12 hours after the final dose. A mean of 88.4% of the administered radioactivity was recovered in excreta; <0.011% of the dose was transferred to eggs.

Low concentrations of radioactivity were detected in kidney (0.0176 µg equivalents/g) and liver (0.0065 µg equivalents/g); all other tissues contained <0.0041 µg equivalents/g. Concentrations of radioactivity in eggs were either low or less than the limit of detection (0.004 µg equivalents/g); the highest concentration detected was 0.004 µg equivalents/g in yolk.

Excreta, liver, kidney and egg white contained one major metabolite identified as CGA153433 (Muller, 1992).

In a second study in laying hens (Close et al., 2003), 12.5 mg [¹⁴C]-Cloquintocet-mexyl (7.4 mg/kg bodyweight equivalent to 95 ppm in feed) was given orally for 8 days. Radioactivity was detected in excreta (66%), liver (0.04%), muscle (0.02%), fat (0.02%); egg yolk and white contained <0.01% each. Detectable concentrations of radioactivity were found in muscle (0.010 ppm), fat (0.070 ppm), liver (0.146 ppm), egg white (0.024-0.042 ppm; highest on day 1) and egg yolk (0.002-0.018 ppm; highest on days 7-8).

No unchanged [¹⁴C]-Cloquintocet-mexyl was detected; CGA153433 accounted for the majority of the radioactivity in muscle (50.5%), liver (64.9%), fat (73.3%), egg white (78.0%) and egg yolk (50.5%). Additionally, hydroxyl-CGA153433 was identified in liver accounting for 10.2% of the radioactivity present.

Discussion on absorption rate:

In an in-vitro percutaneous absorption study (Mueller, 1996), a simulated Daratech WP formulation containing [¹⁴C]-cloquitocet-mexyl and [¹⁴C]-clodinafop-propargyl was applied to rat and human epidermis (0.64 cm²). Doses of 0.01, 0.1 and 1 mg/cm² [¹⁴C]-cloquitocet-mexyl were applied; exposure was for 8 hours. For rat epidermis, 68, 32 and 2% of the dose was absorbed at 0.01, 0.1 and 1 mg/cm², respectively; the corresponding absorption values for human epidermis were 6, 5 and 0.1% of the dose. Cloquintocet-mexyl remained unchanged while exposed to and after penetrating rat and human epidermis.

The dermal absorption of a 25 g/L formulation containing [¹⁴C]-cloquitocet-mexyl was determined in-vitro using human epidermis (Hadfield, 2003). The formulation was applied either neat (25 g/l; 4 µL/cm²) or as a 1:167 v/v spray dilution (0.15 g/L; 6 µL/cm²); exposure was for up to 24 hours. Absorption values for the neat formulation were 0.83, 1.33, 1.93 and 7.15% after 6, 8, 10 and 24 hours, respectively; the corresponding absorption values for the spray dilution were 3.74, 5.46, 7.58 and 18.8%, respectively.