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Effects on fertility

Effect on fertility: via oral route
Dose descriptor:
30 mg/kg bw/day
Additional information

A 2-generation oral feeding study was performed according to OECD Guideline 416 (Two-Generation Reproduction Toxicity Study) in Wistar rats with 2,4-dichlorophenoxyacetic acid (RA-S, CAS 94-75-7, Key, Kita, 1997, two generation reprotox, rat, RL2).

The assessment of systemic effects of salts of 2,4-D is based on data generated with 2,4-D acid. This read across is justified because 2,4-D acid and its salts are toxicologically equivalent once they have entered the system. This is due to the only diffusion-limited rate of reaching the acid-base equilibrium between the protonated acid and its deprotonated salt form in an aqueous environment like the human body. Thus, salts of 2,4-D will exert the same systemic effects as the corresponding acid.

Doses of 200, 600 and 1800 ppm (approx. 10, 30, and 90 mg/kg bw/day based on mean body weight and food consumption) were given to groups of 16 male and 31 female rats. Females of the parental generation were exposed for 70 days prior to mating, during mating, during gestation and during the time of lactation. The F1 generation had free access to the feed and was therefore directly exposed after weaning and treated analogously until the end of the experiment (28-day weaning period). F1 parental animals not mated until 10 weeks after selected from the F1 litters.

Mating behavior, conception, clinical signs, mortality, body weight, food consumption, gross pathology, histopathology, number of matings, fertility index, duration of pregnancynumber of pubs, live birth index, litter size, pup weight, sex ratio, survival index, viability index were determined for all dose groups and both generations. The ovaries, uterus, cervix, vagina, testes, seminal vesicles, prostate, coagulating gland and pituitary gland were examined histopatologically.

No significant or substance related changes were noted for the clinical signs or mortality. Significant changes were observed in the highest dose group with reduced body weight and body weight gain in the parental generation (female) and the offspring (both sexes). At the end of the weaning the mean body weight was reduced by 37% and 39% for the F1 and F2 generation, respectively. A higher food consumption of the females in the exposed groups was observed compared to the control. This was statistically significant in F1-females in the low dose-group, partly in the medium dose-group and also in the high dose-group (but only in the last week). All females were successfully mated. No differences were observed in the general reproductive behaviour, pregnancy, amount of dead pups and the success of breeding. Gross pathology and histopathology of the parental generation did not show treatment related changes.

There was an increase incidence of convulsion and dejection noticed in the offspring in the high dose-group. The mortality of pups was higher in the high dose-group in both generations, beginning from the 8th day of life. The general mortality in the generation F1 was 5.4%, 8.4%, 5.4%, and 26% respectively in treatment groups with increasing doses, respectively. In the F2 generation, the mortality was 2.6%, 1.6%, 7.5% and 43.5%. The 14-days survival index, the general survival index and the lactation index of the 1800 ppm-group of the F2-generation were significantly smaller than in the control.

Mating behavior and fertility were unaffected in both sexes and no increased incidence of teratogenicity was observed. Adverse effects on the infants (reduced body weight, clinical signs, mortality) were observed only at concentrations with signs of maternal toxicity and therefore they are likely to be secondary consequences. The overall NOAEL for the parental generation as well as for the offspring was 600 ppm (approx. 30 mg/kg bw/d) which s in good correlation to the results of the developmental toxicity and subchronic repeated dose studies.

Short description of key information:
Toxicity to reproduction
RA-S, CAS 94-75-7, Key, Kita, 1997, two generation reprotox, rat, RL2 - A NOAEL of 30 mg/kg bw/d was identified in rats based on parental body weight gain and mortality, survival index and lactation index of the offspring generation (F1 and F2)

Effects on developmental toxicity

Description of key information
RA-S, CAS 2008-39-1, Key, Charles, 2001, Developmental Tox, rabbit, RL2 – the NOAEL (maternal) is 36.1 mg/kg bw/day; the NOAEL (developmental) is 108.44 mg/kg bw/day 
RA-S, CAS 2008-39-1, Charles, 2001, Developmental Tox, rat, RL2 – the NOAEL (maternal) is 15 mg/kg bw/day; the NOAEL (developmental) is 60.2 mg/kg bw/day
Effect on developmental toxicity: via oral route
Dose descriptor:
108.44 mg/kg bw/day
Additional information

A developmental toxicity study was conducted with dimethylammonium 2,4-dichlorophenoxyacetate (CAS 2008-39-1), a structural analogue substance ofsodium 2,4-dichlorophenoxyacetate (CAS No. 2702-72-9) and used for read across. The study was performedaccording to the EPA-Pesticide Assessment Guidelines, Subdivision F, Hazard Evaluation, Human and Domestic Animals, Series 81, 82, and 83, 1991 (RA-S, CAS 2008-39-1, Key, Charles, 2001, Developmental Tox, rabbit, RL2). Doses of 12, 36.1 and 108.4 mg/kg bw/day (based on active ingredient) were applied once daily via gavage to 20White rabbits throughout gestation days 6-18. Animals were observed for any signs of toxicity and changes in body weight. The ovaries and uterine content was examined after termination (uterus weight, number of corpora lutea, number of implantations, and number of resorptions) and live and dead fetuses were counted. Uteri with no visible implantations were stained with a 10% solution of ammonium sulphide, and examined for evidence of early resorptions. Fetuses were observed for external malformations/variations, skeletal abnormalities, of visceral alterations, body weight and sex.

Maternal toxicity was observed in a dose-related manor (clinical signs, body weight gain (in comparison to the other controls of experiments conducted in parallel) at or above a dose of 36.1 mg/kg bw/day (30 mg/kg bw/day acid equivalent). There were no effects on maternal reproductive parameters observed. The NOAEL (maternal) was determined to be 36.1 mg/kg bw/day

No evidence of teratogenicity was observed in the fetuses and fetal body weights were normal. Low incidences of individual malformations were consistent with historical control data. The NOAEL (developmental) was determined to be 108.44 mg/kg bw/day.


Another study, also conducted withdimethylammonium 2,4-dichlorophenoxyacetate (CAS No. 2008-39-1) and used for read across,was conducted analogously(according to the EPA-Pesticide Assessment Guidelines, Subdivision F, Hazard Evaluation, Human and Domestic Animals, Series 81, 82, and 83, 1991) with 25 Crj: CD(SD) rats (RA-S, CAS 2008-39-1, Charles, 2001, Developmental Tox, rat, RL2). The animals were exposed to 15, 60.2, 120.4 mg/kg bw/day of the test substance (resembles 12.5, 50, 100 mg/kg bw/day acid equivalent) during gestation days 6 to 15 via gavage. Comprehensive examinations were performed including detailed clinical observations, body weight, food consumption and compound intake as well as post mortem examinations (ovaries and uterine content, uterus weight, number of corpora lutea, number of implantations, number of resorptions, live and dead fetus count). Fetuses were subjected to external, skeletal and head examination.Each fetus was individually identified, weighed, sexed, and given a gross examination for external malformations/variations to include observation for palatal defects.

Maternal body weight effects in rats began to be manifested at a dose level of 50 mg/kg bw/day acid equivalent (60.2 mg/kg bw/day). With increasing dose, feed consumption and maternal body weights were more severely affected. At the highest dose, clinical signs of toxicity (ataxia, muscular stiffness, and decreased motor activity) were observed. The NOAEL (maternal) was determined to be 15 mg/kg bw/day

The effects noted in the developing rat fetus were confined to the highest dose level tested which also exhibited a distinct maternal toxicity. Significantly decreased fetal-body weight and a treatment-related increase in fetal variations (reduced ossification of the skull, incomplete or delayed ossification of the sternebrae, delayed ossification of the metatarsals and metacarpals and the presence of extra ribs, either cervical or lumbar) were observed. The NOAEL (developmental) was determined to be 60.2 mg/kg bw/day


Effects observed throughout the two studies summarized above occurred in a dose dependent manner. The effects observed were of minor severity and occurred only at or above dose levels with signs of maternal toxicity in both species, rat and rabbit. The types of effects have been reported to be frequently associated with maternal toxicity. Thus they are likely to be secondary effects due to the maternal toxicity elicited in these animals, rather than a direct effect of the compound.

The NOAEL ot the non-rodent species was used as key value for chemical safety assessment. With respect to the assumption that equitoxic doses scale with body weight to the power of 0.75 and using the allometric scaling factors for different species as compared to humans, both dose levels are in the same range.

Justification for classification or non-classification

According to DSD (67/548/EEC) and CLP (1272/2008/EC) criteria for classification and labelling of dangerous substancessodium 2,4-dichlorophenoxyacetate (CAS No. 2702-72-9) is not classified as toxic to reproduction or development