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Effects on fertility

Additional information

In several subchronic and subacute studies no apparent adverse effects on reproductive organs were observed in rats (Conaway et al., 1984; Sander & Bürkle, 1969; Shea, 1939). Inhalation exposure of rats to 900 mg/m³ for 13 weeks resulted in inflammation in mouth and nose; after 7 weeks, focal metaplasia and necroses in nose muscles of 8/40 animals were seen; these findings were intensified after 13 weeks and lesions of chronic murine pneumonia were registered. Organs and tissues examined at necropsy included brain, adrenals, lungs, heart, liver, spleen, kidneys, testes, ovaries, and nasal cavity (Conaway et al. 1984).

In a subchronic trial on rats damage to liver, kidneys and stomach mucosa first appeared after intake of approx. 160 mg/kg bw (Shea, 1939). Observations of rats treated with 800 mg/kg bw included lethargy, weight loss, intense irritation of the intestinal tract, and congestion of the stomach wall and membrane. Microscopic changes in the liver included cloudy swelling, marked congestion, haemorrhage, necrosis, and an increase in Kupffer and connective tissue cells. The kidneys had tubular congestion, degeneration, swelling and necrosis; desquamation of the epithelium also was noted. The spleens of the 800 mg/kg bw group had congestion and showed an increase in splenocytes and hemosiderin deposits. Necrosis of the epithelium and capillary congestion were observed in the stomach. The lungs had congestion and alveolar desquamation. Intake of 800 mg/kg bw caused the death of 10 out of 20 rats within 20 days. At the end of 30 days, only 1 rat was still alive.

Sander & Bürkle (1969) added Morpholine to feed for eight weeks. Seven rats took in a daily average of 500 mg/kg bw. This dosage did not kill the animals. After 270 days had elapsed, the only symptom noted was moderate adiposis of the liver. Damage caused by subchronic oral intake of Morpholine depended markedly on the individual dose and route of administration.

Due to its corrosivity, Morpholine treatment resulted in irritation and inflammation of the upper digestive tract on oral intake, irritation of the respiratory tract and eyes on being inhaled and, in high concentrations, irritation on contact with the skin. Possible target organs of chronic intoxication were the liver, kidneys and stomach.

Because of a high correlation, histopathology data and organ weights from repeated dose studies were used to assess male fertility (Mangelsdorf, 2003). These parameters, taken from 90 day studies, were in fact shown to be more sensitive than fertility parameters that were measured during multi-generation studies. It could also be shown that exposure for 4 weeks suffices for an assessment of male fertility, although 90 day studies have been regarded as superior in the past because they cover a complete cycle of spermatogenesis (Mangelsdorf, 2003). If such a 28 day study shows neither relevantly elevated testis or ovary weights nor histopathological alterations in those organs, the weight of the evidence is that effects on reproduction are also not expected (BAuA, 2003). A comparison of more than one hundred 90 day studies with two-generation studies that used the same test substance additionally showed that the NOAELs differed by less than the variation limit of studies, i.e. a factor of two (Janer, 2007).

Based on the argumentation of Mangelsdorf (2003), the information gained from a two-generation study can be regarded as minimal if a 90 day study has been performed. Thus, based on the data presented for Morpholine, information gained from a two-generation study are regarded as not necessary with regard to the fact that REACH allows the assessment of the reproductive toxicity of a given chemical with the help of findings from studies with repeated administration. This is in line with the idea that the information requirements under REACH are regarded as the evaluation of endpoints which does not necessarily require data from specific studies.

Short description of key information:
Since REACH allows the assessment of the reproductive toxicity of a given chemical with the help of findings from studies with repeated administration, studies available for Morpholine were incorporated to elucidate effects on fertility. No apparent adverse effects on reproductive organs were observed in rats in several subchronic and subacute studies with Morpholine.

Effects on developmental toxicity

Description of key information
In a developmental toxicity study with Morpholine hydrochloride (97 % ) at doses of 75, 250 and 750 mg/kg bw/d applied orally to rats, no adverse fetal findings of toxicological relevance were evident. The developmental NOAEL was determined as 750 mg/kg bw/day, whereas the maternal NOAEL was 75 mg/kg body weight/day based on statistically significant haematological changes in the dams at 250 and 750 mg/kg bw/day.
Effect on developmental toxicity: via oral route
Dose descriptor:
750 mg/kg bw/day
Additional information

Listed as read across study, Morpholine hydrochloride (97% a.i.) was administered as an aqueous solution to 25 time-mated female Wistar rats (Crl:WI[Han]) by gavage at doses of 75, 250 or 750 mg/kg bw/day on gestation days 6 through 19 in a developmental toxicity study. The control group, consisting of 25 females, was dosed with the vehicle (drinking water) in parallel. A standard dose volume of 10 mL/kg bw was used for each test group. At terminal sacrifice on GD 20, all females (25 per group) had implantation sites. The oral administration of 250 and 750 mg/kg bw/d caused a mild, regenerative anaemia in the dams, along with increased liver weights. Additionally, transiently reduced mean food consumption and bw gain as well as affection of liver cells and liver cell metabolism were noted at high dose. The oral administration of Morpholine hydrochloride to the dams up to 750 mg/kg bw/d had no influence on gestational parameters. Conception rate, mean number of corpora lutea, total implantations, resorptions and live foetuses, foetal sex ratio, and the values calculated for pre- and postimplantation losses were all unaffected. The maternal NOAEL was 75 mg/kg bw/day based on statistically significant haematological changes in the dams at 250 and 750 mg/kg bw/day. Foetal examinations revealed no influence of Morpholine hydrochloride on sex distribution of the foetuses and foetal body weights. Morpholine hydrochloride showed no direct and specific effect on the respective morphological structures. Foetal findings in this study were primarily limited to a slight increase in delayed ossification in the mid- and high-dose groups. These specific skeletal variations mirrored common minor effects on foetal morphology which are considered to be transient in nature, being obviously secondary to maternal toxicity. Thus, these findings were regarded to be of no toxicological relevance and were not classified as adverse events. The developmental NOAEL was 750 mg/kg bw/day. No adverse foetal findings of toxicological relevance were evident at any dose.The developmental toxicity study is classified as acceptable and satisfies the guideline requirement for a developmental toxicity study (OECD 414) in rat.

Justification for classification or non-classification

Classification, Labeling, and Packaging Regulation (EC) No 1272/2008

Since morpholine hydrochloride caused no developmental toxicity and teratogenicity in the rat in a developmental toxicity study according to OECD TG 414 and no apparent adverse effects on reproductive organs or fertility were observed in rats in several subchronic and subacute studies with morpholine, morpholine is considered not to cause damage to the unborn child and is not subject to classification according to Directive 67/548/EEC and Regulation 1272/2008/EC.