These are what we call the 'YMMV items.' Things that some people find in this work. We call them 'your mileage might vary' because not everyone sees these things in the same way. This starts discussions in the trope lists, a thing we don't want. Please use the discussion page if you'd like to discuss any of these items.
Designated Villain: Tuddrussell in "Planet of the Flies" is treated as irresponsible because he swatted a fly in the past, which leads to flies taking over the world. How was he supposed to know that would happen? Later, he is chided by Larry for interfering when he kills a giant fly attacking a medieval town, even though they were there to kill the fly!
Dude, Not Funny!: Child endangerment and neglect is treated in a jarringly cavalier manner throughout the series (even more jarringly cavalier than in such "adult" cartoons as Family Guy or The Simpsons): "Hate and Let Hate" is the most flagrant instance, with "Orphan Substitute" coming in a close second, and "Father Figure of Our Country" third, but Otto is involved in hazardous and/or life-threatening situations in several other episodes besides those.
One hopes that the scriptwriters didn't do their research before writing "Out with the In Crowd," considering that Sir Henry Morton Stanley was commissioned by King Leopold the Second.
Some of the abuse Larry takes (particularly Tuddrussel verbally berating him for his effeminate interests and mannerisms) could be seen as homophobic — if one were to read into it as deeply as they do the Belligerent Sexual Tension between Larry and Tuddrussel.
It's no wonder too that Tuddrussel had those words written. There's some serious Freudan imagery going on there. That circle that Tuddrussel drew by the side of Larry's face is meant to be a testicle, essentially rendering Larry's head to resemble an erect penis. (Even more so)
Genius Bonus: In "Love at First Flight", Otto asks Larry and Tuddrussel, "In what year was the Magna Carta written?" Larry answers randomly yet confidently: "1895" (the correct answer for the Magna Carta is 1215). "Why would Larry pick that year?" you might ask. 1895 is the year that English writer, Oscar Wilde, was convicted and put on three trials for homosexuality that spring.
In "Ivan The Untrainable," Otto asks Larry if he would like to play with his American Founding Fathers action figures with him. He then says that he could be Francis Lightfoot Lee, who is depicted as a toy in a powdered wig, with makeup, and with rather feminine looking hand gestures. Francis Lightfoot Lee was a signer of the Declaration of Independence, and reportedly a closeted homosexual.
Periphery Demographic: There's a fine line between having jokes for both kids and adults and playing out like something that would air in the early days of Cartoon Network's Adult Swim line-up. This show teeters on it like a pinwheeling tight-rope walker (though you do have episodes like "Day of the Larrys" and "Ex Marks the Spot" where it seems like the tight-rope walker slipped and is clinging for dear life by his fingers).
Ship Tease: If the show became a bit more recognized after it's been canceled (or even in its second and final season), that's mainly due to the many Ho Yay hints between Larry and Tuddrussel (especially in such episodes as "Ex Marks the Spot" and "Hate and Let Hate"). The two are described at times as a couple within the series itself, making this one of the few kids' shows that acknowledged the homosexual vibe it exuded (and the only one where no one would be shocked or offended by the slash fanfiction, as the actual show put out more blatant homosexual innuendo than any amateur writer-cum-cartoon fan can and ever will).
Significant Reference Date: The first episode, "Eli Whitney's Flesh Eating Mistake" aired on June 8th, 2001, which deals with Larry and Tuddrussel taking Otto from the 21st century to help them. A year later, on June 7th, 2002 the season 2 episode "Love At First Flight" airs. The significance? The episode deals with Otto's birthday, and when you stop to look at it the shows one year anniversary.